Case#: 1, male, 3 days (onset), 2 y 8 mo (current), Chinese

CasePresentingHPOs: HP:0008344 HP: 0012088, HP: 0001250, HP: 0011968, HP: 0001941, HP: 0001943, HP: 0001987, HP: 0001903, HP:0012751, HP:0002543, HP: 0001276, HP:0011343 (elevated A keto acids in urine, abnormal urinary odor, seizures, feeding difficulties, acidosis, hypoglycemia, hyperammonemia, anemia, abnormal basal ganglia MRI signal intensity, abnormal globus pallidus signals, hypertonia, moderate global developmental delay)

HPOsFreeText: Blood ammonia: 75 uM, Valine: 532.83 uM, Isoleucine: 384.90 uM, Alloisoleucine: 213.09 uM

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: variants also found in parents

Case (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000709.3(BCKDHA): IVS6+1delG (can't search this format of an intronic mutations, how do I change it?)

ClinVar: not sure how to search for BCKDHA IVS6 + 1delG

CAID:

gnomAD:

Variant2: NM_000709.3(BCKDHA):c.740A>G (p.His247Arg)

ClinVar: not found

CAID: CA406012849

gnomAD: not in gnomAD

There are two variants listed for every patient except, one. The text said that all the mutations found were also found in the parents so does that mean they would be in trans?

(didn't see this template at first, so still need to apply it to the other entries)

Case#: Yamagishi Case 1, female, 3yo1mo, Japanese

DiseaseAssertion: MPS1-Hurler

FamilyInfo: consanguinity

CasePresentingHPOs: HP:0001510, HP:0002240

CaseHPOFreeText: mental delay, height -1.5SD

CaseNotHPOs:

CaseNotHPOFreeText: cardiac involvement

PreviouslyPublished: n/a

Variant: 704ins5 homozygous

ClinVar: 11921

CAID: CA256123

SupplementalData: n/a

Case#: Family IV-II:1, 58 years old, male

CaseHPOs: HP:0003563 (decreased LDL cholesterol)

CaseHPOsFreeText: Type 2 diabetes and severe non-alcoholic steatohepatitis (NASH) with pre-cirrhotic lesions and well differentiated hepatocellular carcinoma (HCC) diagnosed on liver biopsy

CasePreviousTesting: TC 120 mg/dl, LDL-C 50 mg/dl, HDL-C 55 mg/dl, TG 89 mg/dl (see additional values in Table 1) ApoB100 19 mg/dl (normal range 49-88) (Supplemental data)

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-I:1

Case#: Family II-II:1, 41 year old, male

CaseHPOs: HP:0003563, HP:0001397 (decreased LDL cholesterol, hepatic steatosis)

CaseHPOsFreeText: Prediabetes

CasePreviousTesting: TC 113 mg/dl, LDL-C 38 mg/dl, HDL-C 69 mg/dl, TG 32 mg/dl (see additional values in Table 1). ApoB100 22 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.

CaseGenotypingMethod: Next generation sequencing panel for high-throughput sequencing of the coding regions of genes previously linked to FHBL (APOB, PCSK9, ANGPTL3) and ABL (MTTP, SAR1B). Sanger sequencing was performed for validation.

Variant: NM_000384.2:c.7711C>T (p.Gln2571Ter), heterozygous

CAID: CA43502110

gnomAD: Absent

Family#: Family III

PresentingHPOs: HP:0003563 (decreased LDL cholesterol)

PresentingHPOsFreeText: FHBL diagnosis was based on low levels of fasting calculated plasma LDL-C < 50 mg/dL without lipid lowering therapy. Affected relatives were diagnosed by LDL-C < 80 mg/dL and/or ApoB <50 mg/dL.

FamilyMethod1: Next generation sequencing

FamilyGenotypingMethod: Next generation sequencing panel for high-throughput sequencing of the coding regions of genes previously linked to FHBL (APOB, PCSK9, ANGPTL3) and ABL (MTTP, SAR1B). Sanger sequencing was performed for validation and co-segregation analysis among family members.

