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

Case# A13, male, 7

CasePresentingHPOs HP:0003124 Hypercholesterolemia

CasePreviousTesting The APOB domains, including amino acids 2955–3092 and amino acids 3303–3492, were analysed in the 600 molecularly undefined ADH cases by direct Sanger sequencing

CaseMethod1 as mentioned

CaseMethod2 as mentioned

CaseGenotypingMethod Exome sequencing

Variant NM_000384.2(APOB):c.9175C>T (p.Arg3059Cys)

ClinVar 69508

gnomAD 0.00003249 link

VariantEvidence Deficient LDL uptake (fig. 2)

Case#: KMP 8, female, 60 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic, LVOTO yes; LVEF 55-60%; ECG; echocardiography;

CaseNotHPOs: n/a

CaseNotHPOFreeText: no ICD

CasePreviousTesting: Additional Sanger sequencing of exons 12, 24, 25 of MYBPC3, exon 12 NEBL, exons 12, 20, 21 of SCN5A, exon 7 of TNNI3, and exon 9 of TNNT2 gene

CaseGenotypingMethod: Sanger sequencing;

Variant: NM_000257.4(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093 https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

CAID: n/a

gnomAD: absent

MultipleGeneVariants:

(1) SCN5A Variant:

Variant: NM_198056.2(SCN5A):c.3784G>A (p.Gly1262Ser)

ClinVar: 9399 https://www.ncbi.nlm.nih.gov/clinvar/variation/9399/

CAID: n/a

gnomAD: 0.0001307 South Asian https://gnomad.broadinstitute.org/variant/3-38607956-C-T

Case#: KMP 4, female, 69 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic; LVEF 60%; NYHA II.-III.; ECG; echocardiography;

CaseNotHPOs: n/a

CaseNotHPOFreeText: no LVOTO; no ICD

CasePreviousTesting: Additional Sanger sequencing of exons 12, 24, 25 of MYBPC3, exon 12 NEBL, exons 12, 20, 21 of SCN5A, exon 7 of TNNI3, and exon 9 of TNNT2 gene

CaseGenotypingMethod: Sanger sequencing;

Variant: NM_000257.4(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093 https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

CAID: n/a

gnomAD: absent

Case#: KMP 22, male, 21 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic; LVEF 60%; ICD yes; ECG; echocardiography;

CaseNotHPOs: n/a

CaseNotHPOFreeText: no LVOTO

CasePreviousTesting: Additional Sanger sequencing of exons 12, 24, 25 of MYBPC3, exon 12 NEBL, exons 12, 20, 21 of SCN5A, exon 7 of TNNI3, and exon 9 of TNNT2 gene

CaseGenotypingMethod: Sanger sequencing;

Variant: NM_000257.4(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093 https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

CAID: n/a

gnomAD: absent

Case#: KMP 18, female, 71 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic; LVEF 60%; NYHA I.-II.; ECG; echocardiography;

CaseNotHPOs: n/a

CaseNotHPOFreeText: no LVOTO; no ICD

CasePreviousTesting: Additional Sanger sequencing of exons 12, 24, 25 of MYBPC3, exon 12 NEBL, exons 12, 20, 21 of SCN5A, exon 7 of TNNI3, and exon 9 of TNNT2 gene

CaseGenotypingMethod: Sanger sequencing;

Variant: NM_000257.4(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093 https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

CAID: n/a

gnomAD: absent

Case# Subject 8, male, 10yo, European

CasePresentingHPOs HP:0011968, HP:0002033, HP:0002360, HP:0002020, HP:0011848, HP:0000483, HP:0000349, HP:0000494, HP:0011230, HP:0000347, HP:0000691, HP:0003186, HP:0200055, HP:0004209, HP:0010862, HP:0000750, HP:0000729, HP:0007018, (Poor feeding, Poor suck, Difficulty sleeping, Gastroesophageal reflux, Abnormal colic, Astigmatism, Widow's peak, Downslanted palpebral fissures, Laterally extended eyebrow, Micrognathia, Microdontia, Small hands, 5th finger clinodactyly, Fine motor delay, Speech delay, Autisim spectrum disorder, ADHD

HPOFreeText: Poor latch and suck, narrow dental arches, small lower arch teeth and other phenotypes reported postnatally. Fine motor delay, speech delay, autistic spectrum, and ADHD reported at 11 months. Brain MRI normal.

CaseNotHPOs HP:0001250, HP:0001252, HP:0000708, HP:0001285, HP:0001273, HP:0006808, HP:0002334, HP:0002119, HP:0007361, HP:0025100, HP:0030301, HP:0012448, HP:0000589, HP:0000648, HP:0000568, HP:0000659, HP:0000525, HP:0000581, HP:0000407, HP:0000453, HP:0410030, HP:0001629, HP:0001655, HP:0001643, HP:0010772, HP:0002247, HP:0001734, HP:0002021, HP:0000076, HP:0000107, HP:0000047, HP:0000028, HP:0001159, HP:0001385, HP:0002650, HP:0002938, HP:0001511, HP:0000098, HP:0004322, HP:0000256, HP:0000252, HP:0011328, HP:0002007, HP:0000325, HP:0000601, HP:0000316, HP:0000582, HP:0045025, HP:0000286, HP:0000490, HP:0000598, HP:0004467, HP:0000414, HP:0000463, HP:0000319, HP:0012471, HP:0000160, HP:0000221, HP:0000187, HP:0000218, HP:0002557, HP:0011297, HP:0001792, HP:0010490, HP:0004532, HP:0000957, (Seizures, Hypotonia, Behavioral problems, Spastic quadriparesis, Abnormal Corpus Callosum, Cerebral hypomyelination, Abnormality of cerebellar vermis, Ventriculomegaly, Abnormality of the pons, Abnormal morphology of the hippocampus, Abnormality of the anterior commissure, Delayed myelination, Coloboma, Optic atrophy, Microphthalmia, Peter's anomaly, Iris anomalies, Blepharophimosis, Sensorineural hearing loss, Choanal atresia, Cleft lip, Ventricular septal defect, Patent foramen ovale, Patent ductus arteriosus, Anomalous pulmonary venous return, Duodenal atresia, Annular pancreas, Pyloric stenosis, Vesicoureteral reflux, Cystic kidney, Hypospadias, Cryptorchidism, Syndactyly, Hip dysplasia, Scoliosis, Lumbar lordosis, Intrauterine growth retardation, Tall stature, Short stature, Macrocephaly, Microcephaly, Fontanel abnormality, Frontal bossing, Triangular face, Hypotelorism, Hypertelorism, Upslanting palpebral fissures, Small palpebral fissures, Epicanthal folds, Deeply set eyes, Abnormal ears, Preauricular pits, Bulbous nose, Anteverted nares, Flat philtrum, Full lips, Small mouth, Furrowed tongue, Broad alveolar ridges, High-arched palate, Small nipples, Digital Anomalies, Nail hypoplasia, Abnormal palmar creases, Sacral hypertrichosis, Café Au Lait spots)

CasePreviousTesting n/a

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with sanger

Variant NM_012102.3(RERE):c.1104delA, (p.Leu369Cysfs∗16)

CAID CA658820843

gnomAD n/a

VariantEvidence n/a

CaseAddInfo No paternal DNA to prove de novo status, variant suspected to trigger NMD

CasePMIDs n/a

Case# Subject 7, male, 11yo, Dutch

CasePresentingHPOs HP:0410030, HP:0001263, HP:0001252, HP:0000494, HP:0000954, HP:0007018, HP:0001256, HP:0001273, HP:0030301, HP:0006808, HP:0011968, HP:0004322, HP:0000252 (Cleft lip, Developmental delay, Hypotonia, Down-slanting palpebral fissures, Single palmar crease, ADHD, Mild intellectual disability, Abnormal Corpus Callosum, Abnormality of the anterior commissure, Cerebral hypomyelination, Poor feeding, Short Stature, Microcephaly)

HPOFreeText: Phenotypes recorded postnatally. Brain MRI at 7 years showed phenotypes including small anterior commissure and blunting of rostrum.

CaseNotHPOs HP:0001250, HP:0000708, HP:0001285, HP:0002334, HP:0002119, HP:0007361, HP:0025100, HP:0012448, HP:0000589, HP:0000648, HP:0000568, HP:0000659, HP:0000525, HP:0000581, HP:0000407, HP:0000453, HP:0001629, HP:0001655, HP:0001643, HP:0010772, HP:0002020, HP:0002247, HP:0001734, HP:0002021, HP:0000076, HP:0000107, HP:0000047, HP:0000028, HP:0001159, HP:0001385, HP:0002650, HP:0002938, HP:0001511, HP:0000098, HP:0000256, HP:0011328, HP:0002007, HP:0000325, HP:0000534, HP:0000601, HP:0000316, HP:0000582, HP:0045025, HP:0000286, HP:0000490, HP:0000598, HP:0004467, HP:0000414, HP:0000463, HP:0000319, HP:0012471, HP:0000160, HP:0000221, HP:0000164, HP:0000187, HP:0000218, HP:0000347, HP:0002557, HP:0003186, HP:0200055, HP:0004209, HP:0011297, HP:0001792, HP:0000349, HP:0004532, HP:0000957 (Seizures, Behavioral problems, Spastic quadriparesis, Abnormality of cerebellar vermis, Ventriculomegaly, Abnormality of the pons, Abnormal morphology of the hippocampus, Delayed myelination, Coloboma, Optic atrophy, Microphthalmia, Peter's anomaly, Iris anomalies, Blepharophimosis, Sensorineural hearing loss, Choanal atresia, Ventricular septal defect, Patent foramen ovale, Patent ductus arteriosus, Anomalous pulmonary venous return, Gastroesophageal reflux, Duodenal atresia, Annular pancreas, Pyloric stenosis, Vesicoureteral reflux, Cystic kidney, Hypospadias, Cryptorchidism, Syndactyly, Hip dysplasia, Scoliosis, Lumbar lordosis, Intrauterine growth retardation, Tall stature, Macrocephaly, Fontanel abnormality, Frontal bossing, Triangular face, Abnormal eyebrows, Hypotelorism, Hypertelorism, Upslanting palpebral fissures, Small palpebral fissures, Epicanthal folds, Deeply set eyes, Abnormal ears, Preauricular pits, Bulbous nose, Anteverted nares, Flat philtrum, Full lips, Small mouth, Furrowed tongue, Abnormal teeth, Broad alveolar ridges, High-arched palate, Micrognathia, Small nipples, Inverted nipples, Small hands, 5th finger clinodactyly, Digital Anomalies, Nail hypoplasia, Widow's peak, Sacral hypertrichosis, Café Au Lait spots)

CasePreviousTesting Tested negative for presence of de novo c.3382_3383delGA variant in ANKRD11 that twin sister had.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES results confirmed with sanger sequencing in patient and parents

Variant NM_012102.3:c.1411G>A(p.Val471Ile), de novo

ClinVar n/a

CAID CA571729

gnomAD 0.0001824(other), 0.00002032(total)

VariantEvidence n/a

CaseAddInfo Compound heterozygous for a frameshift and missense variant in FSIP2, encodes a sperm flagellum protein and is not currently associated with a human disease. Healthy older sister, but twin sister has KBG syndrome brought on by de novo deletion variant in ANKRD11 gene.

CasePMIDs n/a

Case# Subject 6, female, 6yo, Northern European/Hispanic

CasePresentingHPOs HP:0001263, HP:0001252, HP:0002938, HP:0000256, HP:0000325, HP:0000316, HP:0045075, HP:0011229, HP:0000368, HP:0000463, HP:0000319, HP:0012170, HP:0012168, HP:0001270, HP:0000750, HP:0000708, HP:0002311, HP:0000316, HP:0200055, HP:0011297 (Global developmental delay, Hypotonia, Lumbar lordosis, Macrocephaly, Triangular face, Sparse eyebrows, Broad eyebrows, Low-set-posteriorly rotated ears, Anteverted nares, Flat philtrum, Nail biting, Head bainging, Motor delay, Speech delay, Behavioral problems, Diifficulties in Coordination, Hypertelorism, Small hands, Digital anomalies)

HPOFreeText: Speech and motor delay noted at 2 years. Mildly flattened philtrum and remaining phenotypes presented postnatally.

CaseNotHPOs HP:0001250, HP:0001285, HP:0007018, HP:0011968, HP:0000589, HP:0000648, HP:0000568, HP:0000659, HP:0000525, HP:0000581, HP:0000407, HP:0000453, HP:0410030, HP:0001629, HP:0001655, HP:0001643, HP:0010772, HP:0002020, HP:0002247, HP:0001734, HP:0002021, HP:0000076, HP:0000107, HP:0001159, HP:0001385, HP:0002650, HP:0001511, HP:0000098, HP:0004322, HP:0000252, HP:0011328, HP:0002007, HP:0000601, HP:0000582, HP:0000494, HP:0045025, HP:0000286, HP:0000490, HP:0004467, HP:0000414, HP:0012471, HP:0000160, HP:0000221, HP:0000164, HP:0000187, HP:0000218, HP:0000347, HP:0002557, HP:0003186, HP:0200055, HP:0004209, HP:0011297, HP:0001792, HP:0000349, HP:0004532, HP:0000957 (Seizures, Spastic quadriparesis, ADHD, Poor feeding, Coloboma, Optic Atrophy, Microphthalmia, Peter's anomaly, Iris abnormality, Blepharophimosis, Senseorineural hearing loss, Choanal atresia, Cleft lip, Ventricular septal defect, Patent foramen ovale, Patent ductus arteriosus, Anomalous pulmonary venous return, Gastroesophageal reflux, Duodenal atresia, Annular pancreas, Pyloric stenosis, Vesicoureteral reflux, Cystic kidneys, Syndactyly, Hip dysplasia, Scoliosis, Intrauterine growth retardation, Tall stature, Short stature, Microcephaly, Fontanel abnormality, Frontal bossing, Hypotelorism, Upslanted palpebral fissures, Downslanted palpebral fissures, small palpebral fissures, Epicanthus, Deep set eyes, Preauricular pits, Bulbous nose, Full lips, Small mouth, Furrowed tongue, Abnormal teeth, Broad alveolar ridges, High-arched palate, Micrognathia, Small nipple, Inverted nipples, Small hands, Clinodactyly of the 5th finger, Digital anomalies, Nail hypoplasia, Widow's peak, Sacral hypertrichosis, Cafe-au-lait spots)

CasePreviousTesting n/a

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES results confirmer with sanger

Variant NM_012102.3:c.3122delC(p.Pro1041Lysfs∗40)

ClinVar n/a

CAID CA658820831

gnomAD n/a

VariantEvidence n/a

CaseAddInfo unknown if de novo like the rest, no parent testing. Family history of intellectual disability and mental illness also suggests it may not be de novo. Speculated that due to deletion being in exon 17 or 21 that NMD will occur.

