R167W.
The aim of this study was to establish the characteristics of pheochromocytoma in a population of 58 patients between 4 and 20 years of age studied at Hospital de Niños Ricardo Gutiérrez. They represented a 23% of the total population of 255 pheochromocytoma patients studied. Two children belonging to the same family had VHL type 2A and presented with the missense mutation Arg167Trp. The children both had pheochromocytomas.
The ELST shown in Figure 1 occurred in the left temporal bone of an 8-year-old boy who presented with profound sensorineural hearing loss, intermittent vertigo, and vHL based on mutation analysis that showed a G-to-C nucleotide 601 mutation in the vHL gene on chromosome 3. High-resolution computed tomographic imaging using a bone-window protocol demonstrates a destructive mass involving the posterior aspect of the left petrous temporal bone centered midway between the internal auditory canal and the sigmoid sinus. Bony erosion extends into the posterior semicircular canal, and there are areas of stippling and central calcification within the mass suggestive of an aggressive, erosive process. Magnetic resonance images of ELSTs may demonstrate enhancement on precontrast T1-weighted images and heterogeneous enhancement on T2-weighted images. Larger lesions may show flow voids. Although the diagnosis in this case was relatively straightforward on the basis of the combination of genetic screening studies and characteristic imaging features on computed tomographic scanning, a differential diagnosis of similar lesions should include meningioma, choroid plexus papilloma, paraganglioma, chondrosarcoma, and metastasis.
This paper shows the imaging result of an endolymphatic sac tumor found in the left temporal bone of an 8-year-old boy who presented with profound sensorineural hearing gloss, intermittent vertigo. VHL mutation analysis showed c.388G>C mutation (noted as G-to-C nucleotide 601 mutation in the paper).
c.269A > T p.Asn90Ile
216 patients with clinically expected VHL disease due to family history or presence of VHL typical tumours were routinely examined in an eye centre in Germany between January 2019 and January 2020, majority of which were of European descent (~95%). Since data on the genotype–phenotype correlation of the onset of Retinal Hemangioblastoma (RH) is scarce in relation to VHL disease, this study wanted to inversitage the relationship between VHL gene variants (truncating vs single amino acid substitutions) and the ocular phenotype of the disease. 42 different rare VHL gene variants in 148 patients were detected - some of whom had RH and some who did not. Although date of onset of RH, as well as data on central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renalcell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected, it was not reported on a per patient basis and therefore could not be discussed per variant. There was 1 patient reported with the c.269A>T (p.N90I) mutation. This member presented with retinal hemangiomas. No family information was provided.
Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.
Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (S111R (c.333C>G)) was taken from the National Cancer Institute database, with an unknown number of members belonging to Family ID 4401NCI. It was reported in the paper as c.546C>G due to a difference in transcript reference. As reported in Table 3, this mutation is found in VHL families without pheochromocytoma, and with renal cell carcinoma.
Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.
GroupID/ KindredID: 45CE
DiseaseAssertion: VHL
GroupSize: N/A
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: This germline familial VHL mutation was taken from the Munich, university of Freiburg and Institute of Pathology database, with an unknown number of members belonging to Family ID 45CE. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without pheochromocytoma.
GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)
GroupHPOFreeText: Described as a VHL family with RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication
GroupNotHPOs: HP:0002666 (pheochromocytoma)
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: (c.463+1G>C)
LegacyVariant: Splice (c.676+1G>C)
CaseProblemVariantFreeText: N/A
ClinVarID: 223217 https://www.ncbi.nlm.nih.gov/clinvar/variation/223217
CAID: N/A
gnomAD: N/A
VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.
MutationType: splice_site_variant
CivicName: Splice Site (c.463+1G>C)
MultipleGeneVariants: N/A
Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.
Germline mutational data on VHL was gathered from various countries to assess variation in germline mutations that produce disease within different populations. Families were grouped according to three possible outcomes of disease: renal cell carcinoma without pheochromocytoma, renal cell carcinoma with pheochromocytoma, or pheochromocytoma alone. SSCP and denaturing gradient gel electrophoresis identified mutations in 300/469 (63%) of families affected with VHL. This germline familial VHL mutation (F136C (c.407T>G)) was taken from the Bristol Myers Squibb database, with an unknown number of members belonging to Family ID 10BMS. It was reported in the paper as c.620T>G due to a difference in transcript reference. As reported in Table 4, this mutation is found in VHL families with pheochromocytoma. Other phenotypes are likely, including renal cell carcinoma, however not detailed here.
Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.
GroupID/ KindredID: 28BMS
DiseaseAssertion: VHL
GroupSize: N/A
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: This germline familial VHL mutation was taken from the Bristol Myers Squibb database, with an unknown number of members belonging to family ID: Family 28BMS. Table 5 lists all ID and mutations associated with individuals without detailed clinical information.
GroupPresentingHPOs: N/A
GroupHPOFreeText: Described as multiple VHL families without detailed clinical information. Other phenotypes are possible, however not detailed here.
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: (c.464-2A>G)
LegacyVariant: Splice (c.677-2A>G)
CaseProblemVariantFreeText: N/A
ClinVarID: 223222 https://www.ncbi.nlm.nih.gov/clinvar/variation/223222/
CAID: N/A
gnomAD: N/A
VariantEvidence: This paper declares this variant is predicted to compromise the Elongin-binding site by truncating the protein.
MutationType: splice_site_variant
CivicName: Splice Site (c.464-2A>G)
MultipleGeneVariants: N/A
345C→G Tv Exon 2 115 CAC H H115Q
A study of 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations extracted from the French VHL database revealed that the number of hemangioblastomas appeared higher in patients who had a substitution when compared with patients with a truncated protein. Detected by PCR and SSCP, this missense mutation (p.H115Q (c.345C>G)) was found in a VHL patient without retinal hemangioblastomas. Other manifestations are not clearly stated. No family information was provided. This is possibly previously published in PMID: 15300849
GroupID: 78
DiseaseAssertion: VHL
GroupSize: N/A
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: VHL family found to have a germline rearrangement of the VHL gene. The number of family members included in this study is not specified.
GroupPresentingHPOs: N/A
GroupHPOFreeText: Patients within this family were found to have a clinical diagnosis of VHL disease, however, the presenting phenotypes were not specified.
GroupNotHPOs: HP:0002666 (Pheochromocytoma)
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.E186* (c.556G>T)
LegacyVariant: c.769G>T
CaseProblemVariantFreeText: N/A
ClinVarID: 381602, https://www.ncbi.nlm.nih.gov/clinvar/variation/381602/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: E186* (c.556G>T)
MultipleGeneVariants: N/A
VHL: c.374A>C, p.His125Pro
A cohort of 64 pheochromocytoma and paragangliomas were screened for a BRAF mutation using direct Sanger sequencing and QRT-PCR. Genomic DNA was extracted from fresh or frozen peripheral blood. Germline mutations of VHL, SDHB, SDHD, and RET genes were also observed. The VHL mutation c.374A>C (p.His125Pro) was reported in patient #42, a 24Y male with bilateral pheochromocytoma. No family history was reported here.
PMID: 21461997
4 paediatric patients presenting with pheochromocytomas and paragangliomas were reported. Upon genetic testing of peripheral blood leukocytes on the VHL, SDHB, SDHC, SDHC, and RET genes, 1 patient was found to have the c.374A>C germline mutation. At 13Y the patient had bilateral adrenal pheochromocytoma and retinal capillary hemangiomas. Now, 19Y, he remains in complete remission. Family screening showed the absence of the mutation in the asymptomatic mother; the father was not analyzed. Other family history was negative for VHL syndrome and PCCs.
PatientID: 6
KindredID: III
Case: Sex Unknown, Age Unknown, Chinese
DiseaseAssertion: VHL
FamilyInfo: Patient had three other family members with additional CNS hemangioblastomas and the same splice site mutation. Their one family member, patient 4, also presented with pancreatic tumors.
CasePresentingHPOs: HP:0010797 (hemangioblastoma)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: c.340+5G>C
LegacyVariant: c.553+5G>C
CaseProblemVariantFreeText: N/A
ClinVarID: 36901, https://www.ncbi.nlm.nih.gov/clinvar/variation/36901/
CAID: N/A
gnomAD: 0.01119 https://gnomad.broadinstitute.org/variant/3-10183876-G-C
VariantEvidence: This variant’s large allele frequency means this is likely non disease causing (not deleterious). Mutation was predicted to compromise the elongin-binding region. Refer to table 3 for LOH information on VHL and ZAC1.
MutationType: splice_site_variant
CivicName: Splice Region (c.340+5G>C)
MultipleGeneVariants: N/A
Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. The V166F (c.496G>T) germline missense mutation was found in a VHL type 2A (with pheochromocytoma) patient (patient no. V49). This variant was not found in 8 unaffected family members and previously reported in patients with VHL. This patient was stated to be previously published in PMID 15300849.
Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. Blood samples were isolated and sequenced by direct sequencing using prism-ready reaction dye primer cycle sequencing kits (Applied Biosystem Roissy CDG France) and an ABI 373A automated sequencer (AppliedBiosystem Roissy CDG France).No variants were found in 96 control cases. This stop gain mutation, c.481C>T, was found in 2 unrelated VHL type 1 patients (patient V3, V46). No patient information was provided and no additional family members were screened. Patient V3 was previously published in 8956040.
Screening of 92 unrelated patients with VHL disease revealed 61 DNA variants. No variants were found in 96 control cases. Direct sequencing on peripheral blood was systematically performed on exon 1 PCR products. Southern blotting was used to search for larger alterations to the gene. The F136S (c.407T>C) missense mutation was found in two unrelated VHL type 1 (no pheochromocytoma) patients (patient no. V53, V94). No unaffected individuals from either family were tested for this mutation.
nt 676 +1 G/C Splice defect 676 +1 G/C Splice defect 2
A cohort of 141 patients with hemangioblastomas of the central nervous system was analyzed. 81 patients had germline mutations in the VHL gene, analyzed through peripheral blood by Southern blotting and SSCP analysis. This splice site mutation (c.463+1G>C) was recorded in the paper as c.676+1G>C due to a difference in transcript sequence. It was found in 2 patients with hemangioblastomas of the central nervous system. Any family information or relations is unknown. No other phenotypes described.
nt 407 C/G 65 Ser→Trp S65W Missense 2
GroupID: 2
DiseaseAssertion: hemangioblastoma
GroupSize: 2
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: 2 out of the 81 patients listed in this hemangioblastoma cohort were found with this c.194C>G mutation. Any relation is unknown.
GroupPresentingHPOs: HP:0010797 (hemangioblastoma)
GroupHPOFreeText: all patients had hemangioblastoma of the CNS; other phenotypes are unknown
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.S65W (c.194C>G)
LegacyVariant: p.S65W (c.407C>G)
CaseProblemVariantFreeText: N/A
ClinVarID: 43597 https://www.ncbi.nlm.nih.gov/clinvar/variation/43597/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: S65W (c.194C>G)
MultipleGeneVariants: N/A
PMID: 7977367
KindredID: 9
DiseaseAssertion: VHL
GroupSize: Unknown
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: N/A
GroupAgeRange: N/A
GroupInfo: This is a family belonging to prefigure No. 9. They are described as ‘VHL-affected’.
GroupPresentingHPOs: HP:0005584 (renal cell carcinoma)
GroupHPOFreeText: RCC-affected; other manifestations are possible but not clear.
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
GroupPreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.Q145Hfs*28 (c.435_436delGC)
LegacyVariant: p.215fs (c.648_649delGC)
CaseProblemVariantFreeText: N/A
ClinVarID: 223210 https://www.ncbi.nlm.nih.gov/clinvar/variation/223210/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: minus_2_frameshift_variant
CivicName: Q145fs (c.435_436delGC)
MultipleGeneVariants: N/A
One hundred and sixteen unrelated VHL disease patients have been investigated by molecular genetic analysis. Twenty-two of these were previously shown to have germline deletions on Southern analysis, and in the present study the remaining 94 patients were screened for intragenic mutations via SSCP and heteroduplex analysis of 855 bp of the VHL coding sequence and 800 bp of the 3' UTR. An intragenic mutation was identified in 55 (59%) out of 94 patients without germline deletions on Southern analysis. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This study also investigated the frequency of different mutation classes between kindreds with and without pheochromocytoma. The c.337C>T (p.R113) stop-gain mutation (noted as c.550C>T (p.R184) in the paper due to a difference in reference transcript used) was found in at least one patient in 2 kindreds (families): kindred no. 30 and 136. Pheochromocytoma was not observed in any members of kindred no. 136 (implying the affected patient(s) had VHL disease type 1). No phenotypic information was reported for members of kindred no. 30. ACMG evidence codes: none.
One hundred and sixteen unrelated VHL disease patients have been investigated by molecular genetic analysis. Twenty-two of these were previously shown to have germline deletions on Southern analysis, and in the present study the remaining 94 patients were screened for intragenic mutations via SSCP and heteroduplex analysis of 855 bp of the VHL coding sequence and 800 bp of the 3' UTR. An intragenic mutation was identified in 55 (59%) out of 94 patients without germline deletions on Southern analysis. In all patients with multiple affected family members the missense mutation segregated with the disease. Large deletions or intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without pheochromocytoma (VHL type 1) and 2 of 12 families with pheochromocytoma (VHL type 2). This study also investigated the frequency of different mutation classes between kindreds with and without pheochromocytoma. The p.Y98H (c.292T>C) variant (noted asp.Y169H (c.505T>C) in the paper due to a difference in reference transcript used) was found in at least one patient in kindred 22. No familial phenotypic information could be inferred from the paper.
Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients using PCR and SSCP by peripheral blood leukocytes. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This missense variant (p.R167Q) was found in 4 patients (F8, F18, F56 and F71) all with retinal capillary hemangioma. Patient F8 was 35 years old at onset and noted of familial antecedents of phaeochromocytoma. Patient F18 was 33 years old at onset, had cerebellar hemangioblastoma, pancreatic cysts. Noted of familial antecedents of phaeochromocytoma and a total of 2 affected family members. Patient F56 was 45 years old at onset, had cerebellar hemangioblastoma and renal cyst. Also noted of familial antecedents of phaeochromocytoma and a total of 2 affected family members. Patient F71 was 25 years old at onset, had cerebellar hemangioblastoma, and unilateral pheochromocytoma. Noted a total of 2 affected family members, with the family member reported with clear cell renal cell carcinoma
Thirty-five unrelated patients suspected of having von Hippel-Lindau disease were analyzed and 32 VHL gene variants were found in 35 patients using PCR and SSCP by peripheral blood leukocytes. An association of clear cell renal carcinoma development with a relatively high loss of structural stability in VHL protein missense mutations was discovered. This missense mutation (p.C162Y) was found in a patient, whose age of onset was 15 years old, with retinal hemangioblastomas, unilateral pheochromocytoma, and renal cysts (patient no. F61). Patient has family history of clear cell renal carcinoma.
Case reportThe female patient, aged 49, reported pains in her second and third finger of the right hand that she had had for 2 years. Initial diagnosis revealed isthmus carpalis and the patient was operated on without much success—no improvement was noticed.A year later, intensifying root pains of Root C5 and C6 on the right side were the reason for performing an MRI scan of the cervical spine. The findings from the study showed an intramedullary lesion of 1.5 cm in diameter, localized at the height of C5–C6 with accompanying syrinx stretching from C3 to C7. The patient was consulted neurosurgically several times, but refused to submit to a surgical treatment. Gradually, the pains extended to the entire forearm of the upper right limb, and numbness appeared of both lower limbs. She met the clinical diagnostic criteria for VHL disease [11]. Sequencing of the VHL gene revealed the presence of the 393C>A (N131K) missense mutation (Fig. 1) [12]. VHL disease was also diagnosed in her relatives (shown in Fig. 2).
PatientID: III:2 (case)
KindredID: 1
Case: F, 49Y0M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: VHL disease was diagnosed in her relatives - although no genetic testing was directly performed on them prior to death. 2/3 of her siblings and her father were affected. Her father had retinal hemangioblastoma at 30Y, CNS hemangioblastoma at 40Y and died at 41Y. Her older brother had kidney cancer and died at 48Y, and her sister had retinal hemangioblastoma at 13Y and CNS hemangioblastoma at 29Y. The case’s daughter tested negative and their other living sister.