ProbandLabel: Family III-II:2

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

CAID: CA345993342

gnomAD: Absent

Case#: Severe MPS1 patients, 6 individuals with this genotype

DiseaseAssertion: Severe MPS I

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: n/a

GenotypingMethod: n/a

PreviouslyPublished: possible

Variant: R628X/R628X

ClinVar: 550421

CAID: CA2802462

SupplementalData: Table S1 also lists this variant one time in compound heterozygosity with Q70X

Case# Christensen A, 59 diagnosis, male

CasePresentingHPOs HP:0004756 Ventricular Tachycardia, HP:0010872 T-Wave Inversion, HP:0005133 Right Ventricular Dilation, HP:0031317 Fatty replacement of ventricular myocardial tissue

CasePreviousTesting amplicons were pre‐screened on a LightScanner High‐Resolution Melting Curve Analysis System

CaseMethod1 PCR

CaseGenotypingMethod (PCR) amplification was performed for all TMEM43 exons and flanking introns.

Variant NM_024334.2(TMEM43):c.705+7G>A

ClinVar 46152

gnomAD 0.0007554 link

VariantEvidence N/A

Case18 Male, Finland

CasePresentingHPOs HP:0003826, HP:0000347, HP:0001627, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260

(Stillbirth, Micrognathia, Congenital heart defect, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Type II lissencephaly)

HPOsFreeText Crown-heel bodylength 45cm, body weight 2050g, brain weight 265g, abnormal larynx/trachea, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, leptomeningeal heterotopia, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0000202, HP:0001161, HP:0001829, HP:0007165

(Oral cleft, Hand polydactyly, Foot polydactyly, Periventricular heterotopia)

NotHPOsFreeText Uterus duplex, 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 stillbirth, 36+6wk gestational age

CasePMIDs n/a

Case5 Male, Finland

CasePresentingHPOs HP:0000347, HP:0001161, HP:0001829, HP:0000157, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260, HP:0030449

(Micrognathia, Hand polydactyly, Foot polydactyly, Tongue abnormality, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Type II lissencephaly, Therapeutic aboriton)

HPOsFreeText Crown-heel body length 22cm, body weight 315g, Toe polydactly with multiple extra toes, Abnormal larynx/trachea, Hydrocephalus/open-book, Occipitotemporal hypoplasia, Infratentorial hypoplasia, occipitotemporal hypoplasia, leptomeningeal heterotopia, neuroepithelial rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

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

(Oral cleft, Congenital heart defect, Hypothalamic hamartoma, Periventricular neuronal heterotopia)

NotHPOsFreeText Uterus duplex, hypothalamic hamartoma/bulging, 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+1wk gestational age

CasePMIDs n/a

Case13 Female, 6day old death, Finland

CasePresentingHPOs HP:0000347, HP:0000157, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260, HP:0007165

(Micrognathia, Tongue abnormality, Defective lung lobulation, Hydrocephalus, Olfactory lobe aplasia, Callosal aplasia, Fused thalami, Polymicrogyria, Type II lissencephaly, Periventricular neuronal heterotopia)

HPOsFreeText Crown-heel body length 42cm, Body weight 2326g, brain weight 206g, abnormality larynx/trachea, uterus duplex, 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, small unilateral remnant of the olfactory tract, (Fig2:)small proximal stumps of callosal fibers with a small longitudinal Probst bundle element, lateral periventricular nodular heterotopia, smooth cortical surface without normal gyration; missing midline commissures , large leptomeningeal heterotopia between the ba and brain tissue surface immunopositive for microtubule-associated protein 2 (MAP-2), hypoplastic temporal lobe displays a miniature dentate fascia, dysplastic hippocampus, heterotopic (Fig5:) glioneuronal wart-like eruption, irregular and disrupted bundles of radial glial structures, calretinin (CR)-positive and reelin positive neurons in dysplastic cortex, (Fig6:) minute dysplastic inferior olive only in some neuronal groups, totally narrowed pyramid medially below in the right lower corner of the medulla oblongata, all layers are narrowed in the atrophic cerebellar cortex of HLS, short and small frontal bundle of Probst

CaseNotHPOs HP:0000202, HP:0001829, HP:0001627

(Oral cleft, Foot polydactyly, Congenital heart defect)

NotHPOsFreeText 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 33+5wk gestational age

CasePMIDs n/a

Case: Individual 2, female, AOR= 8yo

CasePresentingHPOs: HP:0001263, HP:0000750, HP:0002342, HP:0007359, HP:0002500, HP:0001290, HP:0002360, HP:0000729, HP:0000739, HP:0025269, HP:0000490, HP:0001840, HP:0000486

