3.1. Patient Cohorts
This variant was found on one allele in the patient cohort, but no further details are provided.
34 Matching Annotations
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Blood samples were collected from 28 MPSI H patients treated and followed up at the Royal Manchester Children’s Hospital over a 4-year period. The samples were collected with informed consent and under permission REC 08H101063 of the hospital’s ethical commission. The patients’ blood samples were processed within 6 h and the serum was separated and stored at −80°C. One group of patients was followed longitudinally and comprised patients who received ERT prior to HSCT (n=8). The second was a cross-sectional group of patients (n=20) studied at least 1 year after HSCT. One patient (patient 5) rejected the donor cells following HSCT and had autologous cells returned to restore hematologic function. This patient subsequently received a second allogeneic HSCT which was successful. Longitudinal data for this patient during both transplants are included in the results. The demographics, enzyme levels, details of HSCT, immune reconstitution, and immunosuppression for all patients in the longitudinal series are presented in Table 1. The transplant details and information on immunosuppression for all patients in the cross-sectional series are shown in Table 2.
This seems like it could be the same proband as from the Kuwait family in PMID:22718273 since both were said to be cases at Royal Manchester Hospital
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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p.(Arg628*)(n = 1)
This variant is mentioned only once as a nonsense allele that some HSCT patients had, but no further details provided.
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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V
Case#: Family V, Patient 9, female, 1yo at diagnosis, 5yo at death, Tunisia (Mahdia), black
DiseaseAssertion: MPS1, Hurler
FamilyInfo: Parental consanguinity (first cousins). Age of parents at proband's birth: 50 years (M) 62 years (F). 6 unaffected siblings
CasePresentingHPOs: HP:0010864, HP:0004322, HP:0001537, HP:0000692, HP:0006482, HP:0030812, HP:0001999, HP:0007957, HP:0000943
CaseHPOFreeText: Height=102cm (-3DS). Weight=18kg (-1 DS). IDUA activity in leukocytes=0,020 μKat/kg (Normal values 1.7-3.5 μKat/kg of protein).
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: n/a
GenotypingMethod: Direct sequencing of PCR products from each of 14 exons and flanking intron-exon junctions
PreviouslyPublished: n/a
Variant: p.R628X homozygous. Proband also had the following polymorphisms: A8A, A20A, H33Q, R105Q, A314A, N181N, T410T, V554I, IVS6+21c>a, IVS7+79c>t, IVS7-45g>c, IVS9+36t>c, IVS10+140c>a, IVS11+33c>t, IVS12+13c>t, IVS12-31c>g
ClinVar: 550421
CAID: CA2802462
gnomAD: The highest population minor allele frequency in gnomAD v4.1.0. is 0.00005038 (2/39700 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).
SupplementalData: n/a
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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p.[Arg628*];[Arg628*]6 (1.6%)0
6 individuals noted to have this variant in homozygosity. This is the same as the MPS registry number of homozygotes and uses the registry, so will only be scoring for Clarke et al. paper
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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184I.OL.0,01 leukocytes {"type":"entrez-nucleotide","attrs":{"text":"NM_000203.5","term_id":"1450641494","term_text":"NM_000203.5"}}NM_000203.5:c.[1882C>T];[1882C>T] SevereUzbek/Uzbekistan
This variant was found in homozygosity in patient #184 from Uzbekistan. The maximum point total for homozygosity has already been reached for this variant.
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www-sciencedirect-com.libproxy.lib.unc.edu www-sciencedirect-com.libproxy.lib.unc.edu
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Two new IDUA mutations (D349Y and R628P) were detected at sites that had previously been reported to have mutations (D349N and R628X)
This variant was mentioned only because a novel variant was found at the same amino acid. No new case or experimental info.
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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In this study we analyzed 30 Italian MPS-I patients with different phenotypes (20 severe, 6 intermediate, 4 mild) in an attempt to recognize the mutational spectrum in our population and to identify major DNA alterations specific to our country.
unable to annotate on PDF.
Case#: Case #20, Lombardia region of Italy
DiseaseAssertion: MPS1, intermediate
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: Diagnosis of was based on the clinical features, excessive urinary glycosaminoglycan excretion, and reduced IDUA activity in fibroblasts and/or leukocytes. Intermediate phenotype is described as an onset of symptoms between 1 and 6 years, variable survival, and mental retardation being absent or mild but never before 3 years of age
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: n/a
GenotypingMethod: direct sequencing
PreviouslyPublished: n/a
Variant: R628X homozygous
ClinVar: 550421
CAID: CA2802462
gnomAD: The highest population minor allele frequency in gnomAD v4.1.0. is 0.00005038 (2/39700 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).