CasePresentingHPOs: HP:0009711; HP:0000107; HP:0009713; HP:0002668 (retinal capillary hemangioblastoma; renal cysts; spine hemangioblastoma; paraganglioma)
CaseHPOFreeText: patient at retinal hemangioblastoma at 22Y. At 47Y she reported pains in her second and third finger of the right hand. She developed large carotid body paraganglioma at the common carotid artery bifurcation, (49Y) coexisting with a hemangioblastoma situated intramedullary in region C5/C6 (the right-sided dorsal part of the spinal cord) at 47Y). 1 year after the hemangioblastoma resection, the spinal symptoms receded and the carotid body paraganglioma still was asymptomatic. Motor issues and Babinski syndrome were also observed.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.N131K (c.393C>A)
LegacyVariant: N/A
CaseProblemVariantFreeText: N/A
ClinVarID: 420074 https://www.ncbi.nlm.nih.gov/clinvar/variation/420074/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: N131K (c.393C>A)
MultipleGeneVariants: N/A
c.362 A>Gap.D121G
53 patients with a molecularly confirmed VHL mutation (by PCR through EDTA-anticoagulated blood) and a pancreatic neuroendocrine tumor (ICT) were collected from the German NET-Registry and the German VHL-registry. An additional 296 patients were stated in this paper with a VHL associated germline mutation, but without pancreatic neuroendocrine tumors. 2 patients were found to have the above mutation (c.362A>G). 1 was a VHL patient with an ICT (pancreatic neuroendocrine tumor) taken from the VHL-registry. The other patient was stated to be in this study with the given mutation, however no ICT. Other clinical manifestations outside of a pancreatic neuroendocrine tumor are possible, but were not discussed. ACMG evidence codes: 'PP2' because they observe a missense variant in a gene where missense variants are a common mechanism of disease.
VHLE2c.414A>Gp.P138P
314 Chinese patients with Pheochromocytoma/paraganglioma (PPGL) from Peking Union Medical College Hospital, China, were included in this study for germline profiling. The majority of patients underwent surgery and were histopathologically diagnosed with PPGL. For patients who had an unresectable or metastatic tumor, PPGL diagnosis was determined based on clinical features (headache, palpitations, sweating, etc). Genomic DNA was extracted from peripheral blood of all 314 PPGL patients, and detect potential variants in 12 known genes associated with hereditary PPGL (SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, RET, NF1, MAX, TMEM127, and KIF1B) using next-generation and Sanger sequencing. Germline variants were detected in 29% of the 314 PPGL patients. Germline genetic testing revealed a synonymous P138P(c.414A>G) variant in exon 2 of the VHL gene, in 2 patients, 2 years after their diagnosis. Patient #86 is a male PPGL patient who first presented with bilateral pheochromocytoma at age 15 and was also diagnosed at age 15. They also have a family history of PPGL, which was not detailed further. Patient #87 is a male PPGL patient who first presented with pheochromocytoma at age 36 and was also diagnosed at age 36. Patient 87 does not have family history of PPGL.
21 missense mutations, 5 nonsense mutations
Among patients prospectively followed by the members of the French VHL Study Group, 35 consecutive patients with well-documented endocrine pancreatic tumour (20 women and 15 men; median age,37 [21Y-57] years) were included. The data from 7 patients with EPT have been partially reported previously in Hammel et al., 1995;2000. All 35 patients had VHL germline mutations and were assessed for the presence of pheochromocytoma and renal carcinoma in addition to pancreatic tumours. The presence of other phenotypes was not described. A missense mutation (c.334T>C) was found in 2 members of the same family. Patient No. 10 and patient no. 17 from family 360 both presented with pancreatic endocrine tumour. Their familial relation and other family members were not described therefore there may not be sufficient evidence for PP1. However, patients' phenotypes are highly specific to VHL disease (PP4) and disease-causing missense variants are common in VHL disease (PP2).
Molecular and clinical analysis of 126 French VHL families tested for renal involvement revealed 92 different mutations. 90 of these families had renal involvement. The p.C162Y (c.485G>A) germline variant of the VHL gene was detected in a family (ID 17). Member 753 presented with moderate renal disease (RCC), member 11338 had unknown renal involvement, member 696 presented with severe renal disease (RCC) and members 2368 and 699 presented with mild renal disease.
germline missense mutation at nucleotide 505 (T to C) of the VHL tumor suppressor gene in 14, apparently unrelated, VHL type 2A families from the Black Forest region of Germany.
GroupID/ KindredID: VHL 1
DiseaseAssertion: assumed VHL
GroupSize: 2
GroupNumberMales: N/A
GroupNumberFemales: N/A
GroupEthnicity: German
GroupAgeRange: N/A
FamilyInfo: 2 affected members belong to this VHL type 2A family. One representative affected member was analyzed with this mutation, and VHL was diagnosed clinically in this index person. It is unclear as to whether the second patient had this precise mutation, although assumed.
GroupPresentingHPOs: HP:0009711; HP:0002666 (retinal capillary hemangioma, pheochromocytoma)
GroupHPOFreeText: both individuals had Pheos, whereas only 1 person had a retinal capillary hemangioma.
GroupNotHPOs: HP:0010797; HP:0005584; HP:0001737; HP:0009715 (hemangioblastoma, renal cell carcinoma, pancreatic cysts, papillary cystadenoma of the epididymis)
GroupNotHPOFreeText: No patients had the above tumors
GroupPreviousTesting: N/A
PreviouslyPublished: 11134110, 9681856, 11850829
SupplementalData: N/A
Variant: p.Y98H (c.292T>C)
LegacyVariant: p.Y98H (c.505T>C)
CaseProblemVariantFreeText: N/A
ClinVar: 2223 https://www.ncbi.nlm.nih.gov/clinvar/variation/2223/
CAID: N/A
gnomAD: 0.00001343 https://gnomad.broadinstitute.org/variant/3-10183823-T-C
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: Y98H (c.292T>C)
MultipleGeneVariants: N/A
709 G-->T transversion present in all affected subjects and in four presymptomatic children.
PatientID: II:7
KindredID: 1
Case: M, Age Unknown, Jewish
DiseaseAssertion: VHL
FamilyInfo: This kindred of Jewish-Kurdish origin consisted of 3 generations of 25 members. 7 were clinically affected subjects with pheochromocytoma (5 of which had the confirmed mutation - I:1, II:2, II:4, II:7 and II:9, as the other 2, II:5 and II:10 were said to have passed due to complications of the disease - prior to any genetic testing), and 4 others were carriers, or pre-symptomatic (III:1, III:3, III:7 and III:12). Subject 11:7 developed a cerebellar hemangioblastoma 25 yr after his initial diagnosis of pheochromocytoma, leading to the clinical diagnosis of VHL in the kindred.
CasePresentingHPOs: HP:0002666; HP:0006880; HP:0030074 (pheochromocytoma, cerebellar hemangiolastoma, chemodectoma)
CaseHPOFreeText: patient had cerebellar HB at 25Y, after his initial diagnosis with bilateral pheochromocytoma, and then also extra-adrenal chromafin tumors (carotid body chemodectoma).
CaseNotHPOs: HP:0005584 (renal cell carcinoma)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: 33471715
SupplementalData: N/A
Variant: p.V166F (c.496G>T)
LegacyVariant: p.V166F (c.709G>T)
CaseProblemVariantFreeText: N/A
ClinVarID: 2224, https://www.ncbi.nlm.nih.gov/clinvar/variation/2224/
CAID: N/A
VariantEvidence: N/A
VariantEvidence: N/A
MutationType: missense_variant;transversion
CivicName: V166F (c.496G>T)
MultipleGeneVariants: N/A
2438Fnt 594, 595 GC to TT, Leu to PheP, 13775
PatientID: 24
KindredID: 3775
Case: F, 39Y3M, Ethnicity Unknown
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0030405 (pancreatic endocrine tumour)
CaseHPOFreeText: She presented with 1 radiographic pancreatic neuroendocrine tumor diagnosed at age 38Y. Follow up 15M after EN surgery, currently no evidence of disease.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.L128F (c.381_382delinsTT)
LegacyVariant: p.L>F (c.594_595GC>TT)
CaseProblemVariantFreeText: N/A
ClinVarID: 223203 https://www.ncbi.nlm.nih.gov/clinvar/variation/223203
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: delins
CivicName: L128F (c.381_382delinsTT)
MultipleGeneVariants: N/A
235 (CAG-TAG)1 (1)163HBr, HBc, HBsc, RCC, Cr
GroupID: None
Case: Sex Unknown, 63Y0M, Dutch
DiseaseAssertion: VHL
FamilyInfo: N/A
CasePresentingHPOs: HP:0009711, HP:0006880, HP:0009713, HP:0005584, HP:0000107 (Retinal capillary hemangioma, Cerebellar hemangioblastoma, Spinal hemangioblastoma, Renal cell carcinoma, Renal cyst)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: This cohort was published later in PMID 31087189
SupplementalData: N/A
Variant: p.R79C (c.235C>T)
LegacyVariant: c.235 (CAG-TAG)
CaseProblemVariantFreeText: written in the publication as c.235 (CAG-TAG), deduced to c.235C>T: p.Arg79Cys updated nomenclature
ClinVarID: 161400 https://www.ncbi.nlm.nih.gov/clinvar/variation/161400/
CAID: N/A
gnomAD: 0.00002168, https://gnomad.broadinstitute.org/variant/3-10183766-C-T
VariantEvidence: N/A
MutationType: missense_variant; transition
CivicName: R79C (c.235C>T)
MultipleGeneVariants: N/A
c.241C>T
Data was collected from 82 VHL mutation carriers in the Dutch VHL surveillance program. Two patients were found with the missense mutation, c.241C>T, in the VHL gene. One patient was 34Y and the other was 59Y at last follow-up. Their phenotypes were grouped together: retinal hemangioblastoma, cerebellar hemangioblastoma, spinal cord hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumour, pheochromocytoma, and renal cysts. Family history was not described. The group was classified as a 2a/b which was described by the author to included de novo VHL mutation carriers or VHL mutation carriers having a family history with diagnosis of pheochromocytoma and other VHL related manifestations.
This study reports 1,548 germline and somatic mutations from 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). This mutation was detected by direct sequencing and MLPA. This frameshift mutation (c.351del) was detected as sporadic germline in case no. 198 with hemangioblastoma of the central nervous system. The case phenotypes are highly specific for a disease with a single genetic etiology (ACMG code: PP4).
c.337C > T (p.Arg113X)
37 Danish patients diagnosed with VHL before 18 years from a prospective cohort study from Denmark's National vHL Research Database (Binderup et al., 2013) were assessed. Parts of the Danish cohort have been previously assesed in the following papers PMID: 19863552, 25834951, 27966541, 27539272. Peripheral blood samples were isolated and sequenced coding exons and exon-intron boundaries using MLPA (Multiplex Ligation-dependent Probe Amplification). One family with one patient (Family ID-10) was found with a germline truncating mutation in the VHL gene (R113*; c.337C>T). Patient 1 was diagnosed at 15Y and had two pancreatic cysts at 15Y, one retinal hemangioblastoma at 17Y, and one epididymal cystadenoma at 17Y. The patient was 37Y by the end of the study.
14EP 1.0VVHLVHL({"type":"entrez-nucleotide","attrs":{"text":"NM_000551.4","term_id":"1779521775","term_text":"NM_000551.4"}}NM_000551.4):c.407T>G (p. Phe136Cys)
This study investigated the effectiveness of whole exome sequencing (WES) and an in-house hybridization based gene panel (ENDOGENE Panel v2.0) at detecting mutations in pheochromocytoma/paraganglioma (PPGL) related genes. The ENDOGENE panel included EGLN1, EPAS1, FH, KIF1B, MAX, MEN1, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, VHL, GOT2, MDH2 and SLC25A11. WES and the ENDOGENE panel were tested on 37 samples with known variants. After optimization of the bioinformatic pipeline, 61 additional samples were tested prospectively. VHL mutations were identified in 3 patients and all were confirmed by Sanger sequencing of blood. Patient 14 was found to have a F136C(c.407T>G) missense variant and diagnosed with VHL.
8684 C->T substitution causing the nonsense R161X mutation
The proband (II/1), of Italian descent, was found to have the c.481C>T change (referred to in the paper as 8684 C->T due to a difference in transcript sequence) causing a p.R161* mutation in the VHL gene. This variant was detected using direct sequencing of PCR products obtained from genomic DNA extracted from the patients peripheral blood leukocytes using the DNA extractor BIO ROBOT EZ 1 (Qiagen). Genetic testing revealed that her parents did not have the VHL gene mutation. She presented with a cerebellar hemangioblastoma at age 33. ACMG evidence codes: 'PS2' since both parents are tested and do not present with the variant (de novo), 'PP4' since the patient presents phenotypes highly specific for a disease with a single genetic etiology.
F4c.337C>T1p.Arg113TerNonsensePathogenicYesF5c.337C>T1p.Arg113TerNonsensePathogenicYes
17 patients from 10 families affected with VHL syndrome, particularly with retinal capillary hemangioblastomas (RCHs) were examined. In 2019, a 14-year-old boy (patient 8) from family 4 was diagnosed with visual impairment, due to visual acuity of 20/20 in the right eye and 20/640 in the left eye. Four peripheral RCHs were detected in the right eye. The visual impairment of the left eye was due to the severe exudative process involving the macula. Moreover, numerous microhemangioblastomas were revealed by fluorescein angiography. Laser therapy was performed in both eyes, but vitreous hemorrhage occurred in the left eye. Bevacizumab was given three times, as well simultaneous cryotherapies were performed under general anesthesia. Many laser sessions were performed for regression of the RCHs to occur. Further testing revealed a cerebellar hemangioblastoma. Genomic DNA was extracted from whole blood for sanger sequencing of the VHL gene and multiplex ligation-dependent probe amplification was performed to identify genomic rearrangements. A nonsense R113(c.337C>T) mutation was identified in exon1 of the VHL gene. The parents of patient 8 were molecularly tested and neither possessed the mutation; thus, the mutation was identified as de novo. Neither parent had VHL syndrome characterized by RCHs. A 32-year-old woman (patient 9) from family 5 had been diagnosed in 2000 with multiple cerebellar and spinal hemangioblastomas. In 2005, she was examined at the eye clinic, and were visual acuity was 20/20 and 20/25 in the right and left eye, respectively. No abnormalities were found in the right eye, but a peripheral RCH that was already partially treated with laser was observed in the left eye. Many tiny RCHs that surrounded the major lesion were also detected in this eye. Further laser treatments were scheduled, but the patient did not follow up and instead came to the ophthalmic emergency service three years later. Visual acuity of the left eye worsened to 20/640, and she presented with retinal detachment. The partially treated RCH of the left eye worsened and more tiny RCHs were detected. Cryotherapy was performed in the left eye but retinal detachment was still present at follow-up. On follow-up, no RCHs were detected in the right eye, and vision loss developed in both eyes. The same nonsense R113(c.337C>T) mutation was identified in exon1 of the VHL gene in this patient. Neither parent of patient 9 had VHL syndrome characterized by RCHs.
recognized in a large family that originated in Newfoundland but has some members who live in New Brunswick and Ontario. A collaborative investigation was begun in 1982 to document the number of affected members and the extent of their disease and to improve management of the disease. The condition has been documented in 38 members of the family, 28 living and 10 dead. The most common manifestations are retinal angioma (present in 60% of the gene carriers) and pheochromocytoma (present in 53%). Of the 28 living affected members 14 had been identified before the study began. Only 3 of the 14 patients in whom the disease was subsequently diagnosed presented with symptoms; in the remaining 11 the condition was detected by routine screening. Overall the mean age at the time of diagnosis was 23 years; in the 21 affected members of the fourth generation it was 18 years.
PatientID: IV-2
KindredID: 1
Case: F, Age Unknown, Ethnicity Unknown
DiseaseAssertion: Assumed VHL
FamilyInfo: 38 family members had been affected at the date of 1986, and 10 had passed away. Pheochromocytoma, cerebellar, spinal and retinal hemangioblastomas, and various cysts were clinical manifestations of VHL seen throughout the family. This patient (IV-2) appears to have inherited this disease from her father, along with many of her siblings. She also had an affected daughter with retinal angiomas. See Fig. 1 for family pedigree.