CasePResentingHPOText: Began walking at 22 months, first words at 2yo,. Seizure onset at 7 yo and are focal, and occur nightly. Reduced white matter bulk on MRI. Referred to as having intoeing or pigeon-toed. Low APGAR scores, brief resuscitation required

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

CasePreviousTesting: ArrayCGH, Fragile X (FMR1), Angelman Syndrome (methylation & UBE3A), Rett syndrome (MECP2), Pitt-Hopkins Syndrome (TCF4), and extensive metabolic screening were all normal

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

Variant: hg19:chr2: g.48066586T>A, c.414A>T, p.(Arg138Ser) or NM_001190274.1:c.414A>T

CA ID: CA346813374

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

gnomAD: n/a

AddCaseInfo: Case was part of the DDD study 2017 PMID: 28135719,

VariantEvidence: Arg138 is located N-terminal to the F-box region of FBXO11, and is conserved across species. Pathogenicity algorithms showing varying predictions, from tolerated to damaging, thus indicating a VUS. No functional assays were performed to indicate the impact of the R138S mutation on FBXO11 function.

Case#: Patient 2.1.1, male, 4yo, Indian

DiseaseAssertion: MPS1

FamilyInfo: No family history reported, but said not to be consanguineous

CasePresentingHPOs:

CaseHPOFreeText: Distended abdomen, developmental delay

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: NGS, Sanger

PreviouslyPublished:

Variant: c.1882C > T p. Arg628Ter homozygous

ClinVar: 550421

CAID: CA2802462

SupplementalData: n/a

Case#: Family 5 Case 1, male, 43yo, south France

DiseaseAssertion: OA plus

FamilyInfo: mother and brother also had optic atrophy, but further details such as genotype and more phenotype information were not confirmed

CasePresentingHPOs: HP:0000648, HP:0000508, HP:0000365, HP:0001251, HP:0002403, HP:0003326, HP:0009830, HP:0003200, HP:0000590, HP:0003688, HP:0003390,

CaseHPOFreeText: visual impairment since childhood, colic occlusion without any evident mechanical cause, impaired sensation to all modalities predominantly in the lower limbs, atrophy of the corpus callosum and brainstem and a mild cerebellar atrophy, bilateral basal ganglia hypointensity was detected at T2-weighted MRI scan

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished:

PreviousTesting: Direct sequencing of the complete coding region and the exon/intron boundaries of the genes POLG1, PEO1 (Twinkle) and SLC25A4 (ANT1). mtDNA multiple deletions present.

GenotypingMethod: genomic DNA was amplified by PCR with specific primers designed to amplify all exons and flanking intronic regions and sequenced. Southern blot analysis, long-range PCR, sequencing in both directions, and quantitation of mtDNA relative to nuclear DNA was performed on mtDNA

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

ClinVar: 30461

CAID: CA10575554

SupplementalData:

unable to annotate in PDF.

Case: Farooq Family 2 Proband, Syrian, female, 16yo at report, onset at 1wk old

CasePresentingHPOs: HP:0030148, HP:0001629, HP:0033190, HP:0004322, HP:0012785, HP:0001730, HP:0002240, HP:0001395

CasePresentingHPOsFreeText: Hyperpigmentation on thighs and later genital area. Hearing started deteriorating progressively after an ear infection. Fasting blood glucose was elevated (350 mg/dl).

CaseNOTHPOs:

CaseNOTHPOSFreeText:

CasePreviousTesting:

CaseGenotypingMethod: All 6 exons including exon-intron boundaries of the SLC29A3 gene were amplified by PCR from the genomic DNA. Direct sequencing analysis. Restriction enzyme digest.

Variant: p.R386Q homozygous

ClinVarID: or CAID: 39870/CA130660

gnomAD: The missense variant p.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: Consanguineous, heterozygous parents. Proband's younger sister was also reported by the parents to be affected, but was not examined by the authors or genotyped.