SupplementalData: n/a
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onlinelibrary-wiley-com.libproxy.lib.unc.edu onlinelibrary-wiley-com.libproxy.lib.unc.edu
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The variant p.(Arg628Ter) was not present in any UK or Ireland individuals but was identified in 14 individuals from other regions, accounting for 4.8% of alleles in all individuals. Supp. Figure S1
14 individuals in the "other" population were found to have this variant and severe Hurler, but no additional information provided about genotype or phenotype since this study focused on the UK subset of the cohort.
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link-springer-com.libproxy.lib.unc.edu link-springer-com.libproxy.lib.unc.edu
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c. 1882 C > T (p.R628*)
This paper focuses on the process of combining machine learning with GAG characterization for differential diagnosis of MPSs. The variant was found in an MPS1 case, but no further details were provided about the individual's genotype or phenotype.
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link-springer-com.libproxy.lib.unc.edu link-springer-com.libproxy.lib.unc.edu
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The patient in family 2 who also had the Hurler phenotype was heteroallelic for the novel missense mutation I270S and the previously reported nonsense mutation R628X.
Article is a PDF, so annotating here.
Case#: Family 2, Proband 3, Tunisia (Mednine), female, death at 5yo
DiseaseAssertion: MPS1, Hurler
FamilyInfo: Offspring of consanguineous marriage between first cousins. Variants were said to be found in parents as well. Mother had I270S and father had R628X
CasePresentingHPOs:
CaseHPOFreeText: Leukocyte IDUA activity= <0.1% of normal
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: n/a
GenotypingMethod: PCR sequencing with possible confirmation by restriction enzyme digestion on a second PCR product.
PreviouslyPublished: n/a
Variant: c.1882C>T p.(R628X) and c.809T>G p.(I270S) compound heterozygous. Confirmed in trans. Also has the following polymorphisms: R105Q, N181N, T410T, V454I, IVS8+2573insC.
ClinVar: 550421
CAID: CA2802462; CA355962322
gnomAD: The highest population minor allele frequency in gnomAD v4.1.0. is 0.00005038 (2/39700 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).
SupplementalData: n/a
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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In 30 families, either one or both of the mutations were not identified, which accounted for 25.9% of the total alleles. Therefore, all 14 exons of the alpha-L-iduronidase gene were screened in these patients and 23 different sequence changes were found, 17 of which were previously unknown. The novel sequence changes include 4 deletions (153delC, 628del5, 740delC, 747delG), 5 nonsense mutations (Q60X, Y167X, Q400X, R619X, R628X), 6 missense mutations (C205Y, G208V, H240R, A319V, P496R, S633L), a splice site mutation (IVS12+5g>a), and a rare polymorphism (A591T)
article is a PDF, so annotating here.
Case#: Beesley Families 3 and 4, Middle Eastern
DiseaseAssertion: MPS1, Hurler
FamilyInfo: said to be from different families, but from the same region
CasePresentingHPOs:
CaseHPOFreeText: reduced/absent enzyme activity. IDUA enzyme activity in leukocytes= range from 0 to 2.47 nmol/h/mg protein (reference range: 28–92 nmol/h/mg protein) for the 85 patients in study, but no individual activity provided. No individual phenotype information given.
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: n/a
GenotypingMethod: intron/exon boundaries of the IDUA gene were analysed by PCR, SSCP and DNA sequencing
PreviouslyPublished: n/a
Variant: p.R628X homozygous
ClinVar: 550421
CAID: CA2802462
gnomAD: The highest population minor allele frequency in gnomAD v4.1.0. is 0.00005038 (2/39700 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).
SupplementalData: n/a
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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2Kuwait1.5M00.54p.Arg628* (c.1882C>T)p.Arg628*b,2 (c.1882C>T)
Case#: Patient 2, Kuwait, 1.5yo at report, male
DiseaseAssertion: MPS1
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: IDUA activity on DBS= 0 nmol/21 h*punch
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: n/a
GenotypingMethod: exon-specific PCR amplification of individual exons together with short flanking intronic sequences, followed by conventional Sanger sequencing
PreviouslyPublished:
Variant: p.Arg628* (c.1882C>T) homozygous
ClinVar: 550421
CAID: CA2802462
gnomAD: The highest population minor allele frequency in gnomAD v4.1.0. is 0.00005038 (2/39700 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).