CasePMIDs n/a

Case# Subject 4, female, 9yo, Northern European

CasePresentingHPOs HP:0001252, HP:0002342, HP:0001250, HP:0001999, HP:0002020, HP:0001385, HP:0000076, HP:0002079, HP:0001320, HP:0006808, HP:0001943, HP:0005968, HP:0000490, HP:0000286, HP:0000356, HP:0000221, HP:0010490, HP:0011304, HP:0001156, HP:0000708, (Hypotonia, Moderate intellectual disability, Seizures, Dysmorphic facies, Gastroesophageal reflux, Hip dysplasia, Vesicoureteral reflux, Thin corpus callosum, Cerebellar vermis hypoplasia, Cerebral hypomyelination, Hypoglycemia, Temperature instability, Deep set eyes, Epicanthus, Auricle abnormality, Furrowed tongue, Abnormal palmar creases, broad thumbs, Brachydactyly, Behavioral problems)

HPOFreeText: Fleshy auricles, deep furrow in posterior third of tongue, bilateral single palmar creases, mild brachydactyly, developmental hip dysplasia, severe vesicoureteral reflux, severe behavioral issues and other phenotypes are postnatal. Brain MRI results including diminished cerebellar vermis with deep fissures at 1 year of age.

CaseNotHPOs HP:0001285, HP:0007018, HP:0011968, HP:0002119, HP:0007361, HP:0025100, HP:0030301, HP:0012448, HP:0000589, HP:0000648, HP:0000568, HP:0000659, HP:0000525, HP:0000581, HP:0000407, HP:0000453, HP:0410030, HP:0001629, HP:0001655, HP:0001643, HP:0010772, HP:0002247, HP:0001734, HP:0002021, HP:0000107, HP:0001159, HP:0002650, HP:0002938, HP:0001511, HP:0000098, HP:0004322, HP:0000256, HP:0000252, HP:0011328, HP:0002007, HP:0000325, HP:0000534, HP:0000601, HP:0000316, HP:0000582, HP:0000494, HP:0045025, HP:0004467, HP:0000414, HP:0000463, HP:0000319, HP:0012471, HP:0000160, HP:0000164, HP:0000187, HP:0000218, HP:0000347, HP:0002557, HP:0003186, HP:0200055, HP:0004209, HP:0001792, HP:0000349, HP:0004532, HP:0000957 (Spastic quadriparesis, ADHD, Poor feeding, Ventriculomegaly, Abnormality of the pons, Abnormal morphology of the hippocampus, Abnormality of the anterior commissure, Delayed myelination, Coloboma, Optic atrophy, Microphthalmia, Peter's anomaly, Iris anomalies,Blepharophimosis, Sensorineural hearing loss, Choanal atresia, Cleft lip, Ventricular septal defect, Patent foramen ovale, Patent ductus arteriosus, Anomalous pulmonary venous return, Duodenal atresia, Annular pancreas, Pyloric stenosis, Cystic kidney, Syndactyly, Scoliosis, Lumbar lordosis, Intrauterine growth retardation, Tall stature, Short stature, Macrocephaly, Microcephaly, Fontanel abnormality, Frontal bossing, Triangular face, Abnormal eyebrows, Hypotelorism, Hypertelorism, Upslanting palpebral fissures, Down-slanting palpebral fissures, Small palpebral fissures, Preauricular pits, Bulbous nose, Anteverted nares, Flat philtrum, Full lips, Small mouth, Abnormal teeth, Broad alveolar ridges, High-arched palate, Micrognathia, Small nipples, Inverted nipples, Small hands, 5th finger clinodactyly, Nail hypoplasia, Widow's peak, Sacral hypertrichosis, Café Au Lait spots)

CasePreviousTesting n/a

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES results confirmed with Sanger in pateint and parents

Variant NM_012102.3:c.4293C>G(p.His1431Gln), de novo

ClinVar n/a

CAID CA338168808

gnomAD n/a

VariantEvidence n/a

CaseAddInfo mosaic, de novo SCN2A missense variant. SCN2A associated with 613721 and 607745

CasePMIDs n/a

Case3: Female, Italy, 7 yrs report

CasePresentingHPOs: HP:0003798, HP:0003325, HP:0001270, HP:0002093, HP:0002650, HP:0002355, HP:0003324, HP:0001283, HP:0003306 (Nemaline bodies, Limb-girdle muscle weakness, Motor delay, Respiratory impairment, Scoliosis, Difficulty walking, Generalized muscle weakness, Bulbar palsy, Spinal rigidity)

HPOsFreeText: Semi-solid diet

CaseNotHPOs: HP:0003560, HP:0003715, HP:0001627, HP:0000602, HP:0001557, HP:0001290 (Muscular dystrophy, Myofibrillar myopathy, Cardiac abnormality, Ophthalmoplegia, Prenatal movement abnormality, Hypotonia)

NotHPOsFreeText: Congenital myasthenic syndromes

CaseAddInfo: Intermediate NM presentation, Parental segregation was confirmed, Variant 2 creates a new splicing donor site and activates an upstream acceptor site which partially expresses intron 125 and causes a premature termination codon

CasePreviousTesting: ACTA1, TPM2 and TPM3 mutations were ruled out via amplification and direct sequencing

CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood leukocytes or fibroblasts. 183 exons of NEB, the relative introns, and the full promoter region was captured via litigation-mediated PCR and high-throughput sequencing of resulting fragments. These were then aligned and filtered for inheritance and pathogenicity. Variants were evaluated for amino acid conservation and confirmed by Sanger sequencing.

Variant1: NM_001271208.2:c.24559C>T (p.Arg8187Ter)

ClinVar: 496135 https://www.ncbi.nlm.nih.gov/clinvar/variation/496135/

gnomAD: Not in gnomAD

Variant2: NM_001271208.1:c.19429-381_19429-379delinsA (p.=)

CAID: CA913203565 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913203565

gnomAD: Not in gnomAD

Case2: Male, Italy, Birth onset

CasePresentingHPOs: HP:0003798, HP:0002033, HP:0003325, HP:0001558, HP:0001270, HP:0002093, HP:0000194, HP:0006830, HP:0003701, HP:0002650, HP:0003458 (Nemaline bodies, Poor suck, Limb-girdle muscle weakness, Decreased fetal movement, Motor delay, Respiratory impairment, Open mouth, Congenital hypotonia, Proximal muscle weakness, Scoliosis, EMG: myopathic abnormalities)

HPOsFreeText: Wheelchair dependent

CaseNotHPOs: HP:0003560, HP:0003715, HP:0001627, HP:0000602, HP:0001283, HP:0003306 (Muscular dystrophy, Myofibrillar myopathy, Cardiac abnormality, Ophthalmoplegia, Bulbar palsy, Spinal rigidity)

NotHPOsFreeText: Congenital myasthenic syndromes

CaseAddInfo: Intermediate NM presentation, Parental segregation was confirmed

CasePreviousTesting: ACTA1, TPM2 and TPM3 mutations were ruled out via amplification and direct sequencing

CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood leukocytes or fibroblasts. 183 exons of NEB, the relative introns, and the full promoter region was captured via litigation-mediated PCR and high-throughput sequencing of resulting fragments. These were then aligned and filtered for inheritance and pathogenicity. Variants were evaluated for amino acid conservation and confirmed by Sanger sequencing.

Variant1: NM_001164507.1:c.17737-2A>T (p.=)

CAID: CA348804839 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_001271208.2%3Ac.17737-2A%3ET

gnomAD: Not in gnomAD

Variant2: NM_001271208.1:c.21423del (p.Lys7141Asnfs*23)

CAID: CA913203564 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913203564

gnomAD: Not in gnomAD

Case#: Consequence 32 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.788T>C (p.Ile263Thr)

ClinVar: 43106 https://www.ncbi.nlm.nih.gov/clinvar/variation/43106/

CAID: n/a

gnomAD: 0.000008792 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23900635-A-G

Case#: Consequence 27 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.2609G>A (p.Arg870His)

ClinVar: 14120 https://www.ncbi.nlm.nih.gov/clinvar/variation/14120/

CAID: n/a

gnomAD: 0.00001549 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23894048-C-T

Case#: Consequence 19 Table 1 in Data Supplement (2 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.1491G>T (p.Glu497Asp)

ClinVar: 14124 https://www.ncbi.nlm.nih.gov/clinvar/variation/14124/

CAID: n/a

gnomAD: 0.0001984 Ashkenazi Jewish https://gnomad.broadinstitute.org/variant/14-23897796-C-A

Case#: Consequence 15 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.2167C>T (p.Arg723Cys)

ClinVar: 14095 https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/

CAID: n/a

gnomAD: 0.00003266 South Asian https://gnomad.broadinstitute.org/variant/14-23895023-G-A

Case#: Consequence 10 Table 1 in Data Supplement (2 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.1816G>A (p.Val606Met)

ClinVar: 14091 https://www.ncbi.nlm.nih.gov/clinvar/variation/14091/

CAID: n/a

gnomAD: 0.00001548 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23896866-C-T

Case: Family B Proband BII-3, male, Arabic, Israeli, 19yo at report

CasePresentingHPOs: HP:0000953, HP:0030053, HP:0000998, HP:0002619, HP:0002240, HP:0001629, HP:0000365, HP:0007380

CasePresentingHPOsFreeText: Dilated scleral vessels, MRI of the lower limbs demonstrated severe, symmetric, diffuse infiltration of the subcutaneous fat of the lower limbs, showing low signal in T1 and high signal intensity in T2 and fat suppressed–weighted images.

CaseNOTHPOs: HP:0008064, HP:0000054, HP:0000520, HP:0012385

CaseNOTHPOSFreeText: scrotal masses

CasePreviousTesting: direct sequencing of AIFM2, ADAMTS14, EIF4EBP2, C10ORF54, PPA1, H2AFY2, LRRC20, NODAL, PRF1, TYSND1, SAR1A, PSAP, NPFFR1, and C10ORF27

CaseGenotypingMethod: microarray, haplotype analysis, direct sequencing of exons of SLC29A3

Variant: G427S homozygous

ClinVarID: or CAID: 563/CA114349

gnomAD: The missense variant G427S is present in gnomAD v4.0.0 with a MAF=0.00005339 (4/74926 alleles) in the African/African American population and 0 homozygotes.

AddCaseInfo: parents were consanguineous, heterozygous. brother (BII-4) is also genotype/phenotype +

PreviouslyPublished: PMID: 18410979

VariantEvidence: Functional studies in Xenopus oocytes demonstrated that G427S results in a total loss of transport activity (Kang et al. 2010; PMID: 20595384).

Case: Family F Proband FII-6, female, Arabic, Israeli, 27yo at report

CasePresentingHPOs: HP:0000953, HP:0030053, HP:0000998, HP:0002619, HP:0000520, HP:0007380, HP:0100324, HP:0100727

CasePresentingHPOsFreeText: dilated scleral vessels

CaseNOTHPOs: HP:0008064, HP:0001433, HP:0011025, HP:0000365, HP:0012385

CaseNOTHPOSFreeText:

CasePreviousTesting: direct sequencing of AIFM2, ADAMTS14, EIF4EBP2, C10ORF54, PPA1, H2AFY2, LRRC20, NODAL, PRF1, TYSND1, SAR1A, PSAP, NPFFR1, and C10ORF27

CaseGenotypingMethod: microarray, haplotype analysis, direct sequencing of exons of SLC29A3, restriction digestion

Variant: G437R homozygous

ClinVarID: or CAID: 565/CA114352

gnomAD: The missense variant G437R is present in gnomAD v4.0.0 with a MAF=0.00006666 (4/60002 alleles) in the Admixed American population and 0 homozygotes.

AddCaseInfo: consanguineous parents, not genotyped. brother (FII-5) is het and unaffected.

PreviouslyPublished: PMID: 18410979

VariantEvidence: Kang et al. (2010; PMID: 20595384) performed functional characterization of the G437R mutation in Xenopus oocytes and observed transport activity that was approximately half that of wildtype SLC29A3. Studies in NIH 3T3 fibroblasts demonstrated accelerated turnover of the G437R mutant compared to wildtype, suggesting decreased stability.

Case# A3054-21, Macedonian, Male, 5yr age of onset

CasePresentingHPOs HP:0001919, HP:0000121, HP:0000074

CasePreviousTesting 30 genes previously linked to nephrolithiasis were screened by exon sequencing in these individuals, but no causative mutations were detected

CaseMethod1 NGS

CaseGenotypingMethod list of 18 hypothetical candidate genes and performed exon amplification with consecutive next-generation sequencing in a multicenter cohort of 348 individuals with nephrolithiasis or isolated nephrocalcinosis

Variant NM_134425.2(SLC26A1):c.554C>T (p.Thr185Met), NM_022042.3(SLC26A1):c.1073C>T (p.Ser358Leu)

ClinVar 242374, 242375

gnomAD 0.0004342, 0.0005655

VariantEvidence Immunofluorescence of SLC26A1 protein, when overexpressed in HEK293 cells, showed that p.Thr185Met causes protein to fail to reach plasma membrane (Figure 2). Monitoring of intracellular pH showed that p.Thr185Met has severely reduced activity (Figure 4). PCR of slc26a1 transcript in H293K cells showed no change in amount of transcript suggesting that the low p.Ser363Leu band levels in the immunoblot (Figure 3) were due to low portein stability.