PreviouslyPublished: n/a

VariantEvidence: n/a

Case2: Male, Birth onset, Australia

CasePresentingHPOs: HP:0008947, HP:0002460, HP:0001270, HP:0003701, HP:0000467, HP:0001488, HP:0002938, HP:0010628, HP:0003391, HP:0002942, HP:0003803, HP:0003755 (Infantile muscular hypotonia, Distal muscle weakness, Motor delay, Proximal muscle weakness, Neck muscle weakness, Bilateral ptosis, Lumbar hyperlordosis, Facial palsy, Gowers sign, Thoracic kyphosis, 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:0030877, HP:0031237 (Nemaline bodies, Abnormal nerve conduction study, Obstructive deficit on pulmonary function testing, Internally nucleated skeletal muscle fibers)

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.505A>G (p.Lys169Glu)

ClinVar: 42115 https://www.ncbi.nlm.nih.gov/clinvar/variation/42115/

gnomAD: Not in gnomAD

Family4: Australia

FamilyPresentingHPOs: HP:0002460, HP:0003701, HP:0000508, HP:0003803, HP:0003755 (Distal muscle weakness, Proximal muscle weakness, Ptosis, Type 1 muscle fiber predominance, Type 1 fibers relatively smaller than type 2 fibers)

HPOsFreeText: Type 2B fibers absent

FamilyNotHPOs: HP:0001249, HP:0030177, HP:0003798 (Intellectual disability, Abnormal nerve conduction study, Nemaline bodies)

NotHPOsFreeText: N/A

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

FamilyGenotypingMethod: 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. In this family, 14 further DNA samples were sequenced and a LOD score analysis was performed.

FamilyAddInfo: Affected members of this family seem to have different symptoms based on age

FamilyPMIDs: N/A

Affected: 5

Segregations: 6

PublishedLOD: 3.01 at θ = 0

AddSegregationInfo: Candidate Gene Sequencing

ProbandLabel: Case 5

Variant: NM_152263.4(TPM3):c.298C>A (p.Leu100Met)

ClinVar: 12452 https://www.ncbi.nlm.nih.gov/clinvar/variation/12452/

gnomAD: Not in gnomAD

CaseF2:III-1: Female, Italy

CasePresentingHPOs: N/A

CaseAddInfo: Proband for F2

NonPatientCell Mouse cell line, EFO:0002887 "Myotubes generated from the homozygous dysgenic (mdg/mdg) mouse cell line GLT were cultured as described previously (44)."

GeneAlteration GFP tagged point mutation transfected into mouse cells

FunctionalEvidence Variant increased channel sensitivity to caffeine/voltage (fig. 2)

FAVariants NM_000069.2(CACNA1S):c.3257G>A (p.Arg1086His), ClinVar ID: 17626

NM_000445.4(PLEC):c.3719G>A (p.Arg1240His), ClinVar ID: 448061

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

MONDO: MONDO:0005144 for FALS

Case#8: Smith 2014 FALS W407X, F, 66 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.1220G>A (p.Trp407Ter)

ClinVar: 180184

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

Case#: Fateen_P4

Demographics: Egyptian

CasePresentingHPOs: HP:0000768, HP:0000943, HP:0002857, HP:0000256, HP:0002808, HP:0001382, HP:0005072, HP:0009769 prominent proximal metaphyses

CaseNotHPOs:

CasePreviousTesting:

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: single gene seq by Sanger of all 14 exons and restriction digest confirmation/ screening of parents and controls

Variant: NM_000512.5(GALNS):c.119A>G (p.Asp40Gly)

ClinVar: 1048369

CAID: CA397100962

gnomAD: n/a

VariantEvidence: hydrophillic>hydrophobic substitution in putative active site and enzyme activity data shows low enzyme function compared to reference range

CaseAddInfo:

CasePMIDs:

Case#: Consequence 1 Table 1 in Data Supplement (1 case)

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.1988G>A (p.Arg663His)

ClinVar: 42875 https://www.ncbi.nlm.nih.gov/clinvar/variation/42875/

CAID: n/a

gnomAD: 0.00003097 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23896042-C-T

Case#: Consequence 17 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.2681A>G (p.Glu894Gly)

ClinVar: 42922 https://www.ncbi.nlm.nih.gov/clinvar/variation/42922/

CAID: n/a

gnomAD: absent

Case#: Consequence 21 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.2945T>C (p.Met982Thr)

ClinVar: 42941 https://www.ncbi.nlm.nih.gov/clinvar/variation/42941/

CAID: n/a

gnomAD: 0.001416 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23892910-A-G

Case#: Consequence 18 Table 1 in Data Supplement (4 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.1750G>C (p.Gly584Arg)

ClinVar: 14090 https://www.ncbi.nlm.nih.gov/clinvar/variation/14090/

CAID: n/a

gnomAD: 0.000008790 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23896932-C-G