SupplementalData: n/a
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www-sciencedirect-com.libproxy.lib.unc.edu www-sciencedirect-com.libproxy.lib.unc.edu
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R628XUGA C
Details on readthrough studies from fibroblast extracts from patients carrying the mutations. References a previous publication PMID: 15081804
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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In another study, Atçeken et al10 analyzed 15 patients with MPSI from Turkey. They used direct sequencing to determine the disease‐caused mutations in IDUA gene and identify nine new different pathologic variants (c.494‐1G > A, c.793‐6C > G, c.793‐5C > A, p.M1L, p.Y64X, p.A327P, p.W402X, p.P533L, and p.R628X).
This variant is mentioned in reference to a previously published report (PMID: 27511503)
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www.gimjournal.org www.gimjournal.org
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Table 2IDUA gene mutations detected in 22 patients with MPS I
Case#: Li Proband, US
DiseaseAssertion: MPS1 (Hurler)
FamilyInfo: n/a
CasePresentingHPOs: deficient IDUA activity in leukocyte, fibroblasts, or cultured trophoblasts. MPS IH defined as "organomegaly, heart disease, severe mental retardation, and death in childhood" but no individual phenotype information provided.
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: n/a
GenotypingMethod: mutation detection using reverse transcriptional polymerase chain reaction (RT-PCR) and genomic PCR sequencing. Polymorphism analyses were performed on controls by restriction enzyme assays of PCR amplicons flanking nine IDUA intragenic single nucleotide polymorphic alleles.
PreviouslyPublished: n/a
Variant: R628X; Q70X (path classification by LD VCEP). Also has Q33H(187G/T) polymorphism
ClinVar: 550421
CAID: CA2802462
gnomAD: The highest population minor allele frequency in gnomAD v4.1.0. is 0.00005038 (2/39700 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).
SupplementalData: n/a
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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15/FH/SInfancy/10m/12yYes/yes/yesDelayed++/++Systolic murmur 3–4/6Inguinal hernia, large tongue; after ERT: decreased illness (obstructive bronchitis), decreased excretion of GAGs in the urine, decreased organomegaly, increased mobilityp.Q70X, p.R628Xp.A8, p.A20, p.Q33H, p.L118
Case#: Vazna Patient #15, female, Czech Republic or Slovakia, onset in infancy, 10mo at dx, 12yo at report
DiseaseAssertion: MPS1, H/S
FamilyInfo:
CasePresentingHPOs: HP:0008301, HP:0002159, HP:0000280, HP:0000943, HP:0007957, HP:0004322, HP:0000256, HP:0001387, HP:0001263, HP:0001433, HP:0031664, HP:0000023, HP:0000158
CaseHPOFreeText: Deficiency of IDUA activity in leukocytes showed either no or very low residual enzyme activity (no exact amount specified), systolic murmur 3–4/6. After ERT: decreased illness (obstructive bronchitis), decreased excretion of GAGs in the urine, decreased organomegaly, increased mobility
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: n/a
GenotypingMethod: Direct sequencing of PCR products
PreviouslyPublished: n/a
Variant: p.Q70X (pathogenic); p.R628X. Compound heterozygosity was confirmed by analysis of parental samples. Also has p.A8, p.A20, p.Q33H, p.L118
ClinVar: 550421
CAID: CA2802462
gnomAD: The highest population minor allele frequency in gnomAD v4.1.0. is 0.00005038 (2/39700 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).
SupplementalData: n/a
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link-springer-com.libproxy.lib.unc.edu link-springer-com.libproxy.lib.unc.edu
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Since 2000 we have performed 54 HSCT procedures (on 44 children) for MPSIH at Manchester (Table 1). Of these, six (13.6 %) displayed significant cardiomyopathy at presentation. Interestingly three of these were from the same extended pedigree (from Kuwait), sharing the R628X IDUA gene mutation. All children were diagnosed within the first 4 months of life with dilated cardiomyopathy and significant LV functional impairment. Symptomatic cardiac failure was the predominant presenting feature in five children, with silent cardiomyopathy identified on screening echocardiography in the other. Median FS and EF at diagnosis were 12.5 % (range 3–20 %) and 35 % (15–40 %) respectively. Electrocardiography (ECG) patterns varied, but included strikingly tall QRS complexes consistent with LV enlargement/hypertrophy and evidence of myocardial ischaemia (ST segment depression; T wave inversion) in several cases. Further detailed cardiac investigation (including serum troponin) was rarely performed.