Case# B641-12, "European," Male

CasePresentingHPOs HP:0000787

CaseNotHPOs HP:0003159

CasePreviousTesting 30 genes previously linked to nephrolithiasis were screened by exon sequencing in these individuals, but no causative mutations were detected

CaseMethod1 NGS

CaseGenotypingMethod list of 18 hypothetical candidate genes and performed exon amplification with consecutive next-generation sequencing in a multicenter cohort of 348 individuals with nephrolithiasis or isolated nephrocalcinosis

Variant NM_134425.2(SLC26A1):c.166G>A (p.Ala56Thr)

ClinVar 242376

gnomAD 0.0005655

VariantEvidence Monitoring of intracellular pH in transfected HEK293 demonstrated that p.Ala56Thr had reduced anion exchange activity. (Figure 4)

CaseAddInfo homozygous, consanguineous parents

NM_017819.3(TRMT10C):c.542G>T (p.Arg181Leu)

ClinVar 224316

CAID CA2520544

gnomAD 0.0003508(Latino), 0.0001121(Total)

Case1: Male, Birth onset

CasePresentingHPOs: HP:0008936, HP:0002058, HP:0200096, HP:0000218, HP:0000774, HP:0005957, HP:0001290, HP:0001284, HP:0002938, HP:0003324, HP:0009046, HP:0008994, HP:0009027, HP:0003722, HP:0002650, HP:0000278, HP:0001724, HP:0002792, HP:0002877, HP:0003557, HP:0100299, HP:0003803 (Muscular hypotonia of the trunk, Myopathic facies, Triangular-shaped open mouth, High-arched palate, Narrow chest, Abnormal breathing, Generalized hypotonia, Areflexia, Exaggerated lumbar lordosis, Generalized muscle weakness, Difficulty running, Proximal muscle weakness in lower limbs, Foot dorsiflexor weakness, Neck flexor weakness, Scoliosis, Retrognathia, Aortic dilatation, Reduced vital capacity, Nocturnal hypoventilation, Increased variation in fiber size, Muscle fiber inclusion bodies, Type 1 muscle fiber predominance)

HPOsFreeText: Crawled at age 10 months and walked independently at age 15 months, Inability to jump, PVC was 37% of predicted, BiPAP commenced at age 20, Cap-like structures

CaseNotHPOs: HP:0003115, HP:0003798 (Abnormal ECG, Nemaline bodies)

NotHPOsFreeText: N/A

CaseAddInfo: No family history of muscle weakness, Variant is de novo and confirmed absent in the parents

CasePreviousTesting: Tested caps appeared pale on all myosin ATPase stains and dark on Gomori Trichrome and NADH stains and were strongly reactive for troponin T, α-actinin-2, myotilin, tropomyosin, actin and desmin by immunoperoxidase, No positive staining for neonatal or embryonic myosin isoforms, Large regions of disorganised thin filament structures containing Z band remnants were present in subsarcolemmal positions

CaseGenotypingMethod: Bidirectional sequencing on TPM2 and TPM3 for all exons and exon-intron boundaries was performed using genomic DNA.

Variant: NM_152263.4(TPM3):c.502C>T (p.Arg168Cys)

ClinVar: 12454 https://www.ncbi.nlm.nih.gov/clinvar/variation/12454/

gnomAD: Not in gnomAD

Case# F2:II-4, 18mo diagnosis, M, Finnish

CasePresentingHPOs HP:0001873, HP:0011950, HP:0001875, HP:0000639, HP:0002141, HP:0001387, HP:0002395, HP:0002863, HP:0002721, HP:0007018, HP:0001310, HP:0002172

HPO free text: "Thrombocytopenia at 2 mo followed by trilineage cytopenia at 14 mo of age. Bronchiolitis at 6 wk and varicella infection at 4 mo of age, both requiring hospitalization; recurrent otitis and laryngitis before the HSCT. MDS −7 at 18 mo of age; normal bone marrow cellularity and dysplastic megakaryocytes and clear myelodysplasia in the megakaryopoiesis." Hb[82-128(28/90) vs 117-122], MCV[73-90(82-98) vs 82-98], Platlets[37-444(32/90) vs 150-360], WBC[2.5-12.3(61-90) vs 3.4-8.2]

CasePreviousTesting Absolute lymphocyte counts and assays of cytotoxic lymphocyte phenotype and function. Hemoglobin(82-128[28/90 abnormal readings/total readings] vs 117-122 normal), Platelets(37-444[32/90] vs 150-360), WBC(2.5-12.3[61/90] vs 3.4-8.2), MCV(73-90[15/90] vs 117-122).

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES then confirmed variant with Sanger

Variant NM_152703.4(SAMD9L):c.2672T>C (p.Ile891Thr)

ClinVar 446529

VariantEvidence (Figure 5) 293FT cells transfected with p.Ile891Thr showed more limited cell proliferation than WT SAMD9L

CaseAddInfo Uniparental Disomy of WT allele in patient

CasePMIDs 28852709

CaseIV-3: Female, 5 years, Turkey

CasePresentingHPOs: HP:0004912, HP:0004322, HP:0002970 (Hypophosphatemic rickets, Short stature, Genu varum)

HPOsFreeText: -3.33 standard deviation score

CaseNotHPOs: HP:0000083, HP:0002024, HP:0001947 (Renal failure, Malabsorption, Renal tubular acidosis)

NotHPOsFreeText: Other tubulopathies that cause secondary hypophosphatemia, Vitamin D-dependent rickets type 1 and 2

CaseAddInfo: Variant is asserted de novo and confirmed with parental testing, Variant is a splice donor-site mutation that skips exon 14

CasePreviousTesting: Calcium levels (9.4 mg/dL), Decreased serum phosphate levels (2.0 mg/dL; reference 3.7-5.6), Elevated serum ALP (559 IU/L; reference 90-325), 25OHD3 levels (28.3 ng/ml), 1,25(OH)2D3 levels (N/A pg/mL), PTH levels (138 ng/L), TPR levels (79.6), Decreased TmP/GFR levels (1.59; reference 2.9-6.1)

CaseGenotypingMethod: Genomic DNA was isolated from peripheral blood leukocytes, amplified, and directly sequenced in all the coding exons and intron-exon boundaries of PHEX. If no mutations were found, FGF23 followed by consecutive analysis of DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1 was performed. Significance of found mutations was predicted by computational programs and sorted.

Variant: NM_000444.5:c.1586+2T>G

CAID: CA412575011 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000444.5%3Ac.1586%2B2T%3EG

gnomAD: Not in gnomAD

CaseXIV-3: Female, 2.7 years, Turkey

CasePresentingHPOs: HP:0004912, HP:0004322, HP:0002970 (Hypophosphatemic rickets, Short stature, Genu varum)

HPOsFreeText: -2.01 standard deviation score

CaseNotHPOs: HP:0000083, HP:0002024, HP:0001947 (Renal failure, Malabsorption, Renal tubular acidosis)

NotHPOsFreeText: Other tubulopathies that cause secondary hypophosphatemia, Vitamin D-dependent rickets type 1 and 2

CaseAddInfo: Proband's mother shares the mutation and disease, Variant is at a splice donor site in intron 12

CasePreviousTesting: Calcium levels (9.4 mg/dL), Decreased serum phosphate levels (2.2 mg/dL; reference 3.8-6.5), Elevated serum ALP (364 IU/L; reference 90-325), 25OHD3 levels (27 ng/ml), PTH levels (49 ng/L), TPR levels (75), Decreased TmP/GFR levels (1.65; reference 2.9-6.1)

CaseGenotypingMethod: Genomic DNA was isolated from peripheral blood leukocytes, amplified, and directly sequenced in all the coding exons and intron-exon boundaries of PHEX. If no mutations were found, FGF23 followed by consecutive analysis of DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1 was performed. Significance of found mutations was predicted by computational programs and sorted.

Variant: NM_000444.5:c.1404+1del

CAID: CA913187413 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913187413

gnomAD: Not in gnomAD

CaseIX-3: Male, 2.1 years, Turkey

CasePresentingHPOs: HP:0004912, HP:0002970 (Hypophosphatemic rickets, Genu varum)

HPOsFreeText: -0.75 standard deviation score

CaseNotHPOs: HP:0000083, HP:0002024, HP:0001947 (Renal failure, Malabsorption, Renal tubular acidosis)

NotHPOsFreeText: Other tubulopathies that cause secondary hypophosphatemia, Vitamin D-dependent rickets type 1 and 2

CaseAddInfo: Proband is hemizyogus for this mutation, Variant is a splice donor site at intron 4

CasePreviousTesting: Calcium levels (10.1 mg/dL), Decreased serum phosphate levels (2.6 mg/dL; reference 3.8-6.5), Elevated serum ALP (827 IU/L; reference 90-325), 25OHD3 levels (32.3 ng/ml), PTH levels (107.1 ng/L), TPR levels (74), Decreased TmP/GFR levels (1.92; reference 2.9-6.1)

CaseGenotypingMethod: Genomic DNA was isolated from peripheral blood leukocytes, amplified, and directly sequenced in all the coding exons and intron-exon boundaries of PHEX. If no mutations were found, FGF23 followed by consecutive analysis of DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1 was performed. Significance of found mutations was predicted by computational programs and sorted.

Variant: NM_000444.5:c.436+1G>T

CAID: CA412571215 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000444.5%3Ac.436%2B1G%3ET

gnomAD: Not in gnomAD

CaseXV-3: Female, 3.3 years, Turkey

CasePresentingHPOs: HP:0004912, HP:0004322, HP:0002970 (Hypophosphatemic rickets, Short stature, Genu varum)

HPOsFreeText: -3.04 standard deviation score

CaseNotHPOs: HP:0000083, HP:0002024, HP:0001947 (Renal failure, Malabsorption, Renal tubular acidosis)

NotHPOsFreeText: Other tubulopathies that cause secondary hypophosphatemia, Vitamin D-dependent rickets type 1 and 2

CaseAddInfo: Variant is de novo and is confirmed by parental testing

CasePreviousTesting: Calcium levels (9.4 mg/dL), Decreased serum phosphate levels (2.9 mg/dL; reference 3.8-6.5), Elevated serum ALP (677 IU/L; reference 90-325), 25OHD3 levels (107 ng/ml), 1,25(OH)2D3 levels (54.2 pg/mL), PTH levels (79.3 ng/L), TPR levels (83.4), Decreased TmP/GFR levels (2.8; reference 2.9-6.1)

CaseGenotypingMethod: Genomic DNA was isolated from peripheral blood leukocytes, amplified, and directly sequenced in all the coding exons and intron-exon boundaries of PHEX. If no mutations were found, FGF23 followed by consecutive analysis of DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1 was performed. Significance of found mutations was predicted by computational programs and sorted.

Variant: NM_000444.5:c.1206del (p.Gln402Hisfs*6)

CAID: CA913187414 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913187414

gnomAD: Not in gnomAD

Case11 Female, Finland

CasePresentingHPOs HP:0000202, HP:0000347, HP:0001161, HP:0001627, HP:0000157, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260, HP:0030449

(Oral cleft, Micrognathia, Hand polydactyly, Congenital heart defect, Tongue abnormality, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Type II lissencephaly, Therapeutic abortion)

HPOsFreeText Crown-heel body length 25cm, body weight 360g, brain weight 40g, abnormal larynx/trachea, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, leptomeningeal heterotopia, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0007165

(Periventricular neuronal heterotopia)

NotHPOsFreeText Uterus duplex, hydranencephaly/anencephaly, neuroepithelial rosettes, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo induced abortion at 20+5wk gestational age

CasePMIDs n/a

Case4 Female, Finland

CasePresentingHPOs HP:0000202, HP:0000347, HP:0001161, HP:0001829, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0030449

(Oral cleft, Micrognathia, Hand polydactyly, Foot polydactyly, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Therapeutic abortion)

HPOsFreeText Crown-heel body length 19cm, Body weight 160g, Brain weight 16g, abnormal larynx/trachea, Hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occititoschisis/keyhole, hypothalamic plate protrusion-hamartoma, steep rhombencephalic flexure with hypoplasia of posterior fossa contents, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0001627, HP:0000157, HP:0007260, HP:0007165

(Congenital heart defect, Tongue abnormality, Type II lissencephaly, Periventricular neuronal heterotopia)

NotHPOsFreeText Uterus duplex, Hydranencephaly/anencephaly, leptomeningeal heterotopia, neuroepithelial rosettes, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo induced abortion at 18+0wk gestational age

CasePMIDs n/a

Case15 Male, Finland

CasePresentingHPOs HP:0003826, HP:0000202, HP:0001161, HP:0001829, HP:0001627, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260, HP:0007165

(Stillbirth, Oral cleft, Micrognathia, Hand polydactyly, Foot polydactyly, Congenital heart defect, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Type II lissencephaly, Periventricular neuronal heterotopia)

HPOsFreeText Crown-heel body length 45cm, body weight 2520g, brain weight 146g, polydactyly of toes with multiple extra toes, abnormal larynx/trachea, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, leptomeningeal heterotopia, neuroepithelial rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0000157

(Tongue abnormality)

NotHPOsFreeText Uterus duplex, hydranencephaly/anencephaly, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo stillborn at 34+0wk gestational age

CasePMIDs n/a

Case10 Male, Finland

CasePresentingHPOs HP:0000347, HP:0001829, HP:0010066, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260, HP:0030449

(Micrognathia, Foot polydactyly, Duplicated hallux, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria,Type II lissencephaly, Therapeutic abortion)

HPOsFreeText Crown-heel body length 25cm, body weight 250g, Brain weight 35g, abnormal larynx/trachea, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, leptomeningeal heterotopia, neuroepithelia rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0000202, HP:0001161, HP:0001627, HP:0000157, HP:0002444, HP:0007165

(Oral cleft, Hand polydactyly, Congenital heart defect, Tongue abnormality, Hypothalamic hamartoma, Periventricular neuronal heterotopia)

NotHPOsFreeText Uterus duplex, hydranencephaly/anencephaly, hypothalamic hamartoma/bulging, true alobar or semilobar holoprosencephaly, widely separated hemispheres without midline structures; only meningeal remnants cross the midline showing classical open-book appearance of HLS

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo induced abortion at 19+5wk gestational age

CasePMIDs n/a

Case1 female, Finland

CasePresentingHPOs HP:0000202, HP:0000347, HP:0001341, HP:0000238, HP:0002126, HP:0007165, HP:0030449

(Oral Cleft, Micrognathia, Olfactory lobe agenesis, Hydrocephalus, Polymicrogyria, Periventricular neuronal heterotopia, Therapeutic abortion)

HPOsFreeText crown-heel length: 8cm, weight: 9g, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, neuroepithelial rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0001161, HP:0001829, HP:0001627, HP:0000157, HP:0002101, HP:0007370, HP:0010664, HP:0002444, HP:0007260

(Hand polydactyly, Foot polydactyly, Congenital heart defect, Tongue abnormality, Defective lung lobation, Callosal agenesis, Fused thalami, Hypothalamic hamartoma, Type II lissencephaly)

NotHPOsFreeText abnormal larynx/trachea, uterus duplex, hydranencephaly/anencephaly, hypothalamic bulging, leptomeningeal heterotopia, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo induced abortion at 12+1wk gestational age

CasePMIDs n/a

Case#: Li 2018 sALS A383T, Chinese, 65 y.o. onset

MonDO: MONDO:0005145 for sALS

CasePresentingHPOs: HP:0007354

CaseGenotypingMethod: Sanger sequencing. TUBA4A sequencing was performed using Sanger. No further details provided.