Case# Family R III:1, Female, 43yo, Bangladesh

CasePresentingHPOs HP:0002066, HP:0001257, HP:0002015, HP:0001260, HP:0001272

CaseMethod1 DNA SNP array

CaseMethod2 Exome sequencing

Variant NM_005186.3:c.337+1G>A

CAID CA381241741

VariantEvidence predicted null

Case 2: male, Dx = n/a, variant identified via direct sequencing

HP:0001712 (left ventricular hypertrophy)

Variant: NM_016599.4(MYOZ2):c.738A>G (p.Ile246Met)

non-LOF

ClinVar ID: 30509, conflicting interpretations of pathogenicity,<br /> https://www.ncbi.nlm.nih.gov/clinvar/variation/30509/

ExAC Score: 0.001897, http://gnomad.broadinstitute.org/variant/4-120107298-A-G

Case: Family 109, female, Dx = 12 yrs, septal thickness 3.2cm

Family had 6 affected individuals sharing MYOZ2 haplotype 4q26-q27

HP:0001635, HP:0001279, HP:0001712, HP:0005110, HP:0004755

heart failure, syncope, left ventricular hypertrophy, atrial fibrillation, supraventricular tachycardia

Variant: NM_016599.4(MYOZ2):c.142T>C (p.Ser48Pro)

Pathogenic, non-LOF

ClinVar ID: 30508 https://www.ncbi.nlm.nih.gov/clinvar/variation/30508/

Not in ExAC or gnomAD

Case# II-1, F, 13yo diagnosis, European

CasePresentingHPOs HP:0001254, HP:0001137, HP:0025404, HP:0008936, HP:0002509, HP:0025430, HP:0003739, HP:0002353, HP:0001508, HP:0000297, HP:0010804, HP:0000218, HP:0000347, HP:0001212, HP:0001864, HP:0040082, HP:0012167, HP:0030820, HP:0000276, HP:0000268, HP:0000549, HP:0000678, HP:0012166, HP:0002465

HPOcont: Lethargy, Alternating esotropia, Abnormal visual fixation, Muscular hypotonia of the trunk, Limb hypertonia, High-pitched cry, Myoclonic spasms, EEG abnormality, Failure to thrive, Facial hypotonia, Tented upper lip vermilion, High palate, Micrognathia, Prominent fingertip pads, Clinodactyly of the 5th toe, Happy demeanor, Hair-pulling, Hooded eyelid, Long face, Dolichocephaly, Abnormal conjugate eye movement, Skin-picking, Poor speech

Free Text: "Birth weight, length and head circumference were 3.149 kg (−0.18SD), 51 cm (+0.99SD), and 33 cm (−0.74SD), respectively. Although she did not cry immediately and was described as sleepy and lethargic, her Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. She has had poor weight gain throughout life. By 2 months of age, she developed alternating esotropia, poor visual fixation, truncal hypotonia, upper and lower extremity hypertonia and a high-pitched cry. She also had myoclonic jerks and jerky movements of her extremities. Her weight, height and head circumference were 4.6 kg (−1.57SD), 51 cm (−3.81 SD) and 39.2 cm (+0.06SD), respectively. A head CT scan detected no anatomical anomalies. An EEG showed excessively slow background without epileptiform activity. Despite intervention, her weight gain continued to fall off, and she was diagnosed with failure to thrive. She rolled over at age 6 months, sat unsupported at 1 year. A follow-up EEG at 14 months showed a slow dysrhythmic background compatible with a seizure predisposition and diffuse cerebral dysfunction. A brain MRI at 18 months of age showed normal anatomy and myelination. In the ensuing months, she demonstrated a happy disposition, low truncal muscle tone and distal hypertonia as well as a myopathic facial appearance, a tented upper lip, a high arched palate, micrognathia, prominent finger pads and mild fifth toe clinodactyly. At age 4 years and 1 month, a developmental assessment defined her overall functioning at no more than a 12-month-old equivalent; she was not autistic. At age 6 years and 11 months, she manifested sparse hair (trichotillomania), hooded eyelids, high arched palate, thin long face and mild micrognathia. At age 12 years, she walked with the support of splints. Her height, weight and head circumference were 127 cm (−3.64 SD), 22.6 kg (−4.06 SD), and 52 cm (−0.94SD), respectively. Her features included dolicocephaly, hooded eyelids, intermittently disconjugate gaze, sparse hair, high palate and crowded dentition. Developmental assessment documented behavioral difficulties including repetitive and self-stimulatory behaviors, sensory issues such as repetitively rubbing her hands on the floor and/or licking them and mouthing objects, rigidity, communication deficits, difficulties with emotional regulation and aggression when frustrated. Her aggression included the self-injurious behaviors of dermatillomania, biting and trichotillomania. She communicated with a few words, signs, gestures and a picture exchange communication system (PECS). She developed menses at age 13 years."