CasePresentingHPOs: HP:0009711 (retinal capillary hemangioma)
CaseHPOFreeText: This member had retinal angiomas which was not further described.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167W (c.499C>T)
LegacyVariant: N/A
CaseProblemVariantFreeText: Although never given at the time of this publication, the germline mutation is confirmed in this family in later publications (PMID 7987306; 29437867) for this specific family. It is only here assumed this member had the VHL mutation.
ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: N/A
gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T?dataset=gnomad_r2_1
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
GroupID/ KindredID: VHL 31
Case: Sex unknown, Age unknown, Italian
DiseaseAssertion: assumed VHL
FamilyInfo: One patient with the given mutation is stated to belong to VHL family 31 - this was said to be not inherited from either parent, indicating a de novo germline mutation.
CasePresentingHPOs: HP:0009711; HP:0010797; HP:0000107; HP:0005584; HP:0001737; HP:0009715 (retinal capillary hemangioma, hemangioblastoma, renal cyst, renal cell carcinoma, pancreatic cysts, papillary cystadenoma of the epididymis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: c.464-2A>G
CaseProblemVariantFreeText: N/A
LegacyVariant: c.677-2A>G
ClinVarID: 223222 https://www.ncbi.nlm.nih.gov/clinvar/variation/223222/
CAID: N/A
gnomAD: N/A
VariantEvidence: N/A
MutationType: splice_site_variant
CivicName: Splice Site (c.464-2A>G)
MultipleGeneVariants: N/A
c.500G>A, p.(R167Q))
This paper analyzed 8 patients with clinical or imaging features consistent with VHL, but who tested negative for an abnormality by Sanger sequencing and deletion analysis. All eight patients were subsequently analyzed by next generation sequencing using peripheral blood lymphocytes. The missense mutation, c.500G>A, was found in Patient 1 in mosaic with a frequency of the mutated allele of 5.7%. This patient presented with CNS hemangioblastoma at the age of 16 and developed pheochromocytoma, pancreatic neuroendocrine tumour, and adrenal pheochromocytoma at the age of 17. The patient had no family history of VHL. This patient is believed to be the same as a patient published in 30731206. That paper offers more updated information on this patient.
c.337C>Tp.Arg113X
Genomic DNA was extracted from whole blood samples for genetic testing of SDHB, SDHC, SDHD, and VHL. 27 patients with urinary bladder paragangliomas, revealed 17 germline mutations, three of which were in the VHL gene. PCR–based bidirectional sequencing was performed along with MLPA on large deletions. This nonsense mutation (p.R113*) was found in a 37-year-old female (patient no. 21). Family history of pheo or paragangliomas was said to be positive.
Patients: Two generations of a family consisting of 15 individuals were studied.
PatientID: III:9
KindredID: 1
Case: F, 25Y, Spanish
DiseaseAssertion: pheochromocytoma
FamilyInfo: Spanish family of 15 members studied, over 2 generations. 6 members had VHL presentations, 1 was a carrier, and 4 others had the mutation, while 2 were not sequenced. This patient’s sister was a carrier, while her mother mother, uncle, and cousins were affected.
CasePresentingHPOs: HP:0002666 (pheochromocytoma)
CaseHPOFreeText: First studied at 19Y, she had a bilateral tumor accumulation (Right, 6cm and Left 4cm).
CaseNotHPOs: HP:0006880; HP:0009711 (cerebellar hemangioblastoma, retinal capillary hemangioma)
CaseNotHPOFreeText: Brain MRI and CT-scans were normal, and no signs of retinal angiomas were present.
CasePreviousTesting: RET
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: p.R167W (c.499C>T)
LegacyVariant: p.R238T, C>T
CaseProblemVariantFreeText: N/A
ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/
CAID: N/A
gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T
VariantEvidence: N/A
MutationType: missense_variant;transition
CivicName: R167W (c.499C>T)
MultipleGeneVariants: N/A
nucleotide 500 (exon 1) resulting in an Arg167Glu
At age 14 the patient presented with a pancreatic neuroendocrine tumor that was resected. At age 19 she had hemangiomas of the fourth ventricle and cervical spinal cord which were operated. At age 27 it was noted that multiple solid tumors in the pancreas had gradually increased in size (the tumor in pancreatic head had a max size of 4.1cm) and she underwent a total pancreatectomy where pathological investigation of these tumors supported a diagnosis of well-differentiated neuroendocrine carcinoma. At age 30 she was found to have renal cell carcinoma and she underwent a nephrectomy. DNA from peripheral blood cells found a G to A point mutation at neucleotide 500 in exon 1 (Arg167Glu). Her father and elder brother were also diagnosed with VHLD. Her father had a history of two surgical resections for pancreatic neuroendocrine tumors and associated metastatic recurrence in the liver.
1
Case#: 1, Female, 0.6 years (diagnosed), 5.2 years (report), 15 kg (weight), 75 cm (height), Iranian
DiseaseAssertion: Hurler Syndrome
FamilyInfo: Parents are not consanguineous
CasePresentingHPOs: HP:0000943, HP:0001387, (Multiple Dysostosis, Joint Stiffness)
CaseHPOFreeText: HM/HSM, Cardiac Manifestations (mitral stenosis)
CaseNotHPOs: HP:0001249, HP:0001999, HP:0100790, HP:0000365, HP:0007957, HP:0000238 (Mental Retardation Facial Dysmorphic Features, Hernia, Deafness, Corneal Opacity, Hydrocephalus)
CaseNotHPOFreeText: Chronic Rhinorrhea
CaseEnzymeAssay: IDUA activity 1.02 (μmol/spot.20h)
CaseUrineGAGs: Quantitative urinary GAG 11.14 (mg/gCr)
CaseERT: N/A
CaseBMT: N/A
GenotypingMethod: Sanger Sequencing
Variant1: p.D257A
Variant2: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
4
Case#: 4, Female, 0.3 years (diagnosed), 7.2 years (report), 23 kg (weight), 112 cm (height), Iranian
DiseaseAssertion: Hurler Syndrome
FamilyInfo: Parents are consanguineous
CasePresentingHPOs: HP:0000943, HP:0001387 (Multiple Dysostosis, Joint Stiffness)
CaseHPOFreeText: HM/HSM
CaseNotHPOs: HP:0001249, HP:0001999, HP:0100790, HP:0000365, HP:0007957, HP:0000238 (Mental Retardation, Facial Dysmorphic Features, Hernia, Deafness, Corneal Opacity, Hydrocephalus)
CaseNotHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations
CaseEnzymeAssay: IDUA activity 1.27 (μmol/spot.20h)
CaseUrineGAGs: Quantitative urinary GAG 13.27 (mg/gCr)
CaseERT: N/A
CaseBMT: N/A
GenotypingMethod: Sanger Sequencing
Variant1: p.D257A
Variant2: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
11
Case#: 11, Female, 0.5 years (diagnosed), 6.2 years (report), 14.5 kg (weight), 100 cm (height), Iranian
DiseaseAssertion: Hurler Syndrome
FamilyInfo: Parents are not consanguineous
CasePresentingHPOs: HP:0001249, HP:0001999, HP:0000943, HP:0001387, HP:0100790, HP:0000365, HP:0007957 (Mental Retardation, Facial Dysmorphic Features, Multiple Dysostosis, Joint Stiffness, Hernia, Deafness, Corneal Opacity, Hydrocephalus)
CaseHPOFreeText: HM/HSM, Chronic Rhinorrhea
CaseNotHPOs: HP:0000238 (Hydrocephalus)
CaseNotHPOFreeText: Cardiac Manifestations
CaseEnzymeAssay: IDUA activity 1.04 (μmol/spot.20h)
CaseUrineGAGs: Quantitative urinary GAG 7.82 (mg/gCr)
CaseERT: N/A
CaseBMT: N/A
GenotypingMethod: Sanger Sequencing
Variant1: p.D301E
Variant2: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
16
Case#: 16, Male, 0.6 years (diagnosed), 5.5 years (report), 11.0 kg (weight), 66 cm (height), Iranian
DiseaseAssertion: Hurler Syndrome
FamilyInfo: Parents are consanguineous
CasePresentingHPOs: HP:0001249, HP:0001999, HP:0100790 (Mental Retardation, Facial Dysmorphic Features, Hernia)
CaseHPOFreeText: HM/HSM
CaseNotHPOs: HP:0000943, HP:0001387, HP:0000365, HP:0007957, HP:0000238 (Multiple Dysostosis, Joint Stiffness, Deafness, Corneal Opacity, Hydrocephalus)
CaseNotHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations
CaseEnzymeAssay: IDUA activity 0.89 (μmol/spot.20h)
CaseUrineGAGs: Quantitative urinary GAG 8.5 (mg/gCr)
CaseERT: N/A
CaseBMT: N/A
GenotypingMethod: Sanger Sequencing
Variant1: p.D301E
Variant2: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Q70X
Case#: Family 11, UK
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: The paper states that "Hurler form is characterized by skeletal abnormalities, hepatosplenomegaly and severe mental retardation" but is not specific to this patient.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: The α-L-iduronidase enzyme activities in leucocytes from all patients in the study was measured using the artificial substrate 4-methylumbelliferyl α-L iduronide (Sigma). Values ranged from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) and did not correlate to the clinical phenotype.
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
H240R
Case#: Family 29, UK
DiseaseAssertion: MPS1-S
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: The Scheie phenotype is characterized by aortic valve disease, corneal clouding, limited skeletal problems, but no mental retardation. This is a general assessment and not specific to this patient.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: The α-L-iduronidase enzyme activities in leucocytes from all patients in the study was measured using the artificial substrate 4-methylumbelliferyl α-L iduronide (Sigma). Values ranged from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) and did not correlate to the clinical phenotype.
α-L-iduronidase activity in COS-7 cells transiently transfected with wild-type or mutagenised cDNAs. α-L-iduronidase activity: 5.6 nmol/h/mg cell protein; values are the means of two experiments.
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.719A>G (p.H240R)
Variant2ClinVarID: 947028
Variant2CAID: CA355962127
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Q70X
Case#: Family 19, Slovenia
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: The paper states that "Hurler form is characterized by skeletal abnormalities, hepatosplenomegaly and severe mental retardation" but is not specific to this patient.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: The α-L-iduronidase enzyme activities in leucocytes from all patients in the study was measured using the artificial substrate 4-methylumbelliferyl α-L iduronide (Sigma). Values ranged from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) and did not correlate to the clinical phenotype.
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
R619X
Case#: Family 5, UK
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: The paper states that "Hurler form is characterized by skeletal abnormalities, hepatosplenomegaly and severe mental retardation" but is not specific to this patient.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: The α-L-iduronidase enzyme activities in leucocytes from all patients in the study was measured using the artificial substrate 4-methylumbelliferyl α-L iduronide (Sigma). Values ranged from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) and did not correlate to the clinical phenotype.
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.1855C>T (p.R619X)
Variant2ClinVarID: 280976
Variant2CAID: CA2802455
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: E182K
Variant1ClinVarID: 2856554
Variant1CAID: CA2739269988
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: N350I
Variant1ClinVarID:
Variant1CAID: CA355963160
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: S260F
Variant1ClinVarID:
Variant1CAID: CA355962251
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: F602I
Variant1ClinVarID:
Variant1CAID: CA355965569
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: A300T
Variant1ClinVarID: 11923
Variant1CAID: CA121772
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: W626R
Variant1ClinVarID:
Variant1CAID: CA355965965
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Pro533Arg
Case#: Variant not associated with a proband in this paper.
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: Pro533Arg
Variant1ClinVarID: 11910
Variant1CAID: CA256112
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: C205Y
Variant1ClinVarID: 1468875
Variant1CAID: CA355961928
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: T364M
Variant1ClinVarID: 11925
Variant1CAID: CA256126
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4
DiseaseAssertion: Mucopolysaccharidosis type I, MPS I
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: T366P
Variant1ClinVarID: 11916
Variant1CAID: CA256117
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
sibling who initiated ERT at 2.5 years
Case#: YS2 of sibship 5 (see Table 1), female, 0.1 years old (age at diagnosis), 2.5 years old (age at ERT enrollment), 8.8 years (duration of ERT)
DiseaseAssertion: MPS1-HS
FamilyInfo: Two affected siblings (OS and YS1 of sibship 5)
CasePresentingHPOs: HP:0007957, HP:0002828, HP:0001270 (Corneal opacity, joint contractures, motor delay)
CaseHPOFreeText: Cardiac disease, ocular disease, organomegaly
CaseNotHPOs: HP:0000943 (Dysostosis)
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: Yes - Organomegaly and motor function delays improved, cardiac symptoms remained stable, and mild joint contractures developed. Pulmonary function was between 70 and 94 % of normal at T2.
CaseBMT: N/A
Variant1: c.1469T>C (p.L490P)
Variant1ClinVarID: 11919
Variant1CAID: CA220503
Variant2: c.1469T>C (p.L490P)
Variant2ClinVarID: 11919
Variant2CAID: CA220503
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
older sibling
Case#: OS of sibship 3, female, 1 year old (age at diagnosis), 12 years old (age at ERT enrollment), 8 years (duration of ERT)
DiseaseAssertion: MPS1-HS
FamilyInfo: Affected female YS (YS of sibship 1)
CasePresentingHPOs: HP:0007957, HP:0000943, HP:0002828, HP:0001263, HP:0010862, HP:0002194 (Corneal opacity, dysostosis, joint contractures, cognitive delay, delayed fine motor development, delayed gross motor development)
CaseHPOFreeText: Cardiac disease, moderate musculoskeletal disease
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: Yes - After ERT all existing symptoms persisted or progressed in this sibling except for improvement in organomegaly.
CaseBMT: N/A
Variant1: N/A
Variant1ClinVarID: N/A
Variant1CAID: N/A
Variant2: N/a
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
MPS-I patients 296
Case#: Patient 296, female, northern European origin, 8 months (age of diagnosis), 4 years and 9 months (age of death)
DiseaseAssertion: MPS1-H, severe
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.1614del (delG1702)
Variant2ClinVarID: 167191
Variant2CAID: CA234129
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Arthropathy-like findings and a carpal tunnel syndrome as the presenting features of Scheie syndrome: Three cases from the same family
Article not publicly available through PubMed.
PMID: 30511553
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
40/M
Case#: Patient 40, male, Han origin, 11 months old (age at diagnosis)
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Global Developmental Delay, Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001263, HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0100790, HP:0006536)
CaseHPOFreeText: Cardiac disease
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity 1.4 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.300-1G>C
Variant1ClinVarID: N/A
Variant1CAID: CA355960962
Variant2: c.123G>A (p.W41X)
Variant2ClinVarID: 2734632
Variant2CAID: CA355945567
AdditionalVariants: N/A
ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.
PreviouslyPublished N/A
33/M
Case#: Patient 33, male, Han origin, 7 year 5 months old (age at diagnosis)
DiseaseAssertion: MPS1-H/S
FamilyInfo: N/A
CasePresentingHPOs: Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0100790, HP:0006536)
CaseHPOFreeText: N/A
CaseNotHPOs: Global Developmental Delay (HP:0001263)
CaseNotHPOFreeText: Cardiac disease
CaseEnzymeAssay: IDUA activity 0.7 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.792+1G>C
Variant1ClinVarID: N/A
Variant1CAID: : CA355962280
Variant2: c.236C>T (p.A79V)
Variant2ClinVarID: 1458769
Variant2CAID: CA356987
AdditionalVariants: N/A
ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.
PreviouslyPublished N/A
31/F
Case#: Patient 31, female, Han origin, 9 years old (age at diagnosis)
DiseaseAssertion: MPS1-H/S
FamilyInfo: N/A
CasePresentingHPOs: Macrocephaly, Joint stiffness, Hepatosplenomegaly, Airway obstruction (HP:0000256, HP:0001387, HP:0001433, HP:0006536)
CaseHPOFreeText: N/A
CaseNotHPOs: Global Developmental Delay, Mongolian macula, Hernia (HP:0001263, HP:0011369, HP:0100790)
CaseNotHPOFreeText: Cardiac disease
CaseEnzymeAssay: IDUA activity 1.3 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1037T>G (p.L346R)
Variant1ClinVarID: 11927
Variant1CAID: CA256128
Variant2: c.1037T>G (p.L346R)
Variant2ClinVarID: 11927
Variant2CAID: CA256128
AdditionalVariants: N/A
ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed by parental testing.