Variant: NM_006000.3(TUBA4A):c.1147G>A (p.Ala383Thr)

ClinVar: 180186

gnomAD: 2-220115274-C-T; total overall AF (non-neuro) = 0.000009611; TUBA4A_A383T_gnomAD

Case#: Li 2018 sALS I243T, Chinese, 51 y.o. onset

MonDO: MONDO:0005145 for sALS

CasePresentingHPOs: HP:0007354

CaseGenotypingMethod: Sanger sequencing. TUBA4A sequencing was performed using Sanger. No further details provided.

Variant: NM_006000.3(TUBA4A):c.701T>C (p.Ile234Thr)

CAID: CA350726345

Family Name: Family 3

FamilyPresentingHPOs: HP:0000705

FamilyNotHPOs:

CountryOrigin: Turkey

Ethnicity: Turkish

Race: n/a

FamilyPreviousTesting: candidate gene sequencing, array comparative genomic hybridization, or exome sequencing

FamilyGenotypingMethod: WES

Affected: 2

Unaffected: 2

Segregations: 1

PublishedLOD: n/a

eLOD: 0.85

AddSegregationInfo: consanguineous marriage of first cousins

ProbandLabel: Family 3: IV:2, male

Variant: NM_033068.2(ACP4):c.226C>T (p.Arg76Cys)

ClinVar or CAID: 374864, https://www.ncbi.nlm.nih.gov/clinvar/variation/374864/

genomAD: 3.422e-5, http://gnomad.broadinstitute.org/variant/19-51294040-C-T

FamilyAddInfo: Parents unaffected

CasePresentingHPOs: HP:0000687, HP:0011073, HP:0006297

CasePresentingHPOTerm: generalized dental spacing, yellow/black discoloration of enamel, thin enamel on incisors and posterior teeth

CaseNotHPOs: HP:0000689, HP:0006479, HP:0006336

AddCaseInfo:

VariantEvidence:

Patient: P13

Variant: c.550G > T (p.Gly184Trp)

CAID: CA380695715

Functional effect: N/A

Patient: ID396

Variant: c.305_317delCCACCCAACCAACnew p.Pro102Tyrfs*41

ClinVarID/CAID: 1460243

Functional effect: Monoallelic expression of full-length allele (wt only)

Patient: ID26

Variant: c.1225_1249 + 19del (p.Met409Asnfs*14)

CAID: CA2580612035

Functional effect: Normal exon inclusion (band B) *, exon 7 skipping (band C), use of cryptic splice site: c.1249 + 64; use of cryptic splice site: c.1249 + 67; use of cryptic splice site: c.1249 + 137 (band A). Observed in blood.

Patient: ID266

Variant: c.685delG

CAID: CA2580612031

Functional effect: Normal exon inclusion (band A) *, exon 4 skipping (band B), exon 4 + 5 skipping. Observed in blood.

Case: Fritzen-Individual 1, male, German, AOR= 14 y.o.

CasePresentingHPOs: HP:0000252, HP:0410034, HP:0008124, HP:0001156, HP:0001741, HP:0001263, HP:0001249, HP:0000752, HP:0000708, HP:0007018, HP:0011174, HP:0030891, HP:0012444, HP:0000582, HP:0000358, HP:0200055, HP:0001169, HP:0009381, HP:0001831, HP:0004691, HP:0001814,

CasePresenting HPOtext: Started talking at 18 months, started walking at 20 months. Deficits in expressive and receptive language. At 4 yo spoke first two word sentence. SON-R test at 5 indicated mild ID. K-ABC test at 8 yo revealed IQ of 53.

CaseNOTHPOs:

CasePreviousTesting: EEG, BERA, visual acuity test and routine cardiological check-ups were normal. Metabolic screening of urine (organic metabolites) was normal. Karotyping (blood lymphocytes), subtelomere screening, chromosomal microarray and Fragile X (FMR gene) screening were normal.

One homozygous mutation in ZNF717 and compound heterozygous mutations in EVPL were found, but ruled out based on too high of a frequency in control population of assertions of benign pathognicity.

CaseGenotypingMethod: Trio WES with parents.

Variant: NM_025133.4(FBXO11):c.190+1dup

Paper has written as NM_001190274.1:c.442 + 1T>G chr2:g.48066557dup

ClinVar ID: 559605

De novo Pathogenic, splice site variant, 1 submitter, no star

gnomAD: n/a

AddCaseInfo:

VariantEvidence: No evidence to show the effect of the splice site mutation, although the authors note that it was "predicted unequivocally to result in aberrant splicing." Therefore, I have reduced the score.

Case: Individual 10, female, AOR= 5 years

CasePresentingHPOs: HP:0000252, HP:0001256, HP:0008935, HP:0002360, HP:0000736, HP:0012434, HP:0000712, HP:0012171, HP:0000490, HP:0030820, HP:0000431, HP:0004467, HP:0000218, HP:0010296, HP:0001010

CasePresentingHPOText: Began walking at 15 months, no notation on speech.

CaseNOTHPOs: HP:0001250, HP:0002719, HP:0000924, HP:0000202, HP:0001155, HP:0001760, HP:0000478, HP:0002719

CasePreviousTesting: No previous testing

CaseGenotypingMethod: Trio-WES.

Variant: hg19:chr2: g.4806607 8_4806607 9del, c.506_507del, p.(Ser169Leufs9) OR* NM_001190274.1:c.506_507del

CA ID: CA658820928

de novo

gnomAD: n/a

AddCaseInfo:

VariantEvidence: The Ser169Leufs*9 mutation causes a frameshift mutation and premature stop codon. The mutation is in exon 4 and thus removes part of the F-BOX, all three CASH domains and the zinc-finger UBR region, thus it should act as a loss of function variation. No functional assays or variant evidence was provided.

Case: Individual 14, male, AOR= 9 years 10 months

CasePresentingHPOs: HP:0001263, HP:0001344, HP:0010864, HP:0001290, HP:0000739, HP:0000718, HP:0000637, HP:0000411, HP:0002019

CasePresentingHPOText: Began walking 4y.o., currently no speech. Noted as having NAD under abnormalities of the hand and feet.

CaseNOTHPOs: HP:0001250, HP:0002376, HP:0002360, HP:0000202, HP:0000924, HP:0002719

CaseNOTtextHPO:

CasePreviousTesting:

CaseGenotypingMethod: Trio-WES performed through the DDD consortium, 2017 PMID:PMID: 28135719.

Variant: g19:chr2: g.4804051 7C>T, c.2084-1G>A, p.(?) OR NM_001190274.1:c.2084-1G>A

CA ID: CA346763489

de novo

gnomAD: n/a

AddCaseInfo:

VariantEvidence: The c.2084−1G>A mutation is most likely a splice site mutation. The mutation arises in exon 18 (Intron 18?), and likely would disrupt exon 18 splicing. Exon 18 is upstream of the third CASH domain, which regulates substrate recognition. No functional assays or variant evidence was provided, so I have downgraded the score.

Case: Individual 4, male, AOR= 8 yo

CasePresentingHPOs:  HP:0001518, HP:0004322, HP:0000252, HP:0001270, HP:0011344, HP:0002187HP:0000750, HP:0002069, HP:0002121, HP:0006829, HP:0100023, HP:0000735, HP:0000248, HP:0001357, HP:0000490, HP:0011229, HP:0000527, HP:0045025, HP:0003196, HP:0000414, HP:0000463, HP:0000288, HP:0000160, HP:0000219, HP:0000232, HP:0000307, HP:0000400, HP:0200055, HP:0001769, HP:0006045, HP:0004209, HP:0010610, HP:0001795, HP:0000193, HP:0003100, HP:0000938, HP:0002750, HP:0002205, HP:0000565, HP:0011968

CasePResentingHPOText: Subject began walking at 5 y.o. First words at 8 y.o. and noted as only having 2 words. Seizure onset at 3 y.o. with general tonic clonic seizures and absence. At 4 y.o. noted as having little social interaction, and intermittent hand flapping. Noted as having a feeding tube until age 8.

CaseNOTHPOs: HP:0002376, HP:0012443, HP:0002360

CasePreviousTesting: Affymetrix Cytogenetics 2.7 array testing was unremarkable.

CaseGenotypingMethod: Trio-WES. Testing also identified a de novo VUS in SMARCAD1 (NM_0011 28429.1):c hr4:g.9520 1881T>A, c.2563T>A, p.(Ser855Thr), this gene is associated with skin disease.

Variant: hg19:chr2: g.4804614 7G>C, c.1868C>G , p.(Thr623Arg) OR NM_001190274.1:c.1868C>G

CA ID: CA346764020

de novo Trio-WES performed so maternity and paternity could be investigated with this method.

gnomAD: n/a

AddCaseInfo:

VariantEvidence: Thr623 is located in the second CASH domain of FBXO11, and is conserved across specieis. These domains are responsible for the substrate recognition. Pathogenicity algorithms showing varying predictions, from tolerated to damaging, thus indicating a VUS. No functional assays were performed to indicate the impact of the T623R mutation on FBXO11 function.

Case#: N6287, M, 59 y.o., Italian

CasePresentingHPOs: HP:0007354, HP:0100543, HP:0002483

CaseNotHPOs:

CaseGenotypingMethod: Sanger sequencing

Variant: NM_006000.3(TUBA4A):c1312G>A p.Asp438Asn

CAID: CA65993021

gnomAD: 2-220115109-C-T; Total overall AF (non-neuro) = 0.000009617; gnomAD_NM_006000.3(TUBA4A):c1312G>A p.Asp438Asn

CaseAddInfo: dbSNP ID: rs913033084. While most cases were found to be negative during pre-screening for known mutations, some cases were positive for mutations in SOD1 (n=4), C9orf72 (n=12), TARDBP (n=4), & FUS/TLS (n=1) genes. Whether this case tested positive for any of these is not specified.

Case# Barletta 3:1, female, 17yo

CasePresentingHPOs HP:0004758

CasePreviousTesting no

CaseMethod1 PCR

CaseGenotypingMethod amplified 11 exons of CASQ2

Variant NM_001232.3(CASQ2):c.500T>A (p.Leu167His), NM_001232.3(CASQ2):c.339_354del16 (p.Ser113Argfs)

ClinVar 17612, 17611

VariantEvidence (fig5.) L167H variant had reduced Ca2+ sparks in infected myoctes comparable to levels in G112+5X and both significantly less than WT.

CaseAddInfo Authors admit that the functional evaluation of L167H is not as convincing as with G112+5X, the latter showing complete functional impairment and the former preserving major biochemical and biophysical properties of CASQ2.

Case# Barletta 3:2, male, 6yo

CasePresentingHPOs HP:0004758

CasePreviousTesting no

CaseMethod1 PCR

CaseGenotypingMethod amplified 11 exons of CASQ2

Variant NM_001232.3(CASQ2):c.339_354del16 (p.Ser113Argfs)

ClinVar 17611

VariantEvidence G112+5X variant decrease in Ca2+ transients and decrease in SR ability to store Ca2+ (fig.4&5)

Case: Family E/Hussain Patient 1, female, Pakistan, 9mo at onset

CasePresentingHPOs: HP:0000508, HP:0000369, HP:0000316, HP:0001993, HP:0001738, HP:0002720, HP:0000953, HP:0000998, HP:0001433, HP:0002594, HP:0006610, HP:0100578, HP:0001508, HP:0001945, HP:0002254, HP:0002716, HP:0001903, HP:0001541, HP:0012398, HP:0000103, HP:0001959, HP:0100651, HP:0004322, HP:0001007, HP:0100679, HP:0003565, HP:0011227, HP:0002094, HP:0001254, HP:4000141, HP:0000545, HP:0000483, HP:0012716, HP:0025289, HP:0034752, HP:0034751, HP:0000581, HP:0003237

CasePresentingHPOsFreeText: Inflammatory symptoms. Hyperpigmentation onset at 9mo; located on limbs and back. Lipoatrophy of buttocks. Biopsies from both lymph nodes and subcutaneous tissue showed fibrofatty connective tissue with fibrosis and mononuclear cell infiltrates around the larger vessels.

CaseNOTHPOs: HP:0000520, HP:0006476, HP:0025329, HP:0001263, HP:0000488, HP:0009830

CaseNOTHPOSFreeText:

CasePreviousTesting: ADAMTS14, C10orf27, CDH23, EIF4EBP2, LRRC2, KIAA1274, NODAL, NPFFR1, PCBD1, PPA1, PRF1, SLC29A3, SGPL1, UNC5B were sequenced since they were positional candidate genes

CaseGenotypingMethod: homozygosity mapping (10K SNP array), candidate gene sequencing

Variant: c.1346C>G (p.Thr449Arg)

ClinVarID: or CAID: CA114354

gnomAD: This missense variant, p.Thr449Arg is present in gnomAD v4.0.0 with a MAF=0.00006956 (6/86258 alleles) in the South Asian population and 0 homozygotes. Downscoring for homozygosity since the parents are consanguineous.

AddCaseInfo: first cousin parents. sister is genotype and phenotype +

PreviouslyPublished: 19175903

VariantEvidence: Functional studies in Xenopus oocytes showed transport activity that was approximately one-fourth lower that of WT SLC29A3. Studies in NIH 3T3 fibroblasts demonstrated slightly increased turnover of the T449R mutant compared to WT, suggesting decreased stability (Kang et al. 2010; PMID: 20595384).