CasePreviousTesting "Family history was negative for intellectual disability, multiple congenital anomalies and recurrent miscarriages. Normal genetic investigations included a karyotype (550 band resolution), subtelomeric FISH, methylation studies of SNRPN, sequence analysis of UBE3A, and DMPK repeat analysis. Normal metabolic tests included transferrin isoelectric focussing, CSF amino acids and neurotransmitters, plasma amino acids, urine organic acids, urine purines and pyrimidines, serum acylcarnitines, blood ammonia and blood lactate. She also had normal audiological testing."

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod SNP array and WES, confirmed with Sanger qt/rtPCR

Variant (1) NM_032504.1:c.3983-3_3994delinsA (p.Ser1328Argfs19), (2) NM_032504.1:c.2431C>T (p.Arg811)

CAID (1) CA658820714, (2) CA350137388

VariantEvidence skin fibroblasts from affected sister showed no unc80 mRNA.

CaseAddInfo nonconsanguineous, confirmed in trans. Affected sister with similar phenotypes died of respiratory distress at age 7.

Wilson_Wisconsin kindred

Family#PresentingHPOs: HP:0001263, HP:0000750, HP:0001249, HP:0002174, HP:0007351, HP:0002362, HP:0002067, HP:0002396, HP:0001260, HP:0000256, HP:0002007, HP:0000218, HP:0001355,

Age at clinical evaluation <2y; early learning difficulty with ability to read and live independently (in some members), age at tremor onset 10-20y, age at Parkinson diagnosis 20s, absent response to L-Dopa, hypokinetic dysarthria, skin depigmented papules, normal cerebellar function and eye examination, normal karyotype, normal copper testing, normal blood count and chemistry, normal urine metabolic testing, normal hearing.

FamilyNotHPOs:

Fragile X syndrome,

CountryOrigin: Germany

Ethnicity:

Race:

Family#PreviousTesting: Multipoint linkage analysis was performed. X chromosome exome sequencing revealed no other variants in the linkage region. Direct sequencing of CLIC2 ruled out variants in the gene.

Family#Method1: Sanger seq

Family#Method2:

Family#GenotypingMethod: RAB39B was directly sequenced

Affected: 16

Unaffected:

Segregations:

PublishedLOD: 6.75

eLOD:

AddSegregationInfo:

ProbandLabel: Wilson_Wisconsin kindred proband

Variant: NM_171998.4(RAB39B):c.503C>A (p.Thr168Lys)

ClinVar: 156532

CAID:

gnomAD: NR

FamilyAddInfo: Family is noted to be of German ancestry, and no consanguinity is noted.

FamilyPMIDs: 1674730, 4025396

PMID: 36292628

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes: Case report

Family Name: Family 5

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: 1

Unaffected: 4

Segregations: n/a

PublishedLOD: n/a

eLOD: n/a

AddSegregationInfo: non-consanguineous family

ProbandLabel:

Variant: NM_033068.2(ACP4):c.713C>T (p.Ser238Leu)

ClinVar or CAID: 374862, https://www.ncbi.nlm.nih.gov/clinvar/variation/374862/

genomAD: 8.127e-6, http://gnomad.broadinstitute.org/variant/19-51297008-C-T

FamilyAddInfo: parents unaffected

CasePresentingHPOs: HP:0006316, HP:0006297, HP:0011055, HP:0011079, HP:0011073

CasePresentingHPOTerm: wide interdental spacing due to thin enamel, missing second mandibular permanent molar, maxillary canine not yet erupted, black staining on maxillary anterior teeth and first permanent molars, brown staining on posterior teeth

CaseNotHPOs: HP:0010299

AddCaseInfo:

VariantEvidence:

Case# Postma 3:3, female, 11yo, white

CasePresentingHPOs HP:0004758, HP:0001688

CasePreviousTesting no

CaseMethod1 PCR

CaseGenotypingMethod amplified/screen of CASQ2, SCN5A, HRC, PLN, RYR2, KCNQ1, KCNH2, and KCNK1 genes