Case#: Patients 2 (male), 4 (male), and 5 (female). Kuwait. Onset between 1wk-3mo.
DiseaseAssertion: MPS I Hurler
FamilyInfo: Patients are from the same extended pedigree (family in Kuwait)
CasePresentingHPOs: α-L-iduronidase activity= 3.73 umol/g/hr (normal range 10–50) after commencing ERT. ERT for 9 wks. Congestive cardiac failure. LV fractional shortening=10%. LV ejection fraction=29%. HSCT at 17mo. α-L-iduronidase activity= 11.24 umol/g/hr (normal range 10–50) at follow up. GAG= 31.3 after transplant. Enzyme replacement therapy results in a significant reduction in urine GAGs (either total or heparan sulfate)
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod:
PreviouslyPublished: n/a
Variant: Arg628Ter homozygous. Proband was homozygous for this variant. 0 points (maximum for homozygous cases has already been reached)
ClinVar: 550421
CAID: CA2802462
SupplementalData: n/a
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Other MPS I-H nonsense mutations (W180X, Y343X, Q400X and R628X), harbored in the compound heterozygous state, were also challenged, resulting in relevant rescue upon treatment with the exception of the Y343X variant. The highest degree of functional rescue was observed for the R628X/W402X heterozygote, suggesting additive effects of the R628X mutation, whose sequence context (UGAC) is predicted to be highly susceptible to suppression over the unresponsive W402X [57].
This paper evaluated factors shaping the outcome of readthrough, namely the nucleotide and protein context, with the latter being pivotal to produce functional full-length proteins. This variant was mentioned as a MPS I-H nonsense mutation, but no new case or experimental information.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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To assess the characteristics and distribution of causal variants for Mendelian disorders in the ChinaMAP, we filtered the pathogenic variants with the annotation of ClinVar database (20180603)22,23 and HGMD (Human Gene Mutation Database, 2016.2),24 and further analyzed the disease-causing variants following the guidelines from the ACMG (American College of Medical Genetics and Genomics).25 A total of 2026 variants or 1619 variants in the HGMD DM set were annotated as pathogenic or likely pathogenic by the ClinVar or ACMG, respectively (Fig. 3c and Supplementary information, Table S7).
Database information for this variant was compiled on supplementary table s7, but no new case or experimental data.
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onlinelibrary-wiley-com.libproxy.lib.unc.edu onlinelibrary-wiley-com.libproxy.lib.unc.edu
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Molecular analysis was done for all 30 patients and a total of 22 different disease-causing variants were identified: p.Met1?, c.158+5delinsAA, p.Ala75Pro, p.Ala75Thr, p.Leu121Pro, p.Trp180*, p.Gly253Cys, p.His262Thrfs*55, p.Glu299*, p.Lys324Arg, c.972-1G>T, p.Thr366Argfs*73, p.Asn372Ser, p.Leu387Pro, c.1402+1G>A, p.Leu490Pro, p.Met504Arg, c.1524+1G>C, p.Gln587*, p.Arg619*, p.Arg621* and p.Ser633Leu (http://www.hgvs.org/mutnomen/recs.html) (Table 1).
This paper was listed in ClinVar, but only because it affects another residue (p.Ser633Leu) downstream which was mentioned in this paper.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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23W402XR628X
Case#: Coletti Patient 23, US
DiseaseAssertion: MPS1, Hurler
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: "diagnosis was confirmed by clinical phenotype and low IDUA activity in peripheral blood leukocytes." umbilical cord blood transplantation
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: n/a
GenotypingMethod: sequencing of the IDUA gene was performed, and mutations were confirmed by restriction fragment length analysis or allele-specific oligonucleotide analysis
PreviouslyPublished: n/a
Variant: W402X; R628X
ClinVar: 550421
CAID: CA2802462
gnomAD: The highest population minor allele frequency in gnomAD v4.1.0. is 0.00005038 (2/39700 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).