PreviouslyPublished N/A
3/M
Case#: Patient 3, male, Han origin, 1 year and 5 months old (age at diagnosis).
DiseaseAssertion: MPS1-H/S
FamilyInfo: N/A
CasePresentingHPOs: Global Developmental Delay, Macrocephaly, Joint stiffness, Mongolian macula, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001263, HP:0000256, HP:0001387, HP:0011369, HP:0001433, HP:0100790, HP:0006536)
CaseHPOFreeText: Cardiac disease
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity 1.0 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.
CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.536C>G (p.T179R)
Variant1ClinVarID: 556358
Variant1CAID: CA355961718
Variant2: c.236C>T (p.A79V)
Variant2ClinVarID: 1458769
Variant2CAID: CA356987
AdditionalVariants: N/A
ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.
PreviouslyPublished N/A
15
Case#: Patient 15, born in 2001 (paper published in 2017), 13 months (age at first treatment), 2 years 9 months (age at last treatment)
DiseaseAssertion: MPSI-H
FamilyInfo: N/A
CasePresentingHPOs: Corneal clouding (HP:0007957)
CaseHPOFreeText: N/A
CaseNotHPOs: Retinopathy, cataract (HP:0000488, HP:0000518)
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 25 ng/mol (56 weight matched enzyme reference assay)
CaseUrineGAGs: 0.80 DS/CS
CaseERT: No
CaseBMT: Yes, from mother
Variant1: c.783delC is not a known variant in IDUA; there is a C at position 783 but the only known variants are c.784del
Variant1ClinVarID: N/A
Variant1CAID: N/A
Variant2: c.783delC; same as above
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
22
Case#: Patient 22, born in 1995 (paper published in 2017), 8 months (age at first treatment). 2 years and 2 months (age at last treatment)
DiseaseAssertion: MPSI-H
FamilyInfo: N/A
CasePresentingHPOs: Corneal clouding (HP:0007957)
CaseHPOFreeText: N/A
CaseNotHPOs: Retinopathy, cataract (HP:0000488, HP:0000518)
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 49.94 ng/mol (38.49 weight matched enzyme reference assay)
CaseUrineGAGs: 0.43 DS/CS
CaseERT: No
CaseBMT: Yes, Sib
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.208C>T (p.Q70X)
Variant2ClinVarID: 11909
Variant2CAID: CA204563
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
3
Case#: Patient 3, male, brother of Patient 7 (see Table 1)
DiseaseAssertion: MPS I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Low IDUA enzyme activity 1.60 (Ref. 4.87 ~ 54.70 μmol/g protein/h)
CaseUrineGAGs: Positive GAG tests
CaseERT: N/A
CaseBMT: N/A
Variant1: c.300-3C>G
Variant1ClinVarID: 551563
Variant1CAID: CA549265042
Variant2: c.1874A>C (p.Y625S)
Variant2ClinVarID: 2910181
Variant2CAID: CA355965961
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
4
Case#: Patient 4, male
DiseaseAssertion: MPS I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Low IDUA enzyme activity 2.06 (Ref. 4.87 ~ 54.70 μmol/g protein/h)
CaseUrineGAGs: Negative GAG tests
CaseERT: N/A
CaseBMT: N/A
Variant1: c.355G>T (p.D119Y)
Variant1ClinVarID: 2432701
Variant1CAID: CA2801882
Variant2: c.617C>T (p.S206L)
Variant2ClinVarID: 1436435
Variant2CAID: CA2802033
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N//A
Hurler disease
Case#: Patient 58, 6 years old (age at report), male, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: Sibling of Patient 59
CasePresentingHPOs: Coarse facial features, corneal clouding, dysostosis multiplex (HP:0000280, HP:0007957, HP:0000943)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 2.4% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1044C>G (p.Asn348Lys)
Variant1ClinVarID: 557870
Variant1CAID: CA2802172
Variant2: c.1598C>G (p.Pro533Arg)
Variant2ClinVarID: 11910
Variant2CAID: CA256112
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler disease
Case#: Patient 43, 2 years old (age at report), male, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, intellectual disability, hernia (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0001249, HP:0100790)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 2.2% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1862C>T (p.Arg621Leu) - There seems to be a typo, either c.1862G>T (p.Arg621Leu) or c.1861C>T (p.Arg621Ter). Unknown which variant is being referred.
Variant1ClinVarID: N/A
Variant1CAID: N/A
Variant2: c.1862C>T (p.Arg621Leu) - There seems to be a typo, either c.1862G>T (p.Arg621Leu) or c.1861C>T (p.Arg621Ter). Unknown which variant is being referred.
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler disease
Case#: Patient 34, 5 years old (age at report), female, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, dysostosis multiplex, intellectual disability, hernia (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0000943, HP:0001249, HP:0100790)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 2.2% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1373T>C (p.Leu458Pro)
Variant1ClinVarID: N/A
Variant1CAID: CA355964255
Variant2: c.1373T>C (p.Leu458Pro)
Variant2ClinVarID: N/A
Variant2CAID: CA355964255
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler disease
Case#: Patient 48, 6 years old (age at report), male, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Hepatosplenomegaly, joint contractures, corneal clouding, recurrent infections (HP:0001433, HP:0002828, HP:0007957, HP:0002719)
CaseHPOFreeText: Cardiac disease
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 2.7% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.(972+1_973-1)(1959?)del in the paper, unsure how to write this in current nomenclature.
Variant1ClinVarID: N/A
Variant1CAID: N/A
Variant2: c.(972+1_973-1)(1959?)del in the paper, unsure how to write this in current nomenclature.
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Hurler disease
Case#: Patient 25, 28 years old (age at report), female, Indian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Coarse facial features, hepatosplenomegaly, joint contractures, corneal clouding, dysostosis multiplex (HP:0000280, HP:0001433, HP:0002828, HP:0007957, HP:0000943)
CaseHPOFreeText: Cardiac disease
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 2.5% (Range of residual enzyme activity: 0.0%-4.8%)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1148G>A (p.Arg388His)
Variant1ClinVarID: 558189
Variant1CAID: CA2802205
Variant2: c.1148G>A (p.Arg388His)
Variant2ClinVarID: 558189
Variant2CAID: CA2802205
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Scheie
Case#: Patient 14 (group 2), Poland, male 5 years old (age at diagnosis), 15 years old (age at baseline), 19 years old (current age)
DiseaseAssertion: MPS1-S
FamilyInfo: N/A
CasePresentingHPOs: Limitation of join mobility, joint stiffness (HP:0001376, HP:0001387)
CaseHPOFreeText: Patients in group 2 had normal mental development or only slightly delayed mental development and, therefore, could undergo active physical rehabilitation.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Diagnosis of MPS I was confirmed by the biochemical determination of α-L-iduronidase activity deficiency in leukocytes and by molecular analysis.
CaseUrineGAGs: N/A
CaseERT: Yes, weekly infusions for 52-208 weeks (depending on the patient)
CaseBMT: N/A
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.793G>C (p.G265R)
Variant2ClinVarID: 638074
Variant2CAID: CA2802098
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Efficacy of recombinant human alpha-L-iduronidase (laronidase) on restricted range of motion of upper extremities in mucopolysaccharidosis type I patients
PMID: 20217237
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
Case#: Patient D3, Druze religious group, located in lower Galilee.
DiseaseAssertion: MPS-H
FamilyInfo: Parents were heterozygous for the same mutation.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1096A>C (p.T366P)
Variant1ClinVarID: 11916
Variant1CAID: CA256117
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
D5
Case#: Patient D5, Druze religious group, located in lower Galilee.
DiseaseAssertion: N/A
FamilyInfo: May have relation with Patient D5 due to being located in the same village. Parents were found to be heterozygous for the mutation.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1096A>C (p.T366P)
Variant1ClinVarID: 11916
Variant1CAID: CA:256117
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
M3)
Case#: Patient M3, Muslim religious group, located in Gaza. The cells of the patient were listed in the catalog of the Human Genetic Mutant Cell Repository as "Hurler/Scheie". However, the patient at age 6 years had been described as having a typical MPS1-H phenotype except for apparently normal intelligence (measured across a language barrier).
DiseaseAssertion: MPS1-H/S or MPS1-H
FamilyInfo: Parents were found to have both mutations were found in heterozygous form in the DNA. Affected brother deceased at age 9.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1225G>A (p.G409R)
Variant1ClinVarID: 1084956
Variant1CAID: CA91169920
Variant2: (p.X654C)
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
M1
Case#: Patient M1, Muslim religious group, located in lower Galilee.
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.192C>A (p.Y64X)
Variant1ClinVarID: 11914
Variant1CAID: N/A
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
36
Case#: Patient 36 (Table 3)
DiseaseAssertion: Attenuated naïve MPS 1
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 7 nmol/h/mg per DBS (dried blood spots) determined during NBS. 13 DBS protein concentration determined by Immuno-SRM (pmol/L). 125.50 relative protein abundance, expressed as the ratio between IDUA/GAA (amol / fmol) in buccal swabs.
CaseUrineGAGs: N/A
CaseERT: Yes
CaseBMT: N/A
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.1070C>T (p.P357L)
Variant2ClinVarID: 1683228
Variant2CAID: CA91169110
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
26
Case#: Patient 26 (Table 3)
DiseaseAssertion: Severe naïve MPS 1
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: Yes
CaseBMT: N/A
Variant1: c.1598C>G (p.P533R)
Variant1ClinVarID: 11910
Variant1CAID: CA256112
Variant2: c.1598C>G (p.P533R)
Variant2ClinVarID: 11910
Variant2CAID: CA256112
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
38
Case#: Patient 38 (Table 3)
DiseaseAssertion: Severe MPS 1
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 59.4 DBS protein concentration determined by Immuno-SRM (pmol/L).
CaseUrineGAGs: N/A
CaseERT: Yes
CaseBMT: N/A
Variant1: c.1205G>A (p.W402X) Listed in Table 3 as c.12095G>A
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.1205G>A (p.W402X) Listed in Table 3 as c.12095G>A
Variant2ClinVarID: 11908
Variant2CAID: CA220498
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
40
Case#: Patient 40 (Table 3)
DiseaseAssertion: Severe MPS 1
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 7 nmol/h/mg per DBS (dried blood spots) determined during NBS. 469.4 DBS protein concentration determined by Immuno-SRM (pmol/L). 15.98 relative protein abundance, expressed as the ratio between IDUA/GAA (amol / fmol) in buccal swabs.
CaseUrineGAGs: N/A
CaseERT: Yes
CaseBMT: N/A
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.1205G>A (p.W402X)
Variant2ClinVarID: 11908
Variant2CAID: CA220498
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
c.531C>G
Case#: Functional assay variant with a clinical significance of being a VUS.
DiseaseAssertion: MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.531C>G (p.P177L)
Variant1ClinVarID: 2432729
Variant1CAID: CA2801983
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
c.898G>A
Case#: Functional assay variant with a clinical significance of having conflicting interpretations.
DiseaseAssertion: MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.898G>A (p.A300T)
Variant1ClinVarID: 11923
Variant1CAID: CA121772
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
c.1706C>T
Case#: Functional assay variant with a clinical significance of being a VUS.
DiseaseAssertion: MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1706C>T (p.S569L)
Variant1ClinVarID: N/A
Variant1CAID: CA355965250
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Functional assessment of IDUA variants of uncertain significance identified by newborn screening
PMID: 39702574
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
c.719A>G
Case#: Functional assay variant with a clinical significance of pathogenic.
DiseaseAssertion: MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.719A>G (p.H240R)
Variant1ClinVarID: 947028
Variant1CAID: CA355962127
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
22
Case#: Patient 22, female, 4 years (age at presentation).
DiseaseAssertion: MPS1-H/S
FamilyInfo: Consanguinity in the family not present for this patient.
CasePresentingHPOs: Corneal clouding, coarse facial features, dystosis multiplex, hepatomegaly, joint stiffness, sleep disturbance, splenomegaly (HP:0007957, HP:0000256, HP:0000943, HP:0002240, HP:0001387, HP:0002360, HP:0001744)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1469T>C (p.L490P)
Variant1ClinVarID: 11919
Variant1CAID: CA220503
Variant2: c.1898C>T (p.S633L)
Variant2ClinVarID: 556406
Variant2CAID: CA355966010
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
28
Case#: Patient 28, female, 2 months (age at presentation).
DiseaseAssertion: MPS1-H
FamilyInfo: Consanguinity in the family present for this patient. Sister is unaffected.
CasePresentingHPOs: Coarse facial features, dysostosis multiplex, global developmental delay, hepatomegaly, joint contractures, splenomegaly (HP:0000256, HP:0000943, HP:0001263, HP:0002240, HP:0100790, HP:0001744)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1855C>T (p.R619X)
Variant1ClinVarID: 280976
Variant1CAID: CA2802455
Variant2: c.1855C>T (p.R619X)
Variant2ClinVarID: 280976
Variant2CAID: CA2802455
AdditionalVariants: N/A
ParentalGenotype: Mother and father are both carriers but does not specify for which variants.
PreviouslyPublished N/A
30
Case#: Patient 30, female, 3 years (age at presentation).
DiseaseAssertion: MPS1-H/S
FamilyInfo: Consanguinity in the family present for this patient. Family had a prenatal diagnosis "CVS-unaffected"
CasePresentingHPOs: Corneal clouding, coarse facial features, dysostosis multiplex, hepatomegaly, joint stiffness, splenomegaly, short stature, umbilical hernia (HP:0007957, HP:0000256, HP:0000943, HP:0002240, HP:0001387, HP:0001744, HP:0004322, HP:0001537)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1861C>T (p.R621X)
Variant1ClinVarID: 11917
Variant1CAID: CA256118
Variant2: c.1861C>T (p.R621X)
Variant2ClinVarID: 11917
Variant2CAID: CA256118
AdditionalVariants: N/A
ParentalGenotype: Mother and father are both carriers but does not specify for which variants.
PreviouslyPublished N/A
c.1240_1240delA
Case#: No additional case information provided
DiseaseAssertion: N/A
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.09 umol/g hr, reference range 10–50 umol/g hr.
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1240_1240delA (p.S414AfsTer26)
Variant1ClinVarID: N/A
Variant1CAID: CA645372298
Variant2: c.614G>A (p.C205X)
Variant2ClinVarID: 1468875
Variant2CAID: CA355961928
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
c.41T > G
Case#: No additional case information provided
DiseaseAssertion: MPSI-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Not detectable
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.41T>G (p.L14R)
Variant1ClinVarID: N/A
Variant1CAID: CA355945322
Variant2: c.386-2A>G
Variant2ClinVarID: 222994
Variant2CAID: CA356991
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
To assess the potential utility of these genotype–phenotype relationships, the associations suggested were applied to test cohort derived from a previously published cohort of MPS I patients (Beesley et al., 2001). This study described the variants identified in a cohort of 85 families with MPS I, and identified nine common variants. Phenotypic information was available for a subset of individuals in whom neither or only one variant was a common variant. Up to date genotypes and phenotypic classification was obtained for 31 such individuals in whom both IDUA variants were identified (Clare Beesley, personal communication), and this was used as the test cohort (Supp. Table S5).
This variant can be found in supp table s5, mentioned from a previous publication (Beesley et al., 2001).
c.506_513delinsGGAA
Case#: No additional case information provided
DiseaseAssertion: MPSI-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Not detectable
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.506_513delinsGGAA (p.L169RfsTer24)
Variant1ClinVarID: N/A
Variant1CAID: CA645372296
Variant2: c.506_513delinsGGAA (p.L169RfsTer24)
Variant2ClinVarID: N/A
Variant2CAID: CA645372296
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
P3-IDUAMNorth AfricaMorocco1.774.4IDUAc.1598C > G/wtp.Pro533Arg/wtMissenseHurler/wt
Case#: P3-IDUA, M, North Africa, Morocco DiseaseAssertion: MPS1 - Hurler/wt FamilyInfo: CasePresentingHPOs: CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: NBS 1.77 triplex / 4.4 single CaseUrineGAGs: CaseERT: CaseBMT: Variant1: c.1598C>G Variant1ClinVarID: 11910 Variant1CAID: CA256112 Variant2: wt Variant2ClinVarID: Variant2CAID:<br /> AdditionalVariants: ParentalGenotype: PreviouslyPublished
Case#: TW1-1 ID number, Table S1.1 of Supplementary Material. Stored Frozen (-20ºC). Other identifying factors N/A
DiseaseAssertion: Severe MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: 301 fmol/punch
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1874A>C (p.Y625S)
Variant1ClinVarID: 2910181
Variant1CAID: CA355965961
Variant2: c.300-3C>G
Variant2ClinVarID: 551563
Variant2CAID: CA549265042
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: MN-400 ID number, Table S1.1 of Supplementary Material. Female, 1.5 months old (age at diagnosis). Stored frozen (-20ºC) 0.7 yr
DiseaseAssertion: Severe MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Probable heart features, small curve in the spine
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: 1632 fmol/punch
CaseERT: N/A
CaseBMT: N/A
Variant1: N/A
Variant1ClinVarID: N/A
Variant1CAID: N/A
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: NY-605 ID number, Table S1.1 of Supplementary Material. Additional health information not provided.