CaseP1 male, 45yo report, Tunisia

CasePresentingHPOs HP:0012207, HP:0012865, HP:0012868, HP:0003251

(reduced sperm motility, sperm head anomaly, sperm tail anomaly, male infertility)

HPOsFreeText Patient's sperm volume: 4mL(lower reference limit: 1.5), sperm concentration: 11.3 million/mL(reference: 15), total motility after 1hr: 2%(reference: 40), vitality: 53%(reference:53%), normal spermatozoa: 0%(reference: 4), abnormal acrosome: 66%, abnormal head morphology: 42%, abnormal base: 36%, absent flagella: 31%, short flagella: 34%, coiled flagella: 20%, flagella of irregular caliber: 4%, multiple anomalies index: 2.5%.

CaseNotHPOs n/a

CasePreviousTesting Previously screened all patients for DNAH1, CFAP43, and CFAP44 variants. Somatic karyotypes were normal.

Variant NM_144668.5:c.3007_3337del

ClinVar 586974

gnomAD not in gomAD

CaseAddInfo consanguinity

CasePMIDs 29449551

Case#: Family NO-1, 60yo, male, Norwegian

DiseaseAssertion: DOA+

FamilyInfo: positive family history: affected sister with same genotype, 2 unaffected daughters with only the c.768C>G p.S256R variant. Parents are deceased but were apparently healthy

CasePresentingHPOs: HP:0000648, HP:0001251, HP:0003198, HP:0009830, HP:0001257

CaseHPOFreeText: corticospinal tract involvement

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

GenotypingMethod: The entire OPA1-coding region and flanking exon–intron boundaries were amplified by the polymerase chain reaction (PCR) and sequenced with BigDye terminator cycle chemistries on an appropriate genetic analyser. All genetic variants were confirmed by reverse sequencing. Initial screens for POLG1, POLG2, PEO1 and SLC25A4 were found to be negative,

Variant: c.768C > G (p.S256R) and c.854A > G (p.Q285R), confirmed in trans by haplotype analysis

CAID: CA355787228

SupplementalData: n/a

Case#: Family FR-1, 30yo, male, French

DiseaseAssertion: DOA+

FamilyInfo: positive family history, but no information provided

CasePresentingHPOs: HP:0000648, HP:0000365, HP:0001251, HP:0003198, HP:0001138

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

GenotypingMethod: The entire OPA1-coding region and flanking exon–intron boundaries were amplified by the polymerase chain reaction (PCR) and sequenced with BigDye terminator cycle chemistries on an appropriate genetic analyser. All genetic variants were confirmed by reverse sequencing

Variant: c.1635C>G (p.S545R) aka c.1800C>G (p.S600R)

ClinVar: 30461

CAID: CA10575554

SupplementalData:

Case: de Pontual Family VII Patient 7, male, 14yo at dx, 5yo at onset, Moroccan

CasePresentingHPOs: HP:0100651, HP:0001738, HP:0031685, HP:0002570, HP:0001742, HP:0003565, HP:0010702, HP:0030044, HP:0030839, HP:0002833

CasePresentingHPOsFreeText: Levels of fat in stool at 12 g/24 hr. Infiltrates found in both the nose and the right maxillary sinus. initial diagnosis of rhinoscleroma. High erythrocyte sedimentation rate (>50 mm). Polyclonal hypergammaglobulinemia (IgG = 15.3 g/l, IgA = 4.2 g/l, IgM = 2.8 g/l). Lytic bone lesions of both patellas on X-ray. Diabetic retinopathy. Mucosa displayed fibrosis and a mild to moderate inflammatory infiltrate containing plasma cells, lymphocytes and some vacuolated histiocytes. Parts of the biopsy specimens also displayed specific features of Rosai-Dorfman histiocytosis, as they contained several large histiocytes with emperipolesis. These histiocytes were positive for CD68, CD4 and S100 protein. Mononucleated vacuolated and spumous macrophages.

CaseNOTHPOs: HP:0012090, HP:0001627, HP:0000998, HP:0000554, HP:0000953, HP:0000407, HP:0002240, HP:0004322, HP:0000135, HP:0000771, HP:0000823, HP:0001822, HP:0011974, HP:0005200, HP:0002716

CaseNOTHPOSFreeText: Cystic fibrosis. Histiocytic infiltration. Wartin-Starry, Grocott and periodic acid-Schiff (PAS) stains

CasePreviousTesting:

CaseGenotypingMethod: genome-wide linkage (GWL) analysis by homozygosity mapping and whole-exome sequencing (WES) by next-generation deep sequencing. Sanger sequencing for validation.

Variant: c.243delA (p.Lys81fs) homozygous

ClinVarID: or CAID: 636986 / CA913184824

gnomAD: This frameshift variant, Lys81fs which is occurs in exon 2, is absent from gnomAD. Down-scoring for consanguinity and alternative splicing.

AddCaseInfo: First-cousin, heterozygous parents. Proband has 1 affected sister who is also a homozygote. Proband also has a variant in VCL (c.610G>C) which is predicted benign and associated with HCM, which the proband does not have.

PreviouslyPublished: PMID: 18947330

VariantEvidence: This mutation decreases the levels of transcript variant 1 through NMD and results in an absence of the WT protein, but allows the expression of a mutated mRNA transcript variant 3, which would ordinarily be subject to NMD. This hENT3-variant3-81fs variant was expressed but displayed lower levels of adenosine transporter activity than the hENT3-variant1-WT protein.

Case# Subject 2, F, 6mo onset, Hispanic/European

CasePresentingHPOs HP:0001942, HP:0003128, HP:0002919, HP:0001987, HP:0002094, HP:0006682, HP:0004756, HP:0045045, HP:0001288, HP:0002013, HP:0007340, HP:0002913, HP:0002058, HP:0002307, HP:0001260, HP:0001251, HP:0003201, HP:0002151, HP:0001249, HP:0001943, HP:0003236, HP:0005184, HP:0002910, HP:0012544, HP:0006956, HP:0100960, HP:0001254

HPOcont: Metabolic acidosis, Lactic acidosis, Ketonuria, Hyperammonemia, Dyspnea, Ventricular extrasystoles, Ventricular tachycardia, Elevated acylcarnitine, Gait abnormality, Emesis, Lower limb muscle weakness, Myoglobinuria, Myopathic facies, Drooling, Dysarthria, Ataxia, Rhabdomyolysis, Elevated Lactate, Intellectual Disability, Hypoglycemia, Elevated CPK, Prolonged QTc interval, Elevated Transaminases, Elevated aldolase, Lateral ventrical dilation, Asymmetric ventricles, Lethargy

HPOFreeText: (6 months) metabolic acidosis, lactic acidemia, ketonuria, elevated blood ammonia and Kussmaul breathing, in addition to prolonged QTc interval, premature ventricular contractions just short of ventricular tachycardia, and elevated acycarnitine profile. (16 months) gait abnormality, weakness, sore troat, and vomiting. (5 years) after infection, lethargy, lower limb weakness, myoglobinuria, elevated CPK, transaminases, lactate, and aldolase in additon to myopathic face, drooling, dysarthric speech and ataxia.

CaseNotHPOs HP:0001250

NotHPOcont: Seizures

CasePreviousTesting "metabolic acidosis (pH of 7.0; base deficit of 20 mEq/l) and lactic acidemia of 15 mmol/l (normal range 0.2–2.0 mmol/l), serum ammonia was mildly elevated to 138 μmol/l. Acylcarnitine profile showed a primary peak of C14:1 in addition to C14:2, C16, C18, and some hydroxy derivatives." At 15 months of age "CPK of 1,126 U/l, AST of 158 U/L, mildly elevated ammonia of 71 μmol/l, and lactate of 7.0 mmol/l, then at 5 years, CPK of 287,230 U/l, hypoglycemia (glucose of 17 mg/dl), elevated transaminases (AST of 7,618 U/l and ALT of 2,564 U/l), lactate was 2.0 mmol/l, aldolase level was 595 U/l (normal range 2.7–8.8 U/l). Renal function tests remained stable throughout admission. Etiologic evaluations, including DNA sequencing of ACADVL for VLCAD deficiency, muscle histopathology, quantitative mtDNA studies in muscle, and mitochondrial genome sequencing for common point mutations and deletions, were normal."

CaseMethod1 WES

CaseMethod2 PCR

CaseGenotypingMethod WES and cSNP array, validated deletion variant with PCR

Variant (1) NM_152906.6:c.460G>A (p.Gly154Arg), (2) ~34kb, exon3-9del

ClinVar (1) 208823

CAID (1) CA358646

gnomAD (1) 0.001549(Other), 0.0001208(Overall)

VariantEvidence (1)(Figure 3) using "EBV-transformed B-lymphoblastoid cell lines (BLCLs) from another individual, subject 4 with homozygous c.460G>A (p.Gly154Arg) mutation, and evaluated the Golgi by intracellular staining with WGA, as well as cis Golgi marker, anti-GM130 antibody." WGA stain resolved lower area of golgi bodies in p.Gly154Arg cells than WT. Measured immunoglobulin heavy chain binding protein levels in WT and and patient fibroblasts, BiP levels in patient cells lower than WT after ER induced stress by Brefeldin A.

CaseAddInfo nonconsanguineous, found deletion variant in with PCR father and mother carried missense

CasePMIDs n/a

Case# Subject 6, M, 1yo onset, Hispanic

CasePresentingHPOs HP:0001263, HP:0002098, HP:0002013, HP:0001943, HP:0001942, HP:0002151, HP:0001290, HP:0001987, HP:0001249, HP:0001946, HP:0045045, HP:0040145, HP:0001508, HP:0003648

HPOcont: Global developmental delay, Respiratory Distress, Emesis, Hypoglycemia, Metabolic acidosis, Elevated Lactate, Generalized hypotonia, Hyperammonemia, Intellectual Disability, Ketosis, Elevated acylcarnitine, Dicarboxylic acidemia, Failure to thrive, Lacticaciduria

HPOFreeText: (1 year) developmental delay, emesis, difficulty breathing, elevate metabolites, elevated urine organic acids, elevations of 3-hydroxy-N-butyric and acetoacetic acids (ketone bodies), as well as adipic, suberic, sebacic, and 3-hydroxysebacic (dicarboxylic) acids. Found to also have a head circumference in 6th percentile and hypotonia.

CaseNotHPOs HP:0001250, HP:0011675, HP:0003201

NotHPOcont: Seizures, Arrhythmia, Rhabdomyolysis

CasePreviousTesting Tested blood gas pH (7.1), serum bicarbonate(16 mEq/L (normal range 22-28 mEq/L)), serum lactate(11.7 mmol/L), serum ammonia( 102 μmol/L), elevated very long chain acylcarnitine species, especially C14, normal serum CPK. Chromosomal microarray and Fragile X results were normal.

CaseMethod1 WES

CaseMethod2 n/a

CaseGenotypingMethod WES and cSNP array

Variant NM_152906.6(TANGO2):c.605+1G>C

ClinVar 521699

CAID CA358646

VariantEvidence splice site

CaseAddInfo consanguineous parents

CasePMIDs n/a

Case# Subject 3, male, 21yo report, European

CasePresentingHPOs HP:0030842, HP:0001631, HP:0001263, HP:0001249, HP:0001252, HP:0001251, HP:0000722, HP:0002474, HP:0001488, HP:0000565, HP:0010535, HP:0002650, HP:0002079, HP:0002363, HP:0000961, HP:0000733, HP:0002058, HP:0000490, HP:0000218, HP:0001222, HP:0001795 (Choking episodes, Atrial septal defect, Developmental delay, Intellectual disability, Hypotonia, Ataxia, OCD, Expressive language deficit, Bilateral ptosis, Esotropia, Sleep apnea, Scoliosis, Thin corpus callosum, Cyanosis, Stereotypy, Myopathic facies, Deep set eyes, High-arched palate, Spatulate thumbs, Hyperconvex nails

HPOFreeText: Choking episodes and atrial septal defect in infancy; recurrent cyanosis, mild hypotonia, ataxia, scoliosis, bilateral ptosis, esotropia, developmental delay and OCD (7 years); sleep apnea, throbbing headaches, thin corpus callosum, flattening of braistem, thin rim of sella, chronic right temporal membrane perforation and mild left sensorineural hearing loss(8 years); repetitive hand movements, limited speech, elongated/myopathic face/midfacial retraction, bilateral ptosis, deep-set eyes, high arched palate, spatulate thumbs and finger/toenail hyperconvexity(19 years).

CaseNotHPOs HP:0012372, HP:0000453, , HP:0000077 (Abnormal eye morphology, Choanal atresia, Renal anomaly)

CasePreviousTesting Reduced succinate cytochrome c reductaseactivity (19%), NADH and NADH cytochrome c activity were 40% of control.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with sanger in patient and parents

Variant NM_012102.3:c.4300T>C(p.Ser1434Pro), de novo

ClinVar n/a

CAID CA338168793

gnomAD n/a

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs n/a

Patient: 5 unrelated patients

Variants: c.550G>C; c.550G>A; c.550+5G>A

CAIDs: CA380695714; CA219267; CA599664126

FunctionalEffect: RT-PCR of mRNA samples from patients blood showed an additional transcript lacking exon 3. Expression in agarose gels revealed a higher expression of the exon 3 skipped variant in these pts vs controls.

Case: Kameli Proband, male, 4yo at dx, Iran

CasePresentingHPOs: HP:0000256, HP:0000271, HP:0100540, HP:0001537, HP:0045075, HP:0000348, HP:0012811, HP:0000286, HP:0000494, HP:0000343, HP:0000308, HP:0012471, HP:0000280, HP:0000212, HP:0006288, HP:0001763, HP:0000974, HP:0005692, HP:0000978, HP:0001053, HP:0002500

CasePresentingHPOsFreeText: hypopigmented skin lesion under anterior abdominal region around umbilicus. Brain MRI revealed diffuse abnormal white matter signals high in long TR sequence more pronounced at superficial subcortical and deep peritrigonal regions at the level of basal ganglia and centrum semiovale in T2 weighted spin echo and FLAIR sequence images. In addition, bilateral anterior temporal small subcortical cysts formation and increased perivascular spaces on posterior deep white matter were noticed clearly in T2 weighted and FlAIR sequence images.