Variant NM_001232.3(CASQ2):c.97C>T (p.Arg33Ter)

ClinVar 41043 link

gnomAD 0.000008968 link

VariantEvidence not in this article

annotating here since this is a PDF

Case#: Yamagishi Case 3, female, 3y4m at dx

DiseaseAssertion: Hurler/Scheie

FamilyInfo: Case 4 is this patient's sibling. Same genotype and similar phenotype

CasePresentingHPOs: HP:0001433

CaseHPOFreeText: height=90cm (-1.2SD)

CaseNotHPOs:

CaseNotHPOFreeText: mental delay. cardiac involvement

PreviouslyPublished: n/a

Variant: 704ins5; R89Q

ClinVar: 11921; 11922

CAID: CA256123; CA256124

SupplementalData: n/a

annotating here since this is a PDF

Case#: Yamagishi Case 1, female, 3y1m at dx

DiseaseAssertion: Hurler

FamilyInfo: consanguinity

CasePresentingHPOs: HP:0002240

CaseHPOFreeText: mental delay. height=89cm (-1.5SD)

CaseNotHPOs:

CaseNotHPOFreeText: cardiac involvement

PreviouslyPublished: n/a

Variant: 704ins5/704ins homozygous

ClinVar: 11921

CAID: CA256123

SupplementalData: n/a

Case3: Male, Germany, 20 yrs report

CasePresentingHPOs: HP:0010628, HP:0002015, HP:0040288, HP:0001260, HP:0003690, HP:0003798, HP:0002650 (Facial weakness, Swallowing difficulties, Nasogastric tube feeding, Dysarthric speech, Limb weakness, Nemaline bodies, Scoliosis)

HPOsFreeText: 7/8/9 Apgar score

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

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: N/A

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

Variant1: NM_198271.4:c.1648C>T (p.Leu550Phe)

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

gnomAD: Not in gnomAD

Variant2: NM_198271.4:c.1004A>G (p.Gln335Arg)

ClinVar: 374499 https://www.ncbi.nlm.nih.gov/clinvar/variation/374499/

gnomAD: Not in gnomAD

Case#: DD, 21 years, female

CasePresentingHPOsFreeText: apo-B plasma levels <2% of normal and > 50% acanthocytes; total cholesterol 1.27 (normal range 4-6.5 mmol/l), triglyceride 0.3 (normal range 0.3-1.8 mmol/l), apoB 1.5 (normal range 60-140 mg/dl), “virtually no LDL”; diagnosed with “homozygous” (i.e. biallelic) familial hypobetalipoproteinemia because both parents (AD and PD) had total plasma cholesterol and apo-B levels below the 5th percentile. Designated as the proband in the paper. However, only one variant identified (note that full gene sequencing was not performed”), and therefore PD (mother of DD) was added as the proband here as she is heterozygous for the variant and has lipid levels consistent with this.

PresentingNotHPOsFreeText: No neurological or retinal disease.

CasePreviousTesting: On Western blot a truncated species of apo-B was found in the VLDL/chylomicron fraction (fig. 3), predicted based on size to be at the 5’ end of exon 26. The protein was absent from the HDL or infranate fractions.

CaseGenotypingMethod: Genomic DNA was digested with a panel of restriction enzymes and Southern blotted. Based on truncated apoB size (detected on Western blot), the variant was predicted to be at the end of exon 26. Approximately 1.7 kb of genomic DNA including exon 26 was amplified by the polymerase chain reaction (PCR), cloned into M13, and sequenced.

Variant: Variant 1: NM_000384.3(APOB):c.5463del (p.His1822fs)

ClinVar: Variant 1 17882 Variant 2 – Not identified (not that full gene sequencing was not performed)

gnomAD: Variant 1 - 0.000008797 (European non-Finnish) Variant 2 – Not identified ((not that full gene sequencing was not performed)

CaseAddInfo: PD (mother) had the truncated apo-B (apo-B39) in both her VLDL and LDL lipoprotein fractions, but it was present at reduced levels compared to the apo-B100 arising from her one normal apo-B allele (fig. 3). Only apo-B100 and apo-B48 were detected in the father, AD.

Families 1 and 2

Variant, NKX6-2: c.121A>T; p.Lys41∗ (NM_177400.2), results in stop codon at amino acid 41 resulting in mRNA decay which causes the loss of the functional homeobox.