DiseaseAssertion: Severe MPS-I
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: 1412 fmol/punch
CaseERT: N/A
CaseBMT: N/A
Variant1: N/A
Variant1ClinVarID: N/A
Variant1CAID: N/A
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: NJ-500 ID number, Table S1.1 of Supplementary Material. Male, 1 year and 4 months (age at first symptoms), 1 year and 4 months old (age at diagnosis). Stored ambient 3 yr
DiseaseAssertion: Severe MPS-I
FamilyInfo: N/A
CasePresentingHPOs: Macrocephaly, umbilical hernia, hypertension (HP:0000256, HP:0001537, HP:0000822)
CaseHPOFreeText: Some heart issues
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: 1343 fmol/punch
CaseERT: N/A
CaseBMT: N/A
Variant1: N/A
Variant1ClinVarID: N/A
Variant1CAID: N/A
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
missense mutations
Case#: Patient 61, Spain
DiseaseAssertion: MPS1-S
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1475G>C (p.R492P)
Variant1ClinVarID: 11918
Variant1CAID: CA256120
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
distinct mutant IDUA alleles
Case#: Patient 23, Italy
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.1487C>G (p.P496R)
Variant2ClinVarID: 496861
Variant2CAID: CA2802275
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
distinct mutant IDUA alleles
Case#: Patient 92, Turkey, patient belong to the same geographical region as patients 86, 90, and 98
DiseaseAssertion: MPS1-H/S - S (Unsure what this phenotype means)
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.494-1G>A
Variant1ClinVarID: 557942
Variant1CAID: CA355961634
Variant2: c.826G>A (p.E276K)
Variant2ClinVarID: 3233261
Variant2CAID: CA355962355
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient 3, male, 12.2 months (age at HSCT), 8.5 months (age at ERT).
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: RSV pneumonitis, pneumothoraces
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.14 (at diagnosis), 49.9 (after HSCT) Units not provided.
CaseUrineGAGs: N/A
CaseERT: Yes - 96 days duration
CaseBMT: Yes - MUD (matched unrelated donor) with stem cells sourcing from the PBSC (peripheral blood stem cells)
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.1205G>A (p.W402X)
Variant2ClinVarID: 11908
Variant2CAID: CA220498
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient 7, female, 13.2 months (age at HSCT), 10.2 months (age at ERT).
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Norovirus gastroenteritis
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.09 (at diagnosis), 17.1 (after ERT) Units not provided.
CaseUrineGAGs: N/A
CaseERT: Yes - 113 days duration
CaseBMT: Yes - MUD (matched unrelated donor) with stem cells sourcing from the CB (cord blood)
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: N/A
Variant2ClinVarID: N/A
Variant2CAID: N/A
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient 4, female, 8.3 months (age at HSCT), 4.5 months (age at ERT).
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs:
CaseHPOFreeText: Cy-induced acute cardiomyopathy
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.31 (at diagnosis), 15.7 (after HSCT) Units not provided.
CaseUrineGAGs: N/A
CaseERT: Yes - 114 days duration
CaseBMT: Yes - MUD (matched unrelated donor) with stem cells sourcing from the BM (bone marrow).
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.1205G>A (p.W402X)
Variant2ClinVarID: 11908
Variant2CAID: CA220498
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient 2, male, 11.5 months (age at HSCT), 9.2 months (age at ERT)
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Renal tubular acidosis (HP:0001947)
CaseHPOFreeText: Veno occlusive disease (VOD), skin graft-versus-host disease (GVHD)
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.22 (at diagnosis), 27.6 (after HSCT) Units not provided.
CaseUrineGAGs: N/A
CaseERT: Yes - 64 days duration
CaseBMT: Yes - MUD (matched unrelated donor) with stem cells sourcing from the CB (cord blood)
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.1205G>A (p.W402X)
Variant2ClinVarID: 11908
Variant2CAID: CA220498
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
p.L18P: a novel IDUA mutation that causes a distinct attenuated phenotype in mucopolysaccharidosis type I patients
PMID: 25256405
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
9/m
Case#: 9, Male, Han Chinese
DiseaseAssertion: Hurler Syndrome
FamilyInfo: Not Provided
CasePresentingHPOs: HP:0001249, HP:0007957, HP:0001433 (Mental Retardation (severe), Corneal Clouding, Hepatosplenomegaly)
CaseHPOFreeText: Skeletal Deformities
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0 Leukocyte IDUA activity (nmol/h/mg protein) (isolated leukocytes in the latter)
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
GenotypingMethod: Using the artificial substrate 4-methyl-umbelliferyl α-L-iduronide (Sigma)
Variant1: c.1190-1G>A
Variant1ClinVarID: 1204494
Variant1CAID: CA355963511
Variant2: c.792+1G>T
Variant2ClinVarID: N/A
Variant2CAID: CA355962278
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
16/M
Case#: 16, Male, Infancy (onset), 2,5 years (diagnosed), 3 years (report), deceased (at 5y)
DiseaseAssertion: Hurler Syndrome
FamilyInfo: Not Provided
CasePresentingHPOs: HP:0000256, HP:0002240, HP:0000158, HP:0000280, HP:0000943, HP:0007957 (Macrocephaly (hydrocephalus), Hepatomegaly (moderate), Large Tongue, Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)
CaseHPOFreeText: (Mental Development (Delayed since infancy; developmental quotient 68 at 3y), Mild LV Hypertrophy, Frequent respiratory infections, After ERT: decreased illness (obstructive bronchitis), decreased organomegaly, increased mobility)
CaseNotHPOs: HP:0004322, HP:0001744 (Short Stature, Splenomegaly)
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: Decreased excretion of GAGs in the urine
CaseERT: Had an ERT
CaseBMT: N/A
GenotypingMethod: Not Provided
Variant1: p.A327P
Variant1ClinVarID: 167190
Variant1CAID: CA234128
Variant2: c.1727+2T>G (splicing error)
Variant2ClinVarID: N/A
Variant2CAID: CA355965300
AdditionalVariants: p.Q33H
ParentalGenotype: N/A
PreviouslyPublished N/A
5/M
Case#: 5, Male, 1 year (onset), 3 years (diagnosed), 3 years (report)
DiseaseAssertion: Hurler Syndrome
FamilyInfo: Not Provided
CasePresentingHPOs: HP:0001387, HP:0002240, HP:0001744, HP:0000501, HP:0000280, HP:0000943, HP:0007957 (Joint Stiffness, Hepatomegaly (moderate), Splenomegaly (moderate), Glaucoma, Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)
CaseHPOFreeText: Mental Development (delayed since 2y), LV hypertrophy (at 3y)
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
GenotypingMethod: Not Provided
Variant1: p.W402X
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: p.V620F
Variant2ClinVarID: 1067173
Variant2CAID: CA355965934
AdditionalVariants: p.R105Q, p.N181, p.A314, p.T410, p.V454I, p.R489
ParentalGenotype: N/A
PreviouslyPublished N/A
Taiwan National Newborn Screening Program by Tandem Mass Spectrometry for Mucopolysaccharidoses Types I, II, and VI
PMID: 30409495
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
MPS I_Case 02
Case#: MPS I_Case 02, female newborn
DiseaseAssertion: MPS type I, MPS I, MPS-I, attenuated MPS I
FamilyInfo: MPS I_Case 02 and MPS I_Case 03 are twins
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText: This proband is believed to be an affected MPS-patient however, the proband did not have any obvious clinical symptoms to date (up to two years of age). The paper states that this attenuated MPS I case will need a long term follow up.
CaseEnzymeAssay: Proband identified by newborn screening. alpha-L-iduronidase activity in dried blood spot sample is 0.59 umole/L/Hr; this is below the study's DBS enzyme activity cutoff value of 3 umol/L/h
CaseUrineGAGs: Urine DMB GAG ratio is 204.7mg/mmol creatinine. 99.60 ug/ml dermatan sulfate in urine (<0.41 ug/ml is the reference cutoff for dermatan sulfate in this study). 13.31 ug/ml heparan sulfate in urine (<0.8 ug/ml is the reference cutoff for heparan sulfate in this study). 0.83 ug/ml keratan sulfate in urine.
CaseERT: Don't know (would assume no since the proband is a newborn)
CaseBMT: Don't know (would assume no since the proband is a newborn)
Variant1: c.1037T>G, p.L346R
Variant1ClinVarID: 11927
Variant1CAID: CA256128
Variant2: c.1091C>T, p.T364M
Variant2ClinVarID: 11925
Variant2CAID: CA256126
AdditionalVariants: No additional variants mentioned
ParentalGenotype: No parental testing results are available
PreviouslyPublished No statement from the author indicating the proband is previously published. Since this is a newborn study, I strongly believe this is the proband’s first time being published.
PKMPS1P7
Case#: PKMPS1P7, 10 months old (age at presentation), 2.4 years old (age at report), male, Pakastani. He underwent ventriculoperitoneal shunting at the age of 18 months due to significant hydrocephalus.
DiseaseAssertion: MPS-I
FamilyInfo: Parents had a consanguineous marriage
CasePresentingHPOs: Coarse facial features, macrocephaly, rhinorrhea, hydrocephalus, mild to moderate developmental delay, umbilical hernia (HP:0000256, HP:0000256, HP:0031417, HP:0000238, HP:0001263, HP:0001537)
CaseHPOFreeText: Poor growth potential, widening of the wrist and elbow. The abdomen was distended. The liver span was 3 cm.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.784delC (p.H262Tfs*55)
Variant1ClinVarID: 956890
Variant1CAID: CA2802083
Variant2: c.784delC (p.H262Tfs*55)
Variant2ClinVarID: 956890
Variant2CAID: CA2802083
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
PKMPS1P12
Case#: PKMPS1P12, 2.6 years old (age at presentation), male, Pakastani
DiseaseAssertion: MPS-I
FamilyInfo: Born to a non-consanguineous couple
CasePresentingHPOs: Significant developmental delay, stridor, coarse facial features, recurrent chest infections, umbilical hernia, corneal clouding (HP:0001263, HP:0010307, HP:0000256, HP:0002783, HP:0001537, HP:0007957)
CaseHPOFreeText: Running nose, skeletal stigmata were consistent with MPS1, and a liver span on 3 cm.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1469T>C (p.L490P)
Variant1ClinVarID: 11919
Variant1CAID: CA220503
Variant2: c.1469T>C (p.L490P)
Variant2ClinVarID: 11919
Variant2CAID: CA220503
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Mapping of IDUA gene variants in Pakistani patients with mucopolysaccharidosis type 1
PMID: 31473686
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
Case#: Patient W3, 10 years old, Chinese. The patient had normal intelligence based on their performance in school.
DiseaseAssertion: MPS1-H/S
FamilyInfo: Patient received the p.M1I mutation from their mother and received the p.Y343X from their father.
CasePresentingHPOs: Short stature, coarse facial features, severe skeletal deformities (HP:0004322, HP:0000280, HP:0000924)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Expression of Y343X in COS-7 cells showed retention of a very low level of IDUA activity
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.3G>A (p.M1I)
Variant1ClinVarID: 557150
Variant1CAID: CA355945212
Variant2: c.1029C>A (p.Y343X)
Variant2ClinVarID: 222997
Variant2CAID: CA356984
AdditionalVariants: The patient has one IDUA allele with the variant c.3G>A (p.M1I) and an in frame deletion of the whole of exon 2, whereas the other allele has Y343X (an in frame deletion of nucleotides 1061-1117 in exon 8).
ParentalGenotype: Maternal - p.M1I, Paternal - p.Y343X
PreviouslyPublished N/A
two boys
Case#: Boy 3, male, 5 years old, born of normal pregnancy with a birth weight of 3,200 grams
DiseaseAssertion: MPS-I H/S
FamilyInfo: Boy 1 was born to a Chinese family of five members, with a total of 3 boys. Genetic testing was conducted on all 5 family members. The first and third child (boy 1 and boy 3) have MPS I. The second son had a normal phenotype and genotype.
CasePresentingHPOs: N/A
CaseHPOFreeText: Lesions (similar to elder brother; noted at 3 years old)
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 3.29 nmol/h/mg (reference range >21)
CaseUrineGAGs: Positive for urinary polysaccharide toluidine blue staining test
CaseERT: N/A
CaseBMT: N/A
Variant1: c.265C>T (p.R89W)
Variant1ClinVarID: 580286
Variant1CAID: CA2801156
Variant2: c.1633G>T (p.E545X)
Variant2ClinVarID: N/A
Variant2CAID: CA355965099
AdditionalVariants: N/A
ParentalGenotype: Mother carries c.265C>T and father carries c.1633G>T.
PreviouslyPublished N/A
Hurler
Case#: 0.1% residual activity at 37 °C
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.2 ± 0.1 nmol/mg/h IDUA activity at 37 °C
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.208C>T (p.Q70X)
ClinVarID: 11909
Variant2CAID: CA204563
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Scheie
Case#: 0.3% residual activity at 37 °C
DiseaseAssertion: MPS1-S
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.8 ± 0.1 nmol/mg/h IDUA activity at 37 °C
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.979G>C (p.A327P)
Variant1ClinVarID: 167190
Variant1CAID: CA234128
Variant2: c.1148G>A (p.R383H)
ClinVarID: 558189
Variant2CAID: CA2802205
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
3.3.1. Severe patients There were 115 individual genotypes represented in the 380 patients with a severe phenotype and two reported alleles; 31 genotypes were recurrent and 84 genotypes unique (Table 3). The most common genotypes in severe patients were W402X/W402X (109/380; 28.7%), W402X/Q70X (61/380; 16.1%) and Q70X/Q70X (24/380; 6.3%). In total, these two nonsense variants defined the genotypes of 51% (194/380) of severe patients. Of severe patients, 67.6% (257/380) were either homozygous or compound heterozygous for two variants predicted to severely disrupt gene transcription or translation (eg, nonsense variants, frameshifts, consensus splice site disruption or initiator codon variants). No clinically diagnosed attenuated patients were homozygous or compound heterozygous for such variants. Of the remaining 123 severe patients, 76 comprised 19 recurrent genotypes (Table 3) with the remaining 47 patients (12.6%) having unique genotypes (listed in Table S1). Thirty‐seven of the 84 unique genotypes identified in severe patients were compound heterozygous with two severe variants (as defined above) and were comprised of 34 separate severe variants (listed in Table S1). There were nine missense recurrent variants and one intronic recurrent variant that were exclusively seen in severe patients (Table 5A).
Case#: Severe MPS1 patients
DiseaseAssertion: Severe MPS I
FamilyInfo: n/a, "neither the laboratory method used to determine the sequence variants nor whether parental testing confirmed the inheritance or phase of the variants is captured by the Registry"
CasePresentingHPOs:
CaseHPOFreeText: "All patients enrolled in the Registry have confirmation of MPS I diagnosis by either mutation analysis or measurement of IDUA levels."