CaseNOTHPOs: HP:0001270, HP:0000750, HP:0000707, HP:0008064, HP:0002650

CaseNOTHPOSFreeText:

CasePreviousTesting:

CaseGenotypingMethod: WES, Sanger

Variant: NM_001242581.1: c.2251dup; p.(Leu751Profs*9); homozygous

ClinVarID: or CAID: 590794

gnomAD: This proband has a frameshift variant, p.Leu702fs, in exon 11/13 that is absent from gnomAD v2.1.1.

AddCaseInfo: second child born to a consanguineous marriage; parents were heterozygous carriers

PreviouslyPublished: n/a

VariantEvidence: n/a

Case9: Female, 32 yrs report, France

CasePresentingHPOs: HP:0002421, HP:0002205, HP:0003551, HP:0003701, HP:0002460, HP:0000467, HP:0003391, HP:0001488, HP:0002751, HP:0003202, HP:0003782, HP:0005997, HP:0003803, HP:0003755 (Poor head control, Recurrent respiratory infections, Difficulty climbing stairs, Proximal muscle weakness, Distal muscle weakness, Neck muscle weakness, Gowers sign, Bilateral ptosis, Kyphoscoliosis, Skeletal muscle atrophy, Eunuchoid habitus, Neck flexion contracture, Type 1 muscle fiber predominance, Type 1 fibers relatively smaller than type 2 fibers)

HPOsFreeText: Noninvasive BiPAP from 19 yrs, Type 2B fibers absent

CaseNotHPOs: HP:0003798, HP:0030177 (Nemaline bodies, Abnormal nerve conduction study)

NotHPOsFreeText: N/A

CaseAddInfo: Variant is de novo with parental testing confirmation

CasePreviousTesting: Patients were diagnosed with CFTD via clinical notes and muscle biopsies at pathology centers throughout Australia and several international centers.

CaseGenotypingMethod: Two methods were used for genotyping. In 16 patients, the 10 exons spliced onto the muscle-specific isoform of TPM3 were bidirectionally sequenced from genomic DNA. For the other 7 patients, complementary DNA was generated from patient muscle and isoform-specific primers were used to sequence the transcript. Paternity was confirmed in isolated patients using microsatellite markers.

Variant: NM_152263.4(TPM3):c.502C>T (p.Arg168Cys)

ClinVar: 12454 https://www.ncbi.nlm.nih.gov/clinvar/variation/12454/

gnomAD: Not in gnomAD

Case3: Male, 8 yrs onset, Australia

CasePresentingHPOs: HP:0009046, HP:0003701, HP:0003722, HP:0001488, HP:0002938, HP:0010628, HP:0030877, HP:0003803, HP:0003755 (Difficulty running, Proximal muscle weakness, Neck flexor weakness, Bilateral ptosis, Lumbar hyperlordosis, Facial palsy, Obstructive deficit on pulmonary function testing, Type 1 muscle fiber predominance, Type 1 fibers relatively smaller than type 2 fibers)

HPOsFreeText: Type 2B fibers absent

CaseNotHPOs: HP:0003798, HP:0030177, HP:0003391 (Nemaline bodies, Abnormal nerve conduction study, Gowers sign)

NotHPOsFreeText: N/A

CaseAddInfo: Variant is likely de novo, but there is no parental testing to confirm

CasePreviousTesting: Patients were diagnosed with CFTD via clinical notes and muscle biopsies at pathology centers throughout Australia and several international centers.

CaseGenotypingMethod: Two methods were used for genotyping. In 16 patients, the 10 exons spliced onto the muscle-specific isoform of TPM3 were bidirectionally sequenced from genomic DNA. For the other 7 patients, complementary DNA was generated from patient muscle and isoform-specific primers were used to sequence the transcript. Paternity was confirmed in isolated patients using microsatellite markers.

Variant: NM_152263.4(TPM3):c.502C>G (p.Arg168Gly)

ClinVar: 12453 https://www.ncbi.nlm.nih.gov/clinvar/variation/12453/

gnomAD: Not in gnomAD

Case# Arno P3, German, Male

CasePresentingHPOs HP:0000545, HP:0025313, HP:0007994

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod Sanger of RBP3 exons

Variant NM_002900.2:c.1530T>A

CAID CA376670175

CaseAddInfo in trans

Case# Patient2, F, 5yo report, Chinese

CasePresentingHPOs HP:0000325, HP:0002007, HP:0000347, HP:0008897, HP:0001508, HP:0001249, HP:0000750, HP:0001270, HP:0008947, HP:0002360

HPOcont: Triangular face, Frontal bossing, Micrognathia, Postnatal growth retardation, Failure to thrive, Intellectual disability, Delayed speech and language development, Motor delay, Infantile muscular hypotonia, Sleep disturbance

Free Text: "The patient was referred for DD and failure to thrive without feeding difficulty at approximately three years of age. She could speak only simple words such as “baba” and “mama” and could not walk. A physical examination revealed hypotonia. Her head circumference was 44 cm (−3.7 SD). Her facial dysmorphisms included a triangular face; light, sparse hair; frontal bossing; strabismus; a thin upper lip; and micrognathia. At the age of five, she could stand with support but remained unable to ambulate or speak. She suffered from sleep disturbance and a tendency toward self-injury behaviors, such as hitting her head with her hands or bumping her head. Follow-up when the patient was 5 years and 9 months old showed that she could not walk or speak. At that time, her body length was 100 cm (−3.4 SD), and she weighed 11 kg (−4 SD)."

CaseNotHPOs HP:0000494, HP:0000369, HP:0002353, HP:0000358, HP:0000431, HP:0000319, HP:0012299, HP:0001182, HP:0001511, HP:0001250, HP:0002650, HP:0011968, HP:0002019

NotHPOcont: Downslanted palpebral fissures, Low-set ears, EEG abnormality, Posteriorly rotated ears, Wide nasal bridge, Smooth philtrum, Long distal phalanx of finger, Tapered finger, Intrauterine growth retardation, Seizures, Scoliosis, Feeding difficulties, Constipation

CasePreviousTesting Echocardiographic examination, brain magnetic resonance imaging (MRI) and an EEG revealed no abnormalities. Metabolic screening and assessments of the patient's thyroid function at age three produced normal results.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES, confirmed with Sanger

Variant (1) NM_032504.1:c.3719G>A (p.Trp1240Ter ), (2) NM_032504.1:c.4926_4937del (p.Asn1643_Leu1646del)

CAID (1) CA350741683 (2) CA658820715

CaseAddInfo nonconsanguineous parents, no parent testing mentioned, "younger brother presented similar phenotypes such as hypotonia and developmental delay. He died at the age of one year due to severe pneumonia. He was diagnosed as IHPRF2 clinically. However, no genetic analysis was performed, as DNA was unavailable."

Case# Patient1, Male, 1 week onset, Chinese

CasePresentingHPOs HP:0002007, HP:0000319, HP:0012299, HP:0001249, HP:0000750, HP:0001270, HP:0008947, HP:0001250, HP:0002019, HP:0002353, HP:0010804, HP:0000486

HPOcont: Frontal bossing, Smooth philtrum, Long distal phalanx of finger, Intellectual disability, Delayed speech and language development, Motor delay, Infantile muscular hypotonia, Seizures, Constipation, EEG abnormality, Tented upper lip vermilion, Strabismus

Free Text: "He experienced physiologic jaundice one week after birth. Hypotonia and psychomotor retardation were observed. He could raise his head at the age of one year and sit by himself when he was two years of age; he ambulated when he was three years old. At approximately five years of age, he could use only simple speech. He also exhibited poor balance and displayed hyperactive behavior and a happy and excitable disposition with frequent smiling and laughing. In addition, he suffered from constipation. Seizures occurred when he was two years old and were effectively treated with valproate and levetiracetam. When he was referred to our clinic at 6 years and 5 months of age, his height and weight were 120 cm (0 SD) and 20 kg (0 SD), respectively. When followed up at the age of 9.5 years, his height, weight and head circumference were 135 cm (−0.5 SD), 25 kg (−1.3 SD) and 51 cm (−0.5 SD), respectively. His facial features included frontal bossing, strabismus, a tented upper lip, a broad nasal bridge, and a short, smooth philtrum. He had long, slender fingers. An electroencephalograph (EEG) revealed excessively slow background."

CaseNotHPOs HP:0000494, HP:0000325, HP:0000369, HP:0000358, HP:0000431, HP:0000347, HP:0001182, HP:0001511, HP:0008897, HP:0001508, HP:0002650, HP:0011968, HP:0002360

NotHPOcont: Downslanted palpebral fissures, Triangular face, Low-set ears, Posteriorly rotated ears, Wide nasal bridge, Micrognathia, Tapered finger, Intrauterine growth retardation, Postnatal growth retardation, Failure to thrive, Scoliosis, Feeding difficulties, Sleep disturbance ,

CasePreviousTesting "methylation-specific multiplex ligation-dependent probe amplification revealed no abnormalities in the 15q11-q13 region. Chromosomal microarray tests also showed no pathogenic copy number variations."

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES, confirmed with Sanger

Variant (1) NM_032504.1(UNC80):c.4963C>T (p.Arg1655Cys), (2) NM_032504.1:c.8385C>G (p.Tyr2795Ter)

ClinVar (1) 545035

CAID (2) CA350413549

CaseAddInfo nonconsanguineous, parent testing not mentioned

From supplemental tables S2 and S3 (authors used hg19 alignment).

MONDO: MONDO:0005144 for FALS

Case#7: Smith 2014 FALS K430N, F, 64 y.o. onset, Italy

CasePresentingHPOs: HP:0007354

CaseHPOFreeText: spinal-onset ALS with upper and lower motor neuron signs

CasePreviousTesting: All FALS were screened for known causative mutations/repeat expansions in SOD1, C9orf72, TARDBP, FUS, PFN1, UBQLN2, OPTN, VCP and ANG and removed from cohort if positive for variant.

CaseMethod1: This case identified through case-control study

CaseGenotypingMethod: Exome sequencing, confirmed with Sanger sequencing.

Variant: NM_006000.3(TUBA4A):c.1290G>C (p.Lys430Asn)

CAID: CA350721313

CaseAddInfo: This variant found in 0/13023 control samples. This variant did not co-segregate with an affected cousin of the sequenced proband.

From supplemental tables S2 and S3 (authors used hg19 alignment).

MONDO: MONDO:0005144 for FALS

Case#5: Smith 2014 FALS R320H, F, 41 y.o. onset, Italy

CasePresentingHPOs: HP:0007354

CaseHPOFreeText: spinal-onset ALS with upper and lower motor neuron signs

CasePreviousTesting: All FALS were screened for known causative mutations/repeat expansions in SOD1, C9orf72, TARDBP, FUS, PFN1, UBQLN2, OPTN, VCP and ANG and removed from cohort if positive for variant.

CaseMethod1: This case identified through case-control study

CaseGenotypingMethod: Exome sequencing, confirmed with Sanger sequencing.

Variant: NM_006000.3(TUBA4A):c.959G>A (p.Arg320His)

ClinVar: 180183

gnomAD: 2-220115462-C-T; Total overall AF (non-neuro) = 0.000 ; TUBA4A_p.Arg320His_gnomAD

CaseAddInfo: This variant found in 0/13023 control samples.

From supplemental tables S2 and S3 (authors used hg19 alignment).

MONDO: MONDO:0005144 for FALS

Case#2: Smith 2014 FALS, T145P, M, 69 y.o. onset, Italy

CasePresentingHPOs: HP:0007354

CaseHPOFreeText: spinal-onset ALS with upper and lower motor neuron signs

CasePreviousTesting: All FALS were screened for known causative mutations/repeat expansions in SOD1, C9orf72, TARDBP, FUS, PFN1, UBQLN2, OPTN, VCP and ANG and removed from cohort if positive for variant.

CaseMethod1: This case identified through case-control study

CaseGenotypingMethod: Exome sequencing, confirmed with Sanger sequencing.

Variant: NM_006000.3(TUBA4A):c.433A>C (p.Thr145Pro)

ClinVar: 180187

CaseAddInfo: This variant found in 0/13023 control samples.

Case# Patient 1, Caucasian, Male, 69-- Patient 2, Caucasian, Male, 64-- Patient 3, Caucasian, Male, 49-- Patient 4, Caucasian, Male, 42

CasePreviousTesting Screened for prevalent European mutations in apoB with DGGE.

CasePresenting HPOs HP:0005145 Narrowing of Coronary Artery and HP:0003124 Hypercholesterolemia

CaseNotHPOs n/a

CaseGenotypingMethod PCR fraction of exom 26, denaturing gradiant gel electrophoresis

Variant NM_000384.2(APOB):c.10708C>T (p.His3570Tyr)

ClinVar 431988

gnomAD 0.0002614 gnomaD

VariantEvidence high LDL-cholesterol levels(mg/dl) P1=18, P2=62, P3=174, P4=154,

CaseAddInfo significantly lower fractional catabolic rate/production rate according to pending model

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

Case2: Male, 6 yrs report

CasePresentingHPOs: HP:0001252, HP:0002194, HP:0001324, HP:0002355, HP:0009046, HP:0008376, HP:0002788, HP:0004396, HP:0001824, HP:0002058, HP:0003691, HP:0002938, HP:0001763, HP:0001290, HP:0001284, HP:0003722, HP:0003391, HP:0003557, HP:0003803, HP:0003715 (Muscular hypotonia, Delayed gross motor development, Muscle weakness, Difficulty walking, Difficulty running, Nasal and dysarthic speech, Recurrent upper respiratory tract infections, Poor appetite, Weight loss, Myopathic facies, Scapular winging, increased lumbar lordosis, Pes planus, Decreased muscle tone, Areflexia, Neck flexor weakness, Gowers sign, Increased fiber size variation, Type 1 muscle fiber predominance, Myofibrillar myopathy)

HPOsFreeText: Walk unsupported at 17 months, Abnormal, partly irregular, and coarse-meshed intermyofibrillar network, Cap structures, Jagged z-lines

CaseNotHPOs: HP:0001263, HP:0010862, HP:0001371, HP:0002650, HP:0003115, HP:0002877, HP:0002792, HP:0003798 (Global developmental delay, Delayed fine motor development, Joint contracture, Scoliosis, Abnormal EKG/ECG, Nocturnal hypoventilation, Reduced vital capacity, Nemaline bodies)

NotHPOsFreeText: N/A

CaseAddInfo: Healthy parents, Normal pregnancy, delivery, and neonatal period, Variant is de novo

CasePreviousTesting: Laboratory investigations, including muscle enzymes, have been normal, MYH1, ACTA1, MYH2, MYH7, and TPM3 were all sequenced with negative results.