SupplementalData: n/a
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www-sciencedirect-com.libproxy.lib.unc.edu www-sciencedirect-com.libproxy.lib.unc.edu
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R628X/W402XgccTGAcca/ctcTAGgcc0.43±0.063.80±0.202.54±0.14
Case#: Hein Proband, Australian
DiseaseAssertion: MPS I, attenuated
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: IDUA activity=0.43±0.06 pmol/min per mg
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod:
PreviouslyPublished: n/a
Variant: R628X/W402X
ClinVar: 11908; 550421
CAID: CA220498; CA2802462
SupplementalData: n/s
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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550 years (M), 62 years (F)1/6Mahdia (Center)1st degreep.R628XHHurler[11]
Previously published in PMID: 21521498. Annotations on phenotype located on that paper.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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6Kwaitp.Arg628* (c.1882C>T)[27]
This variant was mentioned twice (no. 6 and 12) in reference to previously published cases of MPS1 in Middle Eastern populations.
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Nine different mutations (c.494-1G>A, c.793-6C>G, c.793-5C>A, p.M1L, p.Y64X, p.A327P, p.W402X, p.P533L, and p.R628X) were identified. Computational analysis results supported the pathogenicity of novel mutations, suggesting improper splicing. Seven already-known polymorphisms were detected in the screened cohort as well.
Article is a PDF, so annotating here.
Case#: Atceken Patient 10, Turkey
DiseaseAssertion: MPS1, Hurler
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: n/a
GenotypingMethod: All IDUA exons were amplified using intronic primers flanking the exonic nucleotide sequences by direct DNA sequencing of PCR products, segregation analysis
PreviouslyPublished: n/a
Variant: p.R628X homozygous
ClinVar: 550421
CAID: CA2802462
gnomAD: The highest population minor allele frequency in gnomAD v4.1.0. is 0.00005038 (2/39700 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).
SupplementalData: n/a
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onlinelibrary-wiley-com.libproxy.lib.unc.edu onlinelibrary-wiley-com.libproxy.lib.unc.edu
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p.Arg628Ter
This variant is mentioned as top recurrent variant and refers to several studies that have already been included in the curation. No new data.
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www-sciencedirect-com.libproxy.lib.unc.edu www-sciencedirect-com.libproxy.lib.unc.edu
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R628P0.10711913458Severe[38]Severe
This variant was mentioned as being previously published (PMID: 12559846). Structural changes for this variant were analyzed by calculating RMSD and predicted this variant to result in a severe phenotype. However, this type of prediction is not used by the LD VCEP.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Wiseman et al. [21].
Patients 2, 4, and 5 are all homozygous for this variant. Previously published in PMID: 22718273
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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R628Psevere
This paper uses in silico predictors to evaluate variants. Prediction is severe for this variant.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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p.Arg628Ter
This variant is mentioned in reference to previously published papers that report IEMs
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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R628X/R628X6 (1.6%)
Case#: Severe MPS1 patients, 6 individuals with this genotype
DiseaseAssertion: Severe MPS I
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: n/a
GenotypingMethod: n/a
PreviouslyPublished: possible
Variant: R628X/R628X
ClinVar: 550421
CAID: CA2802462
SupplementalData: Table S1 also lists this variant one time in compound heterozygosity with Q70X
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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2.1.14 year/MDistended abdomen, developmental delayNo − PathogenicIDUAc.1882C > Tp. Arg628TerHomMPS I
Case#: Patient 2.1.1, male, 4yo, Indian
DiseaseAssertion: MPS1
FamilyInfo: No family history reported, but said not to be consanguineous
CasePresentingHPOs:
CaseHPOFreeText: Distended abdomen, developmental delay
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: NGS, Sanger
PreviouslyPublished:
Variant: c.1882C > T p. Arg628Ter homozygous
ClinVar: 550421
CAID: CA2802462
SupplementalData: n/a
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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In this study we report the first development of a denaturating high performance liquid chromatography (dHPLC) protocol for the rapid and accurate detection of recently described mutations in the IDUA gene. Optimal PCR running and dHPLC partial denaturing conditions for mutation detection were established for each PCR amplicon corresponding to 14 IDUA exons and their adjacent intronic/flanking sequences. Results: A total of 12 different mutations, 5 nonsense, 4 missense, 1 deletion, and 2 splice site (intron), in 10 MPS I patients were screened. All mutations revealed a distinct dHPLC pattern thus enabling their accurate detection.
This proband was "described and recently published by Vazna et al." (PMID: 19396826). Patient is compound heterozygous for c.1882C>T (p.Arg628Ter) and c.208C>T (p.Gln70Ter) (P based on classification by the ClinGen Lysosomal Diseases VCEP); phase confirmed in trans. PM3=0 points
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