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: n/a
GenotypingMethod: n/a
PreviouslyPublished: possible since this is a multinational registry
Variant: c.1403-1G>T/c.1728-1G>C
ClinVar: 556064
CAID: CA355965306
SupplementalData: Table S1 has the genotypes listed
3.3.1. Severe patients There were 115 individual genotypes represented in the 380 patients with a severe phenotype and two reported alleles; 31 genotypes were recurrent and 84 genotypes unique (Table 3). The most common genotypes in severe patients were W402X/W402X (109/380; 28.7%), W402X/Q70X (61/380; 16.1%) and Q70X/Q70X (24/380; 6.3%). In total, these two nonsense variants defined the genotypes of 51% (194/380) of severe patients. Of severe patients, 67.6% (257/380) were either homozygous or compound heterozygous for two variants predicted to severely disrupt gene transcription or translation (eg, nonsense variants, frameshifts, consensus splice site disruption or initiator codon variants). No clinically diagnosed attenuated patients were homozygous or compound heterozygous for such variants. Of the remaining 123 severe patients, 76 comprised 19 recurrent genotypes (Table 3) with the remaining 47 patients (12.6%) having unique genotypes (listed in Table S1). Thirty‐seven of the 84 unique genotypes identified in severe patients were compound heterozygous with two severe variants (as defined above) and were comprised of 34 separate severe variants (listed in Table S1). There were nine missense recurrent variants and one intronic recurrent variant that were exclusively seen in severe patients (Table 5A).
Case#: Severe MPS1 patients
DiseaseAssertion: Severe MPS I
FamilyInfo: n/a, "neither the laboratory method used to determine the sequence variants nor whether parental testing confirmed the inheritance or phase of the variants is captured by the Registry"
CasePresentingHPOs:
CaseHPOFreeText: "All patients enrolled in the Registry have confirmation of MPS I diagnosis by either mutation analysis or measurement of IDUA levels."
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: n/a
GenotypingMethod: n/a
PreviouslyPublished: possible since this is a multinational registry
Variant: c.1728-1G>C/W402X
ClinVar: 556064
CAID: CA355965306
SupplementalData: Table S1 has the genotypes listed
3.3.1. Severe patients There were 115 individual genotypes represented in the 380 patients with a severe phenotype and two reported alleles; 31 genotypes were recurrent and 84 genotypes unique (Table 3). The most common genotypes in severe patients were W402X/W402X (109/380; 28.7%), W402X/Q70X (61/380; 16.1%) and Q70X/Q70X (24/380; 6.3%). In total, these two nonsense variants defined the genotypes of 51% (194/380) of severe patients. Of severe patients, 67.6% (257/380) were either homozygous or compound heterozygous for two variants predicted to severely disrupt gene transcription or translation (eg, nonsense variants, frameshifts, consensus splice site disruption or initiator codon variants). No clinically diagnosed attenuated patients were homozygous or compound heterozygous for such variants. Of the remaining 123 severe patients, 76 comprised 19 recurrent genotypes (Table 3) with the remaining 47 patients (12.6%) having unique genotypes (listed in Table S1). Thirty‐seven of the 84 unique genotypes identified in severe patients were compound heterozygous with two severe variants (as defined above) and were comprised of 34 separate severe variants (listed in Table S1). There were nine missense recurrent variants and one intronic recurrent variant that were exclusively seen in severe patients (Table 5A).
Case#: Severe MPS1 patients
DiseaseAssertion: Severe MPS I
FamilyInfo: n/a, "neither the laboratory method used to determine the sequence variants nor whether parental testing confirmed the inheritance or phase of the variants is captured by the Registry"
CasePresentingHPOs:
CaseHPOFreeText: "All patients enrolled in the Registry have confirmation of MPS I diagnosis by either mutation analysis or measurement of IDUA levels."
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: n/a
GenotypingMethod: n/a
PreviouslyPublished: possible since this is a multinational registry
Variant: Q70X/Y343X
ClinVar: 222997
CAID: CA356984
SupplementalData: Table S1 has the genotypes listed
p.Q310X [37]
This paper references a pt from PMID: 12865757 which can no longer be accessed. Links/DOI say they're no longer found.
263
Case#: Patient 26 (see Table 2), 40 weeks (Gestational age)
DiseaseAssertion: MPS1-S
FamilyInfo: Sibling of Patient 25 (see Table 2)
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.1148G>A (p.R383H)
Variant2ClinVarID: 558189
Variant2CAID: CA:2802205
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
6
Case#: Patient 6 was biochemically diagnosed with MPS I because they showed an increase in urinary GAGs and a reduction in IDUA activity in leukocytes. Patient 6 was diagnosed at 1 year.
DiseaseAssertion: MPSI-H/S
FamilyInfo: N/A
CasePresentingHPOs: Coarse facies, corneal clouding, hernias, intellectual disability, skeletal abnormalities, cardiac abnormalities, and hepatosplenomegaly (HP:0000256, HP:0007957, HP:0100790, HP:0001249, HP:0002360, HP:0001627, HP:0001433)
CaseHPOFreeText: N/A
CaseNotHPOs: Growth delay (HP:0001510)
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity of 1.78 nmol/mg/protein/hr. No reference range provided.
CaseUrineGAGs: 2517.8 CPC unit/g creatinine. No reference range provided.
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1487C>G (p.P496R)
Variant1ClinVarID: 496861
Variant1CAID: CA2802275
Variant2: c.1854C>A (p.Y618X)
Variant2ClinVarID: 554826
Variant2CAID: CA355965929
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
4F41.23.3
Case#:Patient Sample unique ID 2
DiseaseAssertion:MPS type I-Hurler children
FamilyInfo:None
CasePresentingHPOs:None
CaseHPOFreeText:None
CaseNotHPOs:Obstructive sleep apnea, HP:0002870
CaseNotHPOFreeText:None
CaseEnzymeAssay:None
CaseUrineGAGs: Tested but amounts not reported
CaseERT:No
CaseBMT:Hematopoietic stem cell transplantation
Variant1:c.208C>T
Variant1ClinVarID:11909
Variant1CAID:CA204563
Variant2:c.1413C>G
Variant2ClinVarID:1094781
Variant2CAID:CA417702021
AdditionalVariants:None
ParentalGenotype:None provided
PreviouslyPublished:N/A
Table 2.
Case#:Not assigned
DiseaseAssertion:MPS type I with evidence of cognitive impairment defined as a score of at least 1 SD below mean on IQ testing or in one domain of neuropsychological function; attenuated MPS I
FamilyInfo:No information
CasePresentingHPOs:HP:0100543
CaseHPOFreeText:
CaseNotHPOs:HP:0032557
CaseNotHPOFreeText:Subjects were excluded if they had undergone hematopoietic stem cell transplantation, were unable to comply with study procedures, had significant lumbar pathology precluding access to the intrathecal space via lumbar puncture, or significantly impaired spinal CSF flow as detected on a nuclear medicine flow study as part of screening.
CaseEnzymeAssay:No information
CaseUrineGAGs:No information
CaseERT:Yes
CaseBMT:No (exclusion criterion)
Variant1:Q70X
Variant1ClinVarID:
Variant1CAID:
Variant2:Q380R
Variant2ClinVarID:550799
Variant2CAID:
AdditionalVariants:N/A
ParentalGenotype:Not specified
PreviouslyPublished
Prenatal diagnosis of mucopolysaccharidosis type I on hepatosplenomegaly and coarse features: a case-report
PMID: 39754079
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
IDUA gene mutations in mucopolysaccharidosis type-1 patients from two Pakistani inbred families
PMID: 31400021
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
Induced Pluripotent Stem Cells to Understand Mucopolysaccharidosis. I: Demonstration of a Migration Defect in Neural Precursors
PMID: 33287330
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
T141S in exon 4, and IVS2+6c>t
Case#: Patient 3, Egyptian, female, 3 years old
DiseaseAssertion: MPS1-H
FamilyInfo: Parents were nonconsanguineous
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.421A>T (p.T141S)
Variant1ClinVarID: N/A
Variant1CAID: CA355961378
Variant2: c.299+6C>T (in the paper the variant is labeled as c.IVS2+6C>T which is old nomenclature)
Variant2ClinVarID: 92640
Variant2CAID: CA145880
AdditionalVariants: A8A, A20A, N297N, IVS11 (3318)C>A, IVS10 (3122)T>C - these are not the current nomenclatures for these variants but they are identified as polymorphisms in the article
ParentalGenotype: All mutations were confirmed in the parental DNA
PreviouslyPublished N/A
P10
Case#: P10, Female, 11.4 years (diagnosed), 15.8 (report), 31 kg (weight), 131 cm (height), Algerian
DiseaseAssertion: Hurler-Scheie Syndrome
FamilyInfo: Parents are consanguineous
CasePresentingHPOs: HP:0001249, HP:0001999, HP:0000943, HP:0001387, HP:0001433, HP:0001387, HP:0000365, HP:0007957, HP:0000238 (Mental Retardation, Facial Dysmorphic Features, Multiple Dysostosis, Joint Stiffness, Hepatosplenomegaly, Hernia(Ombelical), Deafness(perceptive), Corneal Opacity, Hydrocephalus)
CaseHPOFreeText: Chronic Rhinorrhea, Cardiac Manifestations(Mitral Stenosis)
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA Enzyme activity 0 (% to the reference range mean)
CaseUrineGAGs: GAG quantitation 46 (fold change to the reference range mean according to age)
CaseERT: N/A
CaseBMT: N/A
GenotypingMethod: Direct DNA Fragments Sequencing
Variant1: c.1598C>G (p.Pro533Arg)
Variant1ClinVarID: 11910
Variant1CAID: CA256112
Variant2: c.1598C>G (p.Pro533Arg)
Variant2ClinVarID: 11910
Variant2CAID: CA256112
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Treatment of latent tuberculosis in a child with mucopolysaccharidosis type I receiving enzyme replacement therapy: A case report
PMID: 36052356
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal recessive
Patients of family B
Case#: Family B proband, male, 1 year and 4 months old (age of onset), 3 years old (age at report), Tunisia.
DiseaseAssertion: MPS1-H
FamilyInfo: Three affected maternal cousins (one of them, 13 years old, was followed for convulsing encephalopathy and infirmity matrix, the other cousin, 3 years old, was followed in the same Pediatric Unit for encephalopathy). Parents were 2nd degree relatives (second cousins) (See Table 1).
CasePresentingHPOs: HP:0000256, HP:0001433, HP:0001263, HP:0002463, HP:0000470, HP:0000687, HP:0030812, HP:0000158, HP:0012471, HP:0001513 (Macrocephaly, hepatosplenomegaly, global developmental delay, language impairment, short neck, widely spaced teeth, enlarged tonsils, macroglossia, thick lips, obesity)
CaseHPOFreeText: Short trunk
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity (0.08 nmol/h/mg) (usual values: 1-5).
CaseUrineGAGs: Glycosaminoglycans (120 mg/g of creatinine) (usual values: 9-46), abnormal electrophoresis profile with dermatan sulfate and heparan sulfate.
CaseERT: No
CaseBMT: No
Variant1: c.1598C>G (p.P533R)
Variant1ClinVarID: 11910
Variant1CAID: CA256112
Variant2: c.1598C>G (p.P533R)
Variant2ClinVarID: 11910
Variant2CAID: CA256112
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished: N/A
Comment on “report of 5 novel mutations of the α-L-iduronidase gene and comparison of Korean mutations in relation with those of Japan or China in patients with mucopolysaccharidosis I”
PMID: 30286738
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal Dominant
730.248 (3.0)9.6DS 3.3heterozygous VUS: c.1744G>A; p.E582KNormal examinationHS 4.9heterozygous PD: c.235G>A; p.A79Theterozygous PD: c.296C>T; p.T99I
Case#:Patient Sample unique ID 73, Infant screened positive at birth (specimens with activity ≤15% of the DMA for enzyme activity and a CLIR screening algorithm result of indeterminate or MPS I)
DiseaseAssertion:None
FamilyInfo:None
CasePresentingHPOs:None
CaseHPOFreeText:None
CaseNotHPOs:None
CaseNotHPOFreeText: Normal examination at follow up after screening positive at birth (specimens with activity ≤15% of the DMA for enzyme activity and a CLIR screening algorithm result of indeterminate or MPS I)
CaseEnzymeAssay: IDUA activity 0.248 (3.0) umol/L/h (%DMA) during new born screening through dried blood spot (plasma) and 9.6 pmol/punch/h Confirmatory IDUA enzyme
CaseUrineGAGs: DS 3.3 g/mol creatinine and HS 4.9 g/mol creatinine (Normal)
CaseERT:No
CaseBMT:No
Variant1:heterozygous VUS: c.1744G>A; p.E582K (Normal examination)
Variant1ClinVarID:538474
Variant1CAID:CA1944440
Variant2:heterozygous PD: c.235G>A; p.A79T
Variant2ClinVarID:41682
Variant2CAID:CA000358
AdditionalVariants:heterozygous PD: c.296C>T; p.T99I (ClinVarID:53610, CAID:CA326991)
ParentalGenotype:None provided
PreviouslyPublished:N/A
530.351 (4.2)6.9DS 4.6heterozygous PD: c.235G>A; p.A79TNormal examinationHS 3.3heterozygous PD: c.667G>A; p.D223N
Case#:Patient Sample unique ID 53, Infant screened positive at birth (specimens with activity ≤15% of the DMA for enzyme activity and a CLIR screening algorithm result of indeterminate or MPS I)
DiseaseAssertion:None
FamilyInfo:None
CasePresentingHPOs:None
CaseHPOFreeText:None
CaseNotHPOs:None
CaseNotHPOFreeText: Normal examination at follow up after screening positive at birth (specimens with activity ≤15% of the DMA for enzyme activity and a CLIR screening algorithm result of indeterminate or MPS I)
CaseEnzymeAssay: IDUA activity 0.351 (4.2) umol/L/h (%DMA) during new born screening through dried blood spot (plasma) and 6.9 pmol/punch/h Confirmatory IDUA enzyme
CaseUrineGAGs: DS 4.6 g/mol creatinine and HS 3.3 g/mol creatinine (Normal)
CaseERT:No
CaseBMT:No
Variant1:heterozygous PD: c.235G>A; p.A79T (Normal examination)
Variant1ClinVarID:41682
Variant1CAID:CA000358
Variant2:heterozygous PD: c.667G>A; p.D223N
Variant2ClinVarID:2220838
Variant2CAID:CA363422841
AdditionalVariants: None
ParentalGenotype:None provided
PreviouslyPublished:N/A
patient
Case#: 20 months old, Male, 78 cm of height (-3 S.D.), 10 kg of weight (-3 S.D.), head circumference of 50.5 cm (>90th percentile).
DiseaseAssertion: Severe MPS-I
FamilyInfo: First son of healthy non-consanguineous parents with an unremarkable family history.
CasePresentingHPOs: Snoring, noisy breathing (since 3 months old), sleep apnea, upper airway obstruction, breathing cessation, cyanosis, facial dysmorphic features, short stature (since 8 months old), coarse facial features, scaphocephaly, mild corneal clouding, depressed nasal bridge, wide nose, anteverted nares, nasal congestion, long philtrum, thick lips, small and spaced teeth, low set ears, short neck, gibbus deformity, umbilical hernia, claw hands, global developmental delay, frontal bossing, Mongolia spots, dysostosis multiplex, scoliosis, broad ribs bilaterally (HP:0025267, HP:0010307, HP:0010535, HP:0002781, HP:0005943, HP:0000961, HP:0001999, HP:0004322, HP:0000256, HP:0030799, HP:0007957, HP:0005280, HP:0000445, HP:0000463, HP:0001742, HP:0000343, HP:0000219, HP:0000687, HP:0000369, HP:0000470, HP:0002808, HP:0001537, HP:0034337, HP:0001263, HP:0002007, HP:0011369, HP:0000943, HP:0002650, HP:0000885)
CaseHPOFreeText: Had neonatal complications such as being late in crying and breathing. Hyporeactive Apgar 5/8 Silverman-Anderson 3/2. Upper airway infections, bulging frontal bone, enlarged tongue, short trunk, protruding abdomen. The liver edge was palpated 2 cm below the right costal margin and had blue cutaneous pigmentation with dorsal distribution. Limited extension of the arms and small joints. No ability to walk or speak at the age of 20 months. Lumbar gibbus with vertebral hypoplasia. Hand bullet-shaped phalanges and widened metacarpals pointed proximally. Widened diaphysis and cortical thinning of long bones. Pelvis with rounded or flared iliac wings.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: IDUA activity of 0.24 μmol/L/h, enzymatic IDUA activity was 10 times less than the reference minimum level of this enzyme (2.02–16.10 μmol/L/h).