CaseGenotypingMethod: PCR and sequencing analysis were performed on genomic DNA, specifically the entire coding sequence of TPM2. A PCR fragment of exon 2 of TPM2 was sequenced in both parents with negative results.

Variant: NM_003289.3:c.154_156dup (p.Gly52dup)

ClinVar: 140485 https://www.ncbi.nlm.nih.gov/clinvar/variation/140485/

gnomAD: Not in gnomAD

Case1: Male, 42 yrs report

CasePresentingHPOs: HP:0002359, HP:0003324, HP:0002515, HP:0003391, HP:0003273, HP:0000098, HP:0002751, HP:0003691, HP:0000465, HP:0002792, HP:0001620, HP:0001284, HP:0003458, HP:0003557, HP:0003803, HP:0003715 (Frequent falls, Diffuse muscle weakness, Waddling gait, Gowers sign, Hip contracture, Tall stature, Kyphoscoliosis, Scapular winging, Webbed neck, Reduced vital capacity, High-pitched voice, Areflexia, EMG: myopathy, Increased fiber size variation, Type 1 muscle fiber predominance, Myofibrillar myopathy)

HPOsFreeText: Uncomplicated pregnancy and delivery, Difficulty sitting at 8 months, Inability to walk longer distances and must use a wheelchair outdoors at 15 yrs, Extreme gracility of the limb and trunk muscles, Partly irregular and abnormally coarse-meshed pattern of the intermyofibrillar network, Cap structures, Loss of thick filaments, Thickened fragments of Z-bands

CaseNotHPOs: HP:0008947, HP:0010628, HP:0040081, HP:0011675, HP:0003798 (Infantile muscular hypotonia, Facial muscle weakness, Abnormal levels of creatine kinase in blood, Arrhythmia, Nemaline bodies)

NotHPOsFreeText: N/A

CaseAddInfo: Healthy parents and two healthy brothers, Mutation is de novo

CasePreviousTesting: N/A

CaseGenotypingMethod: PCR and sequencing analysis were performed on genomic DNA, specifically the entire coding sequence of TPM2. A PCR fragment of exon 2 of TPM2 was sequenced in both parents and a sibling with negative results.

Variant: NM_003289.3:c.142_144delAAG (p.Lys49del)

ClinVar: 12466 https://www.ncbi.nlm.nih.gov/clinvar/variation/12466/

gnomAD: Not in gnomAD

Case: Family D-Case VIII-1, male, Saudi Arabia, died at 10 months

CasePresentingHPOs: HP:0005957, HP:0030917, HP:0005972, HP:0000414, HP:0000400, HP:0000343, HP:0100259, HP:0002069, HP:0001649, HP:0002104, HP:0011294, HP:0007204, HP:0002536, HP:0002719

CasePresentingHPOText: Authors note his birth weight was 2.3 kg, length 55cm and OFC 30.2cm. Noted as having frequent negative Rolandic sharp waves and fronto-central sharp waves on EEG on the 2nd day of life. Seizures manifestation occured with hyper-rhythmic discharges that emanated from the right frontal and centro-occipital regions. Intractable seizures on keppra, added oral pyridoxine at 2 months with improvement of seizure control. Proband had reccurrent chest infections and died at 10 months of life.

CaseNOTHPOs:

CasePreviousTesting: n/a

CaseGenotypingMethod: Homozygosity mapping and exome sequencing.

Homozygous, parental testing confirmed in trans.

Variant: NM_001031689.2(PLAA):c.68dup (p.Leu24Profs)

ClinVar ID: 427942

Pathogenic, no star, last reviewed Jun 21, 2017. Duplication/ frameshift

gnomAD: n/a

AddCaseInfo: Figure of Pedigree in Fig S1 Family D. Only the proband is homozygous, all others tested were shown to be heterozygous carriers (indicated by the center dots). The father had two brothers that were noted to have the same phenotype that resulted in lethality, but they were not able to be genotyped.

VariantEvidence: n/a

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

paper provided by LD VCEP for this variant. annotating here since the paper is a PDF provided by the library.

Case#: Thomas P61, 1yo, male, Indian

DiseaseAssertion: Hurler

FamilyInfo: n/a

CasePresentingHPOs: HP:0000280, HP:0001433, HP:0007957, HP:0002719, HP:0001249

CaseHPOFreeText: 2.5% residual IDUA activity on DBS

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: c.1195_1197del (p.Glu399del); c.1249_1275del (p.Thr417_His425fs*55)

ClinVar: 2498386; 556156

CAID: CA549264677; CA658823291

SupplementalData: n/a

Case2: Male, Spain, Birth onset

CasePresentingHPOs: HP:0003722, HP:0001324, HP:0000297, HP:0003701, HP:0001252, HP:0001284, HP:0001283, HP:0002540, HP:0002307, HP:0000218, HP:0011471, HP:0002460, HP:0002650, HP:0006466 (Neck flexor weakness, Nemaline bodies, Muscle weakness, Facial hypotonia, Proximal muscle weakness, Muscular hypotonia, Areflexia, Bulbar palsy, Inability to walk, Drooling, High palate, PEG-fed in infancy, Distal muscle weakness, Respiratory insufficiency, Scoliosis)

HPOsFreeText: Bimodal communication, Wheelchair dependence, Mechanic ventilation

CaseNotHPOs: HP:0001249, HP:0001627, HP:0002093, HP:0001382, HP:0003798, HP:0002307 (Ophthalmoplegia, Intellectual disability, cardiac abnormality, Ankle contracture, Joint hypermobility, Drooling)

NotHPOsFreeText: Cephalic support, Sedestation

CaseAddInfo: Severe variant, Paternity/maternity was confirmed, Variant 2 is predicted to be likely benign due to the population frequency and it not being located in any binding sites however no other mutations were found (including CNVs)

CasePreviousTesting: N/A

CaseGenotypingMethod: A research panel with 751 genes relating to neurological disorders, including the coding and intronic flanking regions of ACTA1, CFL2, KBTBD13, NEB, TNNT1, TNNT3, TPM2 and TPM3, was used to locate any variants in the proband. These variants were then prioritized and confirmed by Sanger sequencing in the probands and their relatives.

Variant1: NM_001271208.2:c.21076C>T (p.Arg7026Ter)

ClinVar: 190457 https://www.ncbi.nlm.nih.gov/clinvar/variation/190457/

gnomAD: European (non-Finnish) 5.343e-5, Overall 3.233e-5 https://gnomad.broadinstitute.org/variant/2-152394412-G-A

Variant2: NM_001271208.2:c.23372T>C (p.Met7791Thr)

ClinVar: 167328 https://www.ncbi.nlm.nih.gov/clinvar/variation/167328/

gnomAD: Ashkenazi Jewish 0.01744, Overall 1.605e-3 https://gnomad.broadinstitute.org/variant/2-152369326-A-G

Previously published in PMID: 21521498. Annotations on phenotype located on that paper.

Case# Katagiri019, Female, Japanese

CasePresentingHPOs HP:0007987, HP:0007675, HP:0000551, HP:0007737

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod PCR of exons 4-11 of CNGA1

Variant NM_000087.3(CNGA1):c.265delC (p.Leu89Phefs) and novel "c.1429delG(p.V477YfsX17)"

ClinVar 1st 225315

CAID 2nd CA658820612

gnomAD 0.001378

Case# *II-4, 54yo reported

CasePresentingHPOs HP:0001310, HP:0001260, HP:0001251, HP:0000639, HP:0009072, HP:0008969, HP:0003487

CaseMethod1 WES

Variant NM_152703.4(SAMD9L):c.3587G>C (p.Cys1196Ser)

ClinVar 242373

Case: Zampieri SD4, Male

DiseaseAssertion: Sandhoff Disease

FamilyInfo: patient's genotype was confirmed in parents

CasePresentingHPOs: HP:0000007, HP:0033978

CaseHPOFreeText: neurological symptoms (unspecified)

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: Patients presented with neurological symptoms and diagnosis was confirmed by the demonstration of reduced Hex A and Hex B activity in peripheral white blood cells or cultured fibroblasts.

GenotypingMethod: PCR

PreviouslyPublished: n/a

SupplementalData: n/a

Variant: c.850C>T (p.R284X) same on both alleles

CAID: CA116495

gnomAD: MAF: 0.0002286 South Asian, gnomAD variant ID: 5-74009409-C-T

VariantEvidence: PMID:8162015 previously reported this variant to be associated with the infantile form of SD. A fibroblast line from this patient with the infantile form of the disease was investigated for mutations by single strand conformation polymorphism analysis and direct sequencing of PCR products. A nonsense mutation was found which generated a stop codon at codon 284. The study investigated the steady-state level of mRNA produced by cells containing stop codons using a competitive polymerase chain reaction technique and found that at codon 284, the mRNA levels were 0.8%, as percent of normal per single gene dose.

Case: Zampieri SD5, Female

DiseaseAssertion: Sandhoff Disease

FamilyInfo: patient's genotype was confirmed in parents

CasePresentingHPOs: HP:0000007, HP:0033978

CaseHPOFreeText: neurological symptoms (unspecified)

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: Patients presented with neurological symptoms and diagnosis was confirmed by the demonstration of reduced Hex A and Hex B activity in peripheral white blood cells or cultured fibroblasts.

GenotypingMethod: PCR

PreviouslyPublished: n/a

SupplementalData: n/a

Variant: c.1372C>T (p.Q458X) same on both alleles

CAID: CA360070432

gnomAD: not found in gnomAD

VariantEvidence: This mutation is novel and results in the introduction of a premature stop codon at position 458 that would lead to a truncated protein. This study proved the functional relevance in vivo by conducting a RT-PCR analysis of the HEXB mRNA which detected the mutated HEXB mRNA.

Case4: Female, Austria, 30 yrs report

CasePresentingHPOs: HP:0010628, HP:0002015, HP:0040288, HP:0001260, HP:0003690 (Facial weakness, Swallowing difficulties, Nasogastric tube feeding, Dysarthric speech, Limb weakness)

HPOsFreeText: 8/9/9 Apgar score

CaseNotHPOs: HP:0002015, HP:0002540, , HP:0002098, HP:0002650 (Swallowing difficulties, Non-ambulatory, Respiratory distress, Scoliosis)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: Next generation sequnecing-based panel analysis detected the below variants in LMOD3.

Variant: NM_198271.4:c.1648C>T (p.Leu550Phe)

ClinVar: 374498 https://www.ncbi.nlm.nih.gov/clinvar/variation/374498/

gnomAD: Not in gnomAD

Case#: 4, female, 5 days (onset), 3 y 11 mo (current), Chinese

CasePresentingHPOs: HP: 0008344. HP: 0012088, HP: 0001279, HP:0001254, HP: 0011968, HP: 0001942, HP: 001276, HP: 0002543, HP: 0011344 (elevated A keto acids in urine, abnormal urinary odor, unconsciousness, lethargy, feeding difficulties, metabolic acidosis, hypertonia, abnormal globus pallidus, severe global developmental delay)

HPOsFreeText: liver damage, blood ammomia: 129 uM, Hemoglobin: 59 g/L, Leucin: 1155.27 uM, Valine: 848.19 uM, Isoleucine: 374.34 uM, Alloisoleucine: 128.73 uM

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: unsure whether cis or trans

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_000709.3:c.178G>T (p.Glu60Ter), NM_000709.3c.491T>C (p.Leu164Pro),

ClinVar: n/a

CAID: CA406004676, CA406010453

gnomAD: not found

Case#: Family MZ, Northern European

CasePresentingHPOs: HP:0001639 ( Hypertrophic cardiomyopathy)

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting:

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: PCR amplification followed by Cycle Sequencing

Variant: The nucleotide variant positions here refer to those described in the initial cloning of the gene in 1988 (PMID: 3336363), but nucleotide A595G here aligns to NM_001018005.2(TPM1):c.539A>G (p.Glu180Gly).

ClinVar: 12455

CAID: CA019017

gnomAD: 15-63060915-A-G not in gnomAD v4.0.0

VariantEvidence:

CaseAddInfo:

CasePMIDs: PMID:8327508

genotypes in table S2

Case#: Shi_Proband III-1

Demographics: Male, 20y, China

CasePresentingHPOs: HP:0001300, HP:0001256, HP:0001337, HP:0002071, HP:0002063, HP:0007076, HP:0200085, HP:0001288,

Pregnancy, delivery nd perinatal period were normal. Learning difficulties were identified at 8y. Age at tremor onset was 12y. Hoehn and Yahr staging was 2.5. T1, T2, and Susceptibility Weighted Imaging (SWI)-weighted brain MRI showed low-signal intensities in the bilateral globus pallidus, whereas CT scan showed high-density calcification in the same area. Treatment with Levodopa resulted in slight relief from tremor. Unified Parkinson’s Disease Rating Scale (UPDRS) - 32; Montreal Cognitive Assessment (MoCA) - 15; Mini-Mental State Examination (MMSE) - 20

CaseNotHPOs:

CasePreviousTesting:

CaseMethod1: WES

CaseMethod2: Sanger

CaseGenotypingMethod: WES was performed, followed by sequencing of the entire RAB39B coding region and exon-intron boundaries.

Variant: NM_171998.4:c.536dup (Ile180Aspfs*48)

ClinVar: CA1139768479

CAID:

gnomAD: NR

VariantEvidence: The proband was hemizygous for the null variant, Ile180AspfsTer48. The variant is predicted to cause extension of the protein with loss of the natural stop codon. In the absence of functional evidence supporting loss of function due to the variant, reduced points are awarded.