CaseUrineGAGs: N/A
CaseERT: Yes - at 2 years of age
CaseBMT: N/A
Variant1: c.1898C>G (p.S633W)
Variant1ClinVarID: 286242
Variant1CAID: CA10605410
Variant2: c.1898C>G (p.S633W)
Variant2ClinVarID: 286242
Variant2CAID: CA10605410
AdditionalVariants: N/A
ParentalGenotype: Sequence analysis of parental genomic DNA showed that both parents are heterozygous for c.1898C>G variant, with no clinical phenotype of MPS I. Enzymatic IDUA activity was 1.29 μmol/L/h and 3.25 μmol/L/h for the father and the mother, respectively. These levels were 5.4 and 13.5 higher than the ones observed in the patient, respectively. The low enzyme activity observed in the father, which would be expected to be greater because he is a heterozygous with a normal allele, could be explained by a condition known as pseudodeficiency, in which clinically normal individuals shows levels of enzyme activity below the normal levels.
PreviouslyPublished N/A
1
Case#: Patient 1: Enrolled in study at 18 years, male, onset at 3 years, diagnosed at 14.8 years, ERT started 16.7 years DiseaseAssertion:MPS1 H-S FamilyInfo:Consanguinity Yes CasePresentingHPOs:Corneal opacity (HP:0007957), Joint stiffness (HP:0001387), CaseHPOFreeText: CaseNotHPOs: Hepatosplenomegaly (HP:0001433), Macrocephaly (HP:0000256) CaseNotHPOFreeText: CaseEnzymeAssay: CaseUrineGAGs: 1.07(min)-3.08(max) mg GAG/mmol creatinine while on ERT CaseERT: Laronidase dose-optimization trial : standard regimen – 0.58 mg/kg/week; biweekly regimen – 1.2 mg/kg every two weeks CaseBMT:Nil Variant1:P533R Variant1ClinVarID:11910 Variant1CAID:CA256112 Variant2:P533R Variant2ClinVarID:11910 Variant2CAID:CA256112 AdditionalVariants:Nil ParentalGenotype:NA PreviouslyPublishedNA
Patient 1
Case#:2.2 year female, diagnosed at 0.9 years DiseaseAssertion:MPS1H FamilyInfo:NA CasePresentingHPOs:NA CaseHPOFreeText:NA CaseNotHPOs:NA CaseNotHPOFreeText:NA CaseEnzymeAssay:Undetectable CaseUrineGAGs:NA CaseERT:NA CaseBMT:Yes, Unrelated cord blood, Post HSCT <br /> 29.3 nmol/h/mg of protein ( α-l-Iduronidase Levels) Variant1:IDUA : c.457A>T Variant1ClinVarID:917689 Variant1CAID: Variant2:IDUA: c.1205G>A Variant2ClinVarID: 11908 Variant2CAID:CA220498 AdditionalVariants: ParentalGenotype: PreviouslyPublished
12 base pairs
Case#: One patient from Norway
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.134del12 (p.Arg45ProfsTer?)
Variant1ClinVarID: N/A
Variant1CAID: CA3064219537
Variant2: c.134del12 (p.Arg45ProfsTer?)
Variant2ClinVarID: N/A
Variant2CAID: CA3064219537
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
1 nonsense mutation
Case#: One patient whose country of origin is not identifiable.
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1861C>T (p.R621X)
Variant1ClinVarID: 11917
Variant1CAID: CA256118
Variant2: c.1205G>A (p.W402X)
Variant2ClinVarID: 11908
Variant2CAID: CA220498
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
6
Case#: Patient 6 (see Table 2), male, 16.7 years old (age at report), 10.4 years (duration of treatment), 4 surgeries
DiseaseAssertion: MPS1-HS
FamilyInfo: N/A
CasePresentingHPOs: HP:0002360 (Sleep abnormality)
CaseHPOFreeText: Psychiatric problems
CaseNotHPOs: HP:0000238, HP:0002176 (Hydrocephalus, spinal cord compression)
CaseNotHPOFreeText: Shunt placement
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: Yes
CaseBMT: N/A
Variant1: c.712T>A (p.L238Q) CDNA and protein change do not match. Known variant p.L238Q has a CDNA change of c.713T>A.
Variant1ClinVarID: 265418
Variant1CAID: CA2802065
Variant2: (Int3-2a>g) Current HGVS nomenclature is c.386-2A>G.
Variant2ClinVarID: 222994
Variant2CAID: CA356991
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
In utero adenine base editing corrects multi-organ pathology in a lethal lysosomal storage disease
PMID: 34257302
Gene: IDUA
Disease: MPS1
Inheritance: Autosomal Recessive
10 MPS I patients
Case#: MPS 1 patient
DiseaseAssertion: N/A
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1205G>A (p.W402X)
Variant1ClinVarID: 11908
Variant1CAID: CA220498
Variant2: c.1918_1927del p.E640Cfs
Variant2ClinVarID: N/A
Variant2CAID: CA2586965997
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Growth in individuals with attenuated mucopolysaccharidosistype I during untreated and treated periods: Data from theMPS I registry
PMID: 35869927 Gene: IDUA Disease: MPS1 Inheritance: Autosomal recessive
Two other IDUA mutations occurred in CpG dinucleotides (678 G→A and Y202X) and were found in the same patient, along with M133I. The analysis of parental DNA showed that the mutation M133I was linked to the Y202X mutation in the father whereas the other mutation (678 G→A) was maternally inherited. The 678 G→A mutation, a transition in the first base of intron 6, is also a splice site mutation that would cause the change of a glycine to an aspartic acid in position 196 of the protein. However, since skin fibroblasts from this patient were not available, it was not known whether mutant mRNA coding for the G197D α-l-iduronidase was produced. Therefore, this IDUA change was considered only as a splice mutation and was not expressed in CHO-K1 cells.
Case#: Patient #19, Brazilian
DiseaseAssertion: MPS1, severe(Hurler)
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: underwent bone marrow transplant
CaseNotHPOs:
CaseNotHPOFreeText:
Genotyping Method: Patients were screened for 10 known mutations using PCR and restriction enzymes and all 14 exons of the IDUA gene were amplified and analyzed by single strand conformational polymorphism (SSCP) analysis. PCRs were performed and sequenced using the big dye terminator kit and an ABI 373 automated sequencer (Applied Biosystems). Mutations were confirmed by sequencing the reverse strand using the same method.
PreviouslyPublished: n/a
Variant: allele 1: M133I/ Y202X (father); allele 2: 678 G→A (mother)
other changes: A8, A20, Q33H, L118
ClinVar: CA355961907
215
Case#: 215 12.1 yrs male, age at initial diagnosis 3.6 yrs DiseaseAssertion: MPS IH FamilyInfo:Nil CasePresentingHPOs: CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: IDUA activity: low leukocyte IDUA enzyme activity CaseUrineGAGs: CaseERT: 5.6 yrs, then study drug, valanafusp alpha, also called AGT-181 for 12 months
CaseBMT: No PreviouslyPublished Don't know Variant1:p.P533R Variant1ClinVarID: 11910 Variant1CAID: CA256112 Variant2:p.G208D Variant2ClinVarID: 554590 Variant2CAID:
213
Case#: 213 15.7 yrs male, age at initial diagnosis 3.7 yrs DiseaseAssertion: MPS IH-S FamilyInfo:Nil CasePresentingHPOs: CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CaseEnzymeAssay: IDUA activity: low leukocyte IDUA enzyme activity CaseUrineGAGs: CaseERT: 12 yrs, then study drug, valanafusp alpha, also called AGT-181 for 12 months Variant1: p.R383H Variant1ClinVarID: 558189 Variant1CAID: Variant2:p.W402X Variant2ClinVarID: 11908 Variant2CAID: CA220498 AdditionalVariants: NA ParentalGenotype: NA PreviouslyPublished:NA
7
Case#: Patient 7 (see Table 1), 13 years old (age at report), 5 years old (age at onset), female, height of 110 cm, weight of 15 kg, location at Djerba: Land
DiseaseAssertion: MPS1 - intermediate
FamilyInfo: One affected siblings (Patient 6), parents were 1st cousins (see Table 2), parents have the same grandfather but with a different wife (see Table 4), aged 40 yrs (M) and 49 yrs (F).
CasePresentingHPOs: HP:0004322, HP:0001999 (Short stature, moderate facial dysmorphia)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1598C>G (p.P533R)
Variant1ClinVarID: 11910
Variant1CAID: CA:256112
Variant2: c.1598C>G (p.P533R)
Variant2ClinVarID: 11910
Variant2CAID: CA:256112
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
4/f
Case#: Patient 4, female, 10.9 months (age at diagnosis), 16.5 months (age at HSCT), 8.3 - 17.3 months (age at ERT), 7 MRI + neuropsychological observations over the course of 11 years.
DiseaseAssertion: MPS-1H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 67.7 nmol/h/mg (Normal values: 11-43 nmol/h/mg)
CaseUrineGAGs: N/A
CaseERT: Yes
CaseBMT: Yes
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.1487C>G (p.P496R)
Variant2ClinVarID: 496861
Variant2CAID: CA2802275
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
case 2
Case#: Case 2, male, 5 years old (age at diagnosis).
DiseaseAssertion: MPS1
FamilyInfo: Proband's mother was pregnant and her genomic DNA was extracted from cultured amniocytes, her fetus acquired the same pathogenic gene as the proband and was affected.
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: Proband was diagnosed using enzymatic detection. IDUA enzyme activity in the mother's amniotic fluid cells in the 2nd pregnancy was 0.5 nmol/(h·mg protein).
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.530dupT, in the article this is written as c.531insT (old nomenclature). Various variants from Wang articles have nomenclature errors that are 1 base pair off from the described variant.
Variant1ClinVarID: N/A
Variant1CAID: CA2586973520
Variant2: c.1037T>G (p.Leu346Arg)
Variant2ClinVarID: 11927
Variant2CAID: CA256128
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
Case#: Patient 10, Turkish
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: N/A
CaseUrineGAGs: N/A
CaseERT: N/A
CaseBMT: N/A
Variant1: c.1882C>T (p.R628X)
Variant1ClinVarID: 550421
Variant1CAID: CA2802462
Variant2: c.1882C>T (p.R628X)
Variant2ClinVarID: 550421
Variant2CAID: CA2802462
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
3/F
Case#: Patient 3, female, Russian
DiseaseAssertion: MPS1-H
FamilyInfo: N/A
CasePresentingHPOs: Severe intellectual disability, corneal clouding, skeletal deformities, hepatosplenomegaly (HP:0010864, HP:0007957, HP:0000924, HP:0001433)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CaseEnzymeAssay: 0.05 nmol/mg/h (reference range 135 ± 57 nmol/mg/h)
CaseUrineGAGs: 265.24 mg GAG/mmol/creatinine (reference range 6.17 ± 3.79 mg GAG/mmol creatinine)
CaseERT: No
CaseBMT: No
Variant1: c.208C>T (p.Q70X)
Variant1ClinVarID: 11909
Variant1CAID: CA204563
Variant2: c.208C>T (p.Q70X)
Variant2ClinVarID: 11909
Variant2CAID: CA204563
AdditionalVariants: N/A
ParentalGenotype: N/A
PreviouslyPublished N/A
A novel 196 Leu to Pro substitution in the β3subunit of the αIIbβ3 integrin in a patient with avariant form of Glanzmann thrombasthenia
PMID: 11897046
Gene: ITGB3
HGNC: 6156
[Effects of the ITGA2B Nonsense Mutation (c.2659C > T, p.Q887X) on Platelet Function in a Mouse Model of Glanzmann's Thrombasthenia Generated with CRISPR/Cas9 Technology]
PMID: 35395997
InsufficientEvidence: Article in Chinese, and variant reported doesn't have a corresponding shift reported in humans.
The Role of Conserved Amino Acid Motifs within theIntegrinb3Cytoplasmic Domain in Triggering FocalAdhesion Kinase Phosphorylation*
PMID: 9065456
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions variants in ITGA2B and/or ITGB3; however, no specific GT probands are mentioned harboring these variants mentioned therefore there is insufficient evidence
GT 43
Case13: GT43, Female, India, age of onset is 18 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Patients were recruited as they presented consecutively from 1996 to 1998 for evaluation of a mucocutaneous bleeding disorder
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: All patients examined had defective ADP, epinephrine, and collagen induced aggregation and normal ristocetin induced aggregation
CasePreviousTesting: Mutations were detected by the method of single strand conformation polymorphism (SSCP) analysis, followed by nucleotide sequencing and confirmation by restriction fragment length polymorphism (RFLP) assays. The sequences of the primers employed and the reaction conditions for PCR amplification of the exons, adjacent intronic regions, and 50 and 30 untranslated regions of the aIIb and b3 gene
Gene: ITGA2B
Variant: NM_000419.3:c.1520C>G (p.Pro507Arg)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399802643
gnomAD: N/A
Qualitative disorders of platelets and megakaryocytes
PMID: 16102044
Gene: ITGA2B
HGNC: 6138
InsufficientEvidence: This article mentions variants in ITGA2B; however, the variants are not linked to individuals bearing them therefore we have insufficient evidence
Supplementary Table S1:
Case47: GT54, Arg/Italian, gender and age not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets
PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists
CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene
Gene: ITGB3
Variant: NM_000212.2:c.2014+5G>A and the other variant is a "LR deletion" which is all thats mentioned
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940701
gnomAD: N/A
A dinucleotide deletion in exon 4 of the PlA2 allelic form of glycoprotein IIIa: implications for the correlation of serologic versus genotypic analysis of human platelet alloantigens
Case1: Patient PDJ (found in GT database as well) 57 years old, ethnicity not specified
DiseaseAssertion: Thrombocytopenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Quantitative analysis of GPllb-llla surface expression showed only 20,000 GPllb-llla receptors/platelet, approximately half of the value obtained with control platelets
PlateletAggregation: N/A
CasePreviousTesting: DNA sequence analysis of the GPIIIa gene was performed
Gene: ITGB3
Variant: NM_000212.2:c.709_710del
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8623029
gnomAD: MAF in the European (non-Finnish) population is 0.00001796 https://gnomad.broadinstitute.org/variant/17-45363717-CAG-C
MATERIALS AND METHODS
Case#: HS, 1 year old, female
FamilyInfo: Family H, consanguineous Algerian family, with the parents being first cousins. Pedigree is shown in Figure 3.
ParentalGenotype: mother and father both heterozygous for mutation. Proband's sister is also heterozygous.
PlateletAggregation: proband presented defective platelet aggregation to adenosine diphosphate and collagen in a context of epistaxis and bleeding tendency. no mention of ristocetin.
CaseHPOFreeText: propositus HS was diagnosed as type I GT because her platelets were deficient in GPIIb and GPIIIa both on the platelet surface and in α-granules and had undetectable levels of intragranular fibrinogen as shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and periodic acid schiff (PAS) staining, Western blot, crossed immuno-electrophoresis, and Scatchard analysis.13 Moreover, the patient developed an iso-immunization directed against GPIIb-IIIa after the first platelet transfusion.
ProteinExpression:
CasePreviousTesting: Mutation was detected by SSCP, followed by direct sequencing.
Gene: ITGB3
Variant: NM_000212.3(ITGB3):c.1053_1058del (p.Ile351_Gly353delinsMet). "sequencing of exon 7 showed a 6-nucleotide deletion resulting in the substitution of Ile325Pro326Gly327 by a Met"
CAID: CA915940648
gnomAD: This variant is absent from gnomAD v2.1.1
16
Case16: Male, Arab, age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Table 1 mentions family history available for the proband, however no specific details about family provided in paper
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.409-2_419del
LegacyVariant: N/A
ClinVar: 2889
CAiD: CA10575471
gnomAD: N/A
NM_000212:c.2112delC
GT-50
Case40: (GT-50) Male, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Proband GT49-GT52 are related
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Information not available (See Supplementary Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGB3
Variant: NM_000212.2:c.2113del (p.Leu705Cysfs*4)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8623443
gnomAD: MAF in East Asian population: 0.0001087 http://gnomad.broadinstitute.org/variant/17-45380183-TC-T
GT-11
Case9: (GT-11) Male, age or ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Probands GT12 -GT14 are related to GT-11 see Table 1
ParentalGenotype: Parents may be included in Table 1; however, not specified so no information
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding severity: Moderate (See Supplementary Table 3)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry performed and CD41 and CD61 were observed (See Supplementary Table 3)
PlateletAggregation: Minimal information (See Supplementary Table 3)
CasePreviousTesting: DNA was extracted from peripheral blood samples from patients and family members, and Sanger sequencing and PCR was performed. Samples were processed for targeted sequencing using the available SHGp heme panel of 393 genes.
Gene: ITGB3
Variant: NM_000212.2:c.727G>C (p.Asp243His)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400023600
gnomAD: N/A
3
Case3: No assertion made on age, gender or ethnicity
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: The identified variants were heterozygote in parents.
CasePresentingHPOs: HP:0000978, HP:0005542
(Easy bruising, prolonged clotting time)
CaseHPOFreeText: Bleeding time greater than 20 minutes,
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
CasePreviousTesting: Genetic study of patient was conducted using direct sequencing of entire coding and exon-intron boundaries of the ITGA2B and ITGB3 genes.
Gene: ITGB3
Variant: NM_000212.2:c.401del (p. Glu134GlyfsTer10)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA915940222
gnomAD: N/A
Patient‐III6
Case2: Female, Israeli-Arab, (age is either 3 or 8)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: See Fig 1C for pedigree
ParentalGenotype: See Fig 1C for pedigree
CasePresentingHPOs: HP:0000421, HP:0031364, HP:0000967, HP:0002239
(Severe epistaxis, ecchymosis, petechiae, GI bleeding)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: No surface expression of αIIbβ3 was found in patients’ platelets (See Fig 3)
PlateletAggregation: N/A
CasePreviousTesting: DNA fragments containing exons and flanking intronic regions of the aIIb and B3 genes were amplified by PCR using primers
Gene: ITGA2B
Variant: NM_000419.3:c.97A>G (p.Asn2Asp)
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399806951
gnomAD: N/A
The patient
Case1: The proband of interest is designated as VGTΔ724 in this article
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0000967
(Bruising, petechiae)
CaseHPOFreeText: Mucosal bleeding
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: Platelets fail to aggregate in response to physiologic agonists or spread on fibrinogen
CasePreviousTesting: N/A
Gene: ITGB3
Variant: NM_000212.2:c.2248C>T (p.Arg750Ter) and NM_000212.2:c.1791del (p.Asn597Lysfs*72)
LegacyVariant: (p.Arg724Ter)
ClinVar: 13564 (p.Arg750Ter)
CAiD: CA123246 (p.Arg750Ter) and CA8623358 (Asn597Lysfs*72)
gnomAD: MAF in the African population is 0.0006008 https://gnomad.broadinstitute.org/variant/17-45384950-C-T (p.Arg750Ter)
6FL
Case6: Patient FL (found in the GT database) gender and age are not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0006298 Bruising and prolonged bleeding after tooth extraction
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: 7-10% GPIIIa and GPIIb surface expression
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.1063G>A (p.Glu355Lys)
LegacyVariant: (p.Glu324Lys)
ClinVar: 2899
CAiD: CA115844
gnomAD: MAF in the European (non-Finnish) population is 0.00001978 https://gnomad.broadinstitute.org/variant/17-42461008-C-T
PreviouslyPublished: Reference 17 in this article
Frankfurt I
Case3: Patient Frankfurt I (can be found in the GT database)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0006298 Prolonged bleeding after tooth extraction
CaseHPOFreeText: Blood transfusions were needed
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: 24% GPIIIa and GPIIb surface expression
PlateletAggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.620C>T (p.Thr207Ile)
LegacyVariant: (p.Thr176Ile)
ClinVar: N/A
CAiD: CA399805570
gnomAD: N/A
PreviouslyPublished: PMID: 1602006
Platelet and granulocyte alloimmunisation in multitransfused Tunisian patients
PMID: 16104882
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: The purpose of our study was to determine the frequency of alloimmunisation against platelets and leukocytes in multiply transfused Tunisian patients; there are 3 GT probands in this article; however, no mention of variants in ITGA2B and/or ITBG3; therefore, we have insufficient evidence
A six-year-old boy
Case1: Male, 6 years old
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0004406, HP:0000967
(Recurring nosebleed, petechia)
CaseHPOFreeText: Diffused peliosis
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: aIIb and b3 were absent in the platelets of this patient analyzed by flow cytometry.
PlateletAggregation: There was no concentration aggregation action in response to ADP and adrenaline, but patient platelets could aggregate when treated by ristocetin
CasePreviousTesting: Genomic DNA was isolated from cells, and exon 4 of ITGA2B was amplified. PCR products were resolved via agarose gels, purified for sequencing.
Gene: ITGA2B
Variant: NM_000419.3:c.480C>G and NM_000419.3:c.574+5G>C
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA399805892 and CA913203563
gnomAD: MAF in the East Asian population 0.00005507 http://gnomad.broadinstitute.org/variant/17-42463013-G-C
A naturally occurring mutation near the C terminus of the β‐propeller of αIIb impair the transport of αIIbβ3 complexes from the endoplasmic reticulum to the Golgi apparatus
PMID: 15946231
Gene: ITGA2B
HGNC: 6138
GT11
Case#: 15 year old, female
Disease: Glazmann's Thrombasthenia
CasePresentingHPOs: HP:0000967, HP:0000978, HP:0000225, HP:0006298, HP:0001892
PlateletAgreggation: Defective response to ADP, Adrenaline, Collagen, Arachidonic acid. Normal response to Ristocetin.
GenotypingMethod: Genomic DNA was extracted from peripheral blood leukocytes for mutational analysis of the αIIb and β3 genes by DNA sequencing
Allele 1:
ClinVar: 953046
CAID: CA399802348
Variant: NM_000419.5:c.1651C>T
GnomAD: Highest in East Asian population at a rate of 0.00005045 (1/19820)
Allele 2:
ClinVar: 225393
CAID: CA290947544
Variant: NM_000419.5:c.2333A>C
GnomAD: East Asian: 0.0001087 (2/18394)
ExpressionEvidence:Flow Cytometry of platelet integrin: 7.7% B3 expression, .82% A2B expression
Patient 3
Case3: Male, 10 years old, Korean
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: Figure 1 shows haplotype analysis
CasePresentingHPOs: HP:0001342
(Cerebral hemorrhage)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry analyses revealed decreased expression at 7.2%/5.0% of the normal amount of CD41/CD61
PlateletAggregation: Platelet aggregation tests were performed to evaluate responses to ADP, collagen, epinephrine, and ristocetin agonists
CasePreviousTesting: Polymerase chain reaction for all exons ofITGA2Band/orITGB3were performed using primers. Sequence analysis was performed with reference to M_000419.3 andNP_000410.2 forITGA2Band NM_000212.2 and NP_000203.2 for ITGB3.
Gene: ITGA2B
Variant: NM_000419.3:c.2333A>C (p.Gln778Pro) and NM_000419.3:c.975del
LegacyVariant: N/A
ClinVar: 225393
CAiD: CA290947544 and CA915940385
gnomAD: MAF in the East Asian population is 0.0001087 http://gnomad.broadinstitute.org/variant/17-42453691-T-G
Platelet collagen receptor Glycoprotein VI-dimer recognizesfibrinogen and fibrin through their D-domains, contributing toplatelet adhesion and activation during thrombus formation
PMID: 29210180
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
NoEvidence: Article does not mention GT probands with specific variants in ITGA2B and/or ITGB3
Mr P ..., 67 years
Case1: Male, 67 years old, ethnicity not specified (although lives in Argentina)
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo:
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0100749 (Bruising, chest pain)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: Platelets fail to aggregate and bind to fibrinogen in response to ADP, collagen and thrombin
CasePreviousTesting: N/A
Gene: ITGB3
Variant: NM_000212.2:c.2332T>C (p.Ser778Pro)
LegacyVariant: (p.Ser752Pro)
ClinVar: 13556
CAiD: CA123230
gnomAD: N/A
Novel mutations in Thai patients with glanzmann thrombasthenia
PMID: 28888044
Gene: ITGA2B
HGNC: 6138
MM
Case2: Patient MM, gender, age and ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia type I
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding symptoms were evaluated by examining available hospital records. Mild bleeders were defined as those who had minor symptoms, such as epistaxis or gum bleeds, and moderate bleeders suffered, in addition, from bleeding complications after surgery and trauma. Severe bleeders were defined as those with a history of spontaneous or life-threatening hemorrhages, such as gastrointestinal bleeding, or who had repeated episodes requiring platelet transfusion. See Table 1.
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: See Table 6
PlateletAggregation: See Table 6
CasePreviousTesting: To ascertain the mutations, we sequenced the coding regions of the αIIb and β3 subunits including the exon/intron boundaries
Gene: ITGA2B
Variant: NM_000419.3:c.641T>C (p.Leu214Pro)
LegacyVariant: N/A
ClinVar: 2901
CAiD: CA115848
gnomAD: N/A
M
Case13: Patient ID M, Female, 15 years old, ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: Patient L is related to patient M (See Table 1; very minimal information)
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0000225, HP:0004406
(Easy bruising, gingival bleeding, recurrent epistaxis
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0000967, HP:0000979, HP:0002239, HP:0002239, HP:0000790, HP:0005261, HP:0002248
(Petechiae, purpura, GI bleeding, intracranial hemorrhage, hematuria, hemarthrosis, hematemesis)
CaseNotHPOsFreeText: Hemorrhage after dental, hemorrhage after trauma, ear bleeding, hematoma
ProteinExpression: N/A
PlateletAggregation: Defective response to ADP, adrenaline, collagen, arachidonic acid, and normal response to ristocetin
CasePreviousTesting: Exon PCR was used to amplify coding regions of the ITGA2B and ITGB3 genes. PCR products were purified and Sanger sequenced. Segregation using parental samples was undertaken when available.
Gene: ITGB3
Variant: NC_000017.11:g.47284509T>G (p.Leu143Trp)
LegacyVariant: N/A
ClinVar: 13567
CAiD: CA123252
gnomAD: MAF in Other population 0.0001629 http://gnomad.broadinstitute.org/variant/17-45361875-T-G
PreviouslyPublished: PMID: 9376589
GT15
Case15: GT-15, German, gender or age not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: Mother: c.1594T>C heterozygous and Father: n/a
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding symptoms are severe (See Table 1) Abstract mentions patients' bleeding signs include epistaxis, mucocutaneous bleeding, haematomas, petechiae, GI bleeding and menorrhagia; however, not specified per proband.
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Flow cytometry was performed and expression is stated as pathogenic in Table 1
PlateletAggregation: Platelet aggregation was performed and is stated as pathogenic in Table 1; however, no specific agonists mentioned
CasePreviousTesting: All exons of ITGA2B and ITGB3 genes as well as surrounding intron regions were amplified by PCR using intronic primers as pre-viously described (12). The purified DNA fragments were then di-rectly sequenced.
Gene: ITGB3
Variant: NM_000212.2:c.1594T>C and NM_000212.2:c.2014+1G>A
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA400029953 and CA400033055
gnomAD: N/A
F2.II.1
Case#: 17 year old male
Disease: Glazmann's Thrombasthenia Like Syndrome
CasePresentingHPOs: HP:0032438, HP:0001873 PLT anisocytosis, Thrombocytopenia
CaseNotHPOs: HP:0001892
Abnormal Bleeding
FamilyInfo: Pedigree figure 1. Mother, affected, had significant bleeding abnormalities, brother also affected with frequent epistaxis but PLT normal counts
PlateletAgreggation: Decreased PLT aggregation and diminished ATP release with the agonists ADP, collagen, and AA. Ristocetin not assessed in individual per supplementary table
GenotypingMethod: genetic analysis of ITGA2B and ITGB3 genes was performed by next-generation sequencing (NGS). Sanger sequencing used to confirm variants.
ClinVar: 50233
CAID: CA10575573
Variant: NM_000419.5:c.3076C>T
GnomAD: Not Found
ExpressionEvidence: Level of expression on PLT surface determined by FCM: CD41a (GPIIb/IIIa) 45%, CD61 (GPIIIa) 46%, and CD42b (GPIb) 111%. Healthy control value range: CD41a (GPIIb/IIIa) (85-115%); CD61 (GPIIIa) (80-120%); CD42b (GPIb) (70-130%).
6.
Case6: "French gypsy mutation in the Manouche tribe" No specific gender or age specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: Often severe bleeding (very general-- no other information given on phenotypes)
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: N/A
PlateletAggregation: Minimal information, not specific enough
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.1544+1 G>A (p.Val513Leufs71*)
LegacyVariant: N/A
ClinVar: 2895
CAiD: CA10575473
gnomAD: N/A
Patient 1
Case1: Patient 1, diagnosed at 4 years, gender and ethnicity not specified
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0000421
(Easy bruising, epistaxis)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
ProteinExpression: Immunoblot analysis of platelet lysates showed no detectable pro-αIIb or mature αIIb in any of the patient samples
PlateletAggregation: Absent in vitro platelet aggregation in response to ADP, epinephrine, and collagen
CasePreviousTesting: Polymerase chain reaction (PCR), single strand conformation polymorphism (SSCP) analysis, and DNA sequencing was performed for ITGA2B
Gene: ITGA2B
Variant: NM_000419.3:c.475G>A (p.Gly159Ser)
LegacyVariant: p.Gly128Ser
ClinVar: N/A
CAiD: CA8603454
gnomAD: MAF in the South Asian population is 0.00003267 http://gnomad.broadinstitute.org/variant/17-42463018-C-T
A 10-Base-Pair Deletion in the Gene Encoding Platelet GlycoproteinIIb Associated with Glanzmann Thrombasthenia in a Horse
PMID: 17338169
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article discusses a 10 base pair deletion in GT; however, in a horse, not human therefore there is insufficient evidence
Molecular Basis for Glanzmann’s Thrombasthenia (GT) in a Compound Heterozygote With Glycoprotein IIb Gene: A Proposal for the Classification of GT Based on the Biosynthetic Pathway of Glycoprotein IIb-IIIa Complex
PMID: 1317725
Gene: ITGA2B
HGNC: 6138
Adult woman/Belgium
Case3: Female (adult), 48 years old, Belgium
DiseaseAssertion: Glanzmann thrombasthenia (also has cancer)
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
ProteinExpression: N/A
Platelet Aggregation: N/A
CasePreviousTesting: N/A
Gene: ITGA2B
Variant: NM_000419.3:c.1772A>C (p.Asp591Ala)
LegacyVariant: (p.Asp560Ala)
ClinVar: N/A
CAiD: CA8602942
gnomAD MAF in the European (non-Finnish) population is 0.00001556 https://gnomad.broadinstitute.org/variant/17-42457163-T-G
PreviouslyPublished: PMID: 21919374
Glanzmann thrombasthenia detected because of knee hemarthrosis: a case report
PMID: 20736850
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions a case report of an individual with GT; however, no variants in ITGA2B or ITGB3 are mentioned
17CabGT-17
Case17: (Proband CabGT-17), Male, age not specified, North African
DiseaseAssertion: Glanzmann thrombasthenia
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
ProteinExpression: Flow cytometry showed 13% GPIIb and 27% GPIIIa surface expression
Platelet Aggregation: N/A
CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence
Gene: ITGA2B
Variant: NM_000419.3:c.2929C>T (p.Arg977Ter) and the other mutation could not be found
LegacyVariant: N/A
ClinVar: N/A
CAiD: CA8602528
gnomAD MAF in the South Asian population is 0.00003266 https://gnomad.broadinstitute.org/variant/17-42452041-G-A
A Point Mutation in the Integrin p3 Cytoplasmic Domain (S752 + P) Impairs Bidirectional Signaling Through aIIbP3 (Platelet Glycoprotein IIb-IIIa)
PMID: 8080992
Gene: ITGB3
HGNC: 6138
InsufficentEvidence: This article mentions a variant in ITGB3; however, the article does not mention a GT case report with the variant in detail, rather this paper cites another paper of a proband harboring the variant of interest
Double heterozygosity for a novel missense mutation of Ile304 to Asn in addition to the missense mutation His280 to Pro in the integrin β3 gene as a cause of the absence of platelet αIIbβ3 in Glanzmann's thrombasthenia
PMID: 15634267
Gene: ITGB3
HGNC: 6156