CaseAddInfo: Proband's parents were noted to be nonconsanguineous

CasePMIDs:

Case: Campeau Patient 1/Whyte Proband, female, 3 yo at report, American

CasePresentingHPOs: HP:0004322, HP:0000256, HP:0000592, HP:0410018, HP:0001581, HP:0003565, HP:0002007, HP:0002694, HP:0000885, HP:0000926, HP:0005019, HP:0100039, HP:0002757, HP:0000270, HP:0001518, HP:0002027, HP:0002829, HP:0001387, HP:0001742, HP:0030350, HP:0000348, HP:0005280, HP:0002714, HP:0002705, HP:0000369, HP:0011800, HP:0002857, HP:0012770, HP:0003300, HP:0005789, HP:0011002

CasePresentingHPOsFreeText: Broad ribs with sclerosis. Pelvis, peripheral sclerosis. Diaphyseal relative hypodensity. Painless, episodic erythematous papules usually on lower abdomen, legs, or arms. Serum BAP, osteocalcin, and TRACP-5b levels all were consistently low. Maxillary and ethmoid sinuses were opaque at ages 22 and 33 months, and the mastoid air cells were small. Increased amounts of cartilage, decreased hematopoietic marrow, and an absence of identifiable osteoclasts.

CaseNOTHPOs: HP:0100543, HP:0000504, HP:0000364, HP:0001595, HP:0000164, HP:0011329, HP:0000238, HP:0430048

CaseNOTHPOSFreeText: Abnormal serum glucose level. Bony tenderness.

CasePreviousTesting: Candidate gene sequencing. No notable variants int CLCN7, TCIRG1, or OSTM1. PCR and sequencing in both directions of all coding exons and adjacent mRNA splice sites of TNFRSF11A, TNFRSF11B, CSF1, CSF1R, and ANKH revealed no mutations. (c.107C > G, p.Pro36Arg) was found in TNFSF11, but not thought to be causal. Microarray-based genomic copy-number analysis of the patient and parents also was unrevealing.

CaseGenotypingMethod: WES

Variant: p.Ser203Pro (c.607T>C) and p.Arg386Gln (c.1157G>A)

ClinVarID: or CAID: CA130662; CA130660

gnomAD: The missense variant Ser203Pro is present in gnomAD v4.0.0 with a MAF=0.00002989 (1/33454 alleles) in the African/African American population and 0 homozygotes.

The missense variant Arg386Gln is present in gnomAD v4.0.0 with a MAF=0.00003999 (3/75018 alleles) in the African/African American population and 0 homozygotes.

AddCaseInfo: Heteroygous, non-consanguineous parents. Father is of Turkish ancestry. The mother's family emigrated to Turkey from Greece 70 years ago. Proband has two healthy brothers. No family history of skeletal disease

PreviouslyPublished: Whyte et al. PMID: 20499338

VariantEvidence: n/a

This variant has already been scored in homozygosity. Will consider scoring if necessary, but leaving out of curation for now.

W31R variant in homozygosity

Case#: Family IV-III:1, 26 year old, male

CaseHPOs: HP:0003563 (decreased LDL cholesterol)

CaseNotHPOs: HP:0000819 (Diabetes)

CasePreviousTesting: TC 102 mg/dl, LDL-C 36 mg/dl, HDL-C 57 mg/dl, TG 46 mg/dl (see additional values in Table 1)

Variant: NM_000384.2:c.11153C>G (p.Ser3718Ter), heterozygous

CAID: CA345983128

gnomAD: Absent

Variant evidence: APOB- p.Ser3718* mutations lead to the formation of expected truncated ApoB forms (ApoB-81) of 418 kDa (Fig. 1C, right panel) that can be secreted by the liver and lipidated.

CaseAddInfo: Son of Family IV-II:1

Case: Family III-II:2, female, 24 years

CaseHPOs: HP:0003563, (decreased LDL cholesterol)

CaseNotHPOs: HP:0000819 (Diabetes)

CasePreviousTesting: TC 143 mg/dl, LDL-C 28 mg/dl, HDL-C 110 mg/dl, TG 26 mg/dl (see additional values in Table 1). ApoB100 40 mg/dl (normal range 49-88) (Supplemental data). Normal ranges- total cholesterol (TC) 92-234 mg/dl, LDL-cholesterol (LDL-C) 136-174 mg/dl, HDL-cholesterol (HDL-C) 60-95 mg/dl), triglyceride (TG) 35-132 mg/dl.

Variant: NM_000384.2:c.8799C>A (p.Cys2933*), heterozygous

CAID: CA345993342

gnomAD: Absent

Variant evidence: APOB-p.Cys2933* leads to the formation of expected truncated ApoB form (ApoB-64) of 330 kDa (Fig. 1C, right panel) that can be secreted by the liver and lipidated.

Case# Wang II:3, male, Chinese

CasePresentingHPOs HP:0007675, HP:0001123, HP:0000543, HP:0000572, HP:0007737, HP:0031609, HP:0008043

CaseMethod1 PCR

CaseGenotypingMethod genes related to opthalmological diseases

Variant NM_000087.3(CNGA1):c.265delC (p.Leu89Phefs) and novel "p.Y82X"

ClinVar (1st) 225315 link

CAID (2nd) CA356834547 link

gnomAD 0.001378 link

Case7: Male, 13 yrs report

CasePresentingHPOs: HP:0001288, HP:0003701, HP:0009053, HP:0000765, HP:0002650, HP:0001250, HP:0006466, HP:0003798, HP:0003803 (Abnormal gait, Proximal limb weakness, Distal lower limb muscle weakness, Abnormality of the chest, Scoliosis, Epilepsy, Ankle contracture, Nemaline bodies, Type 1 muscle fiber predominance)

HPOsFreeText: Jaw contracture

CaseNotHPOs: HP:0001627 (Cardiac abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Parental testing not performed

CasePreviousTesting: ACTA1 was sequenced and returned negative.

CaseGenotypingMethod: The TPM2 gene was sequenced and variants identified. No other information is provided.

Variant: NM_003289.3:c.14_16delAGA (p.Lys7del)

ClinVar: 140486 https://www.ncbi.nlm.nih.gov/clinvar/variation/140486/

gnomAD: Not in gnomAD

FamilyName: Family 2

FamilyPresentingHPOS: HP:0002497, HP:0003429

FamilyNotHPOs:

CountryOrigin: Kenya and Tanzania

Ethnicity: n/a

Race: n/a

FamilyPreviousTesting: MRI showed brain hypomyelination

FamilyGenotypingMethod: combination of homozygosity mapping and WES, haplotype analysis

Affected: 2

Unaffected:

Segregations:

PublishedLOD:

eLOD:

AddSegregationInfo:

ProbandLabel: III-2 (individual 4), Female, 44yo, dx at 1yo

Variant: NM_177400.2(NKX6-2):c.121A>T (p.Lys41Ter)

ClinVar: 430622, https://www.ncbi.nlm.nih.gov/clinvar/variation/430622/

gnomAD: n/a

CasePresentingHPOs: HP:0000639, HP:0002066, HP:0002061, HP:0001272, HP:0007366, HP:0002540, HP:0000473, HP:0002451, HP:0002599, HP:0000571, HP:0000666, HP:0000496, HP:0002078, HP:0002070, HP:0008969, HP:0001348

CasePresentingHPOTerm: nystagmus, gait ataxia, lower limb spasticity, cerebellar atrophy, brainstem atrophy, inability to walk, cervical dystonia, lower limb dystonia, head titubation, hypometric saccades, horizontal nystagmus, limited eye movements, truncal ataxia, limb ataxia, lower limb stiffness

CaseNotHPOs: HP:0011730

AddCaseInfo: Cousin with identical phenotype died due to tuberculosis in childhood. (Individual 5)

VariantEvidence:

Case# Xin II:6, Female, 42, Chinese

CasePresentingHPOs HP:0007663, HP:0007675, HP:0001133

CaseMethod1 Sanger Sequencing

CaseGenotypingMethod NGS

Variant NM_000087.3(CNGA1):c.265delC (p.Leu89Phefs), NM_000087.3(CNGA1)c.1537G>A(p.G513R)

ClinVar 225315(1st)

CAID CA2911062(2nd)

VariantEvidence p. G513R protein localized to cytoplasm instead of plasma membrane like wildtype (fig. 3)

Case# Li-AP:II-4, F, 19 report

CasePresentingHPOs HP:0002066, HP:0000639, HP:0001903, HP:0005528, HP:0001251, HP:0001260,

HPO free text: "A bone marrow biopsy at age 14 showed hypocellularity with normal karyotype. A marrow sample obtained at age 17 failed to yield mitotic cells for cytogenetic analyses, both on direct preparation and after culture for up to 48 hr. At age 54 years, she has developed moderately severe ataxia and requires a walker to ambulate. Her mental status is normal and she has mild horizontal and vertical nystagmus, dysarthria, dysmetria, bilateral Babinski responses, and mild decreased appreciation of vibration in her toes. Brain MRI at the age of 52 years showed severe diffuse cerebellar atrophy as well as diffuse bilateral white matter signals throughout the cerebrum."

CasePreviousTesting Clinical genetic testing ruled out abnormalities in an extensive panel of dominant cerebellar ataxia genes.

CaseMethod1 Sanger

CaseGenotypingMethod Targeted Sanger sequencing of the single large coding exon of SAMD9L

Variant NM_152703.4(SAMD9L):c.3587G>C (p.Cys1196Ser)

ClinVar 242373

CasePMIDs 6947857(1981)

Case: Bolino Proband 1 (proband 1945), male, reported at 4yo, symptom onset at 42mo

CasePresentingHPOs: HP:0001349, HP:0003701, HP:0001284, HP:0001288, HP:0003474, HP:0003693, HP:0003722, HP:0003391, HP:0001761, HP:0003383, HP:0012447 (bilateral facial weakness, proximal muscle weakness, areflexia, abnormal gait, sensory impairment, distal limb muscle atrophy, neck flexor weakness, Gower's sign, pes cavus, onion bulb formation, abnormal myelination)

HPOsFreeText: walked at 14mo, eyes reported to be normal, gait - bilateral steppage, pes equinovarus deformity of both feet, frequent falling, had normal early motor milestones, bilateral pes cavus with retraction of Achille's tendon, intellectually normal. Laboratory testing normal: full blood count, fasting blood glucose, serum electrolytes, creatine kinase, lactic acid, urinary organic acids, serum and urine carnitine, EEG, ECG, and liver echography, segmental demyelination in 92% of fibers, redundant loops of myelin sheath irregularly arrayed near axon, muscle biopsy of rectus femoris showed atrophic and angulated fibers in clusters and large type grouping, lipid accumulation

Median nerve conduction studies: compound motor action potential = 4.6uV, distal motor latency = 7.8msec, sensory action potential = 3.3uV, motor nerve conduction velocity = 17msec, sensory nerve conduction velocity = 18msec

Peroneal nerve conduction studies: compound motor action potential = 0.21uV, distal motor latency = 7.8msec, motor nerve conduction velocity = 14

Sural nerve conduction studies: sensory action potential = no response, sensory nerve conduction velocity = no response

CountryOrigin: Italy

FamilyInfo: consanguineous family, parents reported to be normal at clinical and electrophysiological exams

PreviouslyPublished: PMID:10673338, PMID:8817346, PMID: 8628474, PMID: 8017168

GenotypingMethod: RT-PCR of RNA from patient lymphoblastoid cell line, available family members analyzed and segregation of variant with disease confirmed in pedigree - PMID:8817346 - homozygosity mapping and haplotype sharing through microsatellite and linkage analysis

Variant: NM_016156.5(MTMR2):c.1276C>T (p.Gln426Ter) homozygous

ClinVar: 6231, https://www.ncbi.nlm.nih.gov/clinvar/variation/6231/

gnomAD: 0.000007085, https://gnomad.broadinstitute.org/variant/11-95578227-G-A

Case#: Patient #6, male, 22yo

DiseaseAssertion: MPS1, Hurler-Scheie Syndrome

FamilyInfo:

CasePresentingHPOs: HP:0033834, HP:0012378, HP:0001387, HP:0006536, HP:0002719, HP:0001433, HP:0001510, HP:0007957, HP:0010535, HP:0004749, HP:0002094, HP:0000969, HP:0003541, HP:0001537, HP:0000023

CaseHPOFreeText: NYHA class IV at beginning of therapy, cardiac valve disease

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: physical examination including history-taking, magnetic resonance imaging of the abdomen and brain, and range-of-motion measurements. Echocardiography and electrocardiography were performed at base line and at 12, 26, and 52 weeks. Corneal photographs were obtained and a skeletal survey was performed at base line and at weeks 26 and 52. A skin biopsy was performed at base line to establish cultures of fibroblasts for the determination of enzyme activity and genotyping. Biochemical studies included measurement of enzyme activity in leukocytes and brushings of buccal mucosa, urinary glycosaminoglycan excretion, and tests for serum antibodies to α-L-iduronidase.

GenotypingMethod:

PreviouslyPublished:

Variant: 236C>T, compound het with c.1727+2T>A (CA355965298)

ClinVar: 1458769

CAID:

gnomAD: n/a

SupplementalData:

CaseP785: Male, 10 yrs onset

CasePresentingHPOs: HP:0007340, HP:0007210, HP:0002495, HP:0001639 (Lower limb muscle weakness, Lower limb amyotrophy, Impaired vibratory sensation, Hypertrophic cardiomyopathy)

HPOsFreeText: Wheelchair-bound 25 yrs

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: 21.8% fratraxin protein levels

CaseGenotypingMethod: See Group

Variant1: FXN, (GAA)n REPEAT EXPANSION, IVS1

ClinVar: 561195, https://www.ncbi.nlm.nih.gov/clinvar/variation/561195/

gnomAD: Not in gnomAD

Variant2: NM_000144.5:c.99del (p.Ala34ProfsTer?)

CAID: CA193369008, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA193369008

gnomAD: Not in gnomAD

CaseP585: Male, 14 yrs onset

CasePresentingHPOs: HP:0002078, HP:0001152, HP:0000639, HP:0007340, HP:0007210, HP:0002495, HP:0001639 (Truncal ataxia, Saccadic smooth pursuit, Nystagmus, Lower limb muscle weakness, Lower limb amyotrophy, Impaired vibratory sensation, Hypertrophic cardiomyopathy)

HPOsFreeText: Wheelchair-bound 22 yrs

CaseNotHPOs: HP:0000648, HP:0000365, HP:0001760, HP:0002015 (Optic atrophy, Hearing impairment, Abnormal foot morphology, Dysphagia)