PMID 34019641

Phenotypes HP:0031413, HP:0002863

Phenotypes free-text short telomere length, myelodysplastic syndrome

Case1: Female, 12 yrs onset, Dutch

CasePresentingHPOs: HP:0002093, HP:0001288, HP:0003690, HP:0010628, HP:0003722, HP:0003202, HP:0003798 (Respiratory insufficiency, Gait difficulties, Limb muscle weakness, Facial muscle weakness, Neck flexor weakness, Muscle hypotrophy, Nemaline rods)

HPOsFreeText: Mild form of nemaline myopathy, Wheelchair from the age of 48, Selective hypotrophy of Type 1 muscle fibres

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: No family history of neuromuscular disorders, Variant was not detected in healthy mother or 7 unaffected siblings, Father was deceased so no sample was available

CasePreviousTesting: N/A

CaseGenotypingMethod: Genomic DNA and RNA was extracted from blood or lymphoblastoid cell lines. SSCP was used to analyze all 10 exons of TPM2. After locating the mutations, RT-PCR was used to confirm the mutated allele expression and haplotype analysis was performed on the probands and their family.

Variant: NM_003289.3:c.440A>C (p.Gln147Pro)

ClinVar: 12461 https://www.ncbi.nlm.nih.gov/clinvar/variation/12461/

gnomAD: Not in gnomAD

ExperimentName: Accumulation of glycosaminoglycans

GOterm:

FunctionalEvidence: Patient cells assayed with artificial substrates for the N-acetylgalactosamine-6-sulfate sulfatase encoded by GALNS, depending on the severity of the coding sequence alteration, are either unable to break down the substrate or are hindered. Further, in mucopolysaccharidosis IVA patients with known variants, elevated levels of keratan sulfate and chondroitin-6-sulfate can be found in their urine where levels in unaffected individuals are much lower.

HGNC:

GeneEvidence:

SharedGeneImplication:

This variant was said to be in table S2 per Mastermind, but it is actually T364M.

Case#: B1103, M, 57 y.o., Italian

CasePresentingHPOs: HP:0007354, HP:0003202, HP:0007340

CaseNotHPOs: HP:0100543

CaseGenotypingMethod: Sanger sequencing

Variant: NM_006000.3(TUBA4A):c.226+4A>G IVS2+4A>G

CAID: CA2018007638

CaseAddInfo: 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.

potential gene therapy targets to increase TERC (hTR)

Important Table of 16 known telomere biology disorder linked genes with synopses of associated diseases and case counts

Family#PresentingHPOs HP:0000639

FamilyNotHPOs HP:0001251, HP:0001876, HP:0005528

CountryOrigin France

Family#Method1 WES

Family#Method2 Sanger

FamilyGenotypingMethod WES results confirmed with Sanger

Affected 3

Unaffected 2

Segregations 3

AddSegregationInfo family not to score

ProbandLabel UB612, M, 13mo diagnosis

CasePresentingHPOs HP:0005528, HP:0000639, HP:0001876

CaseAddInfo "Transplantation was planned but eventually cancelled because his blood cell counts improved spontaneously," possibly due to UPD.

Variant NM_152703.4(SAMD9L):c.2956C>T (p.Arg986Cys)

ClinVar 446530

VariantEvidence (Figure 5) 293FT cells transfected with p.Arg986Cys showed more limited cell proliferation than WT SAMD9L in 28202457

FamilyAddInfo Monosomy 7 in IV:1, mother and aunt also recovered, likely due to UPD or revertant mosaicism

Patient: ID408

Variant: c.686-12A > G

CAID: CA2580612032

Functional effect: Normal exon inclusion *, use of de novo splice site: c.686-11. Observed in blood.

PMID 30098700

PMID: 9536098

Gene: PAX6

Variant NM_001368894.2:c.-128-2del

Disease: Ocular dysgenesis

InheritancePattern: AD

Disease PAX6-related ocular dysgenesis MONDO:0800183

CaseRoma: France

CasePresentingHPOs: HP:0006785, HP:0003236, (Limb-girdle muscular dystrophy, Elevated serum creatine kinase)

HPOsFreeText: Wheelchair bound before 14 yrs

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Probands are from consanguineous gypsy families supporting a founder event, This mutation segregated with the disease in 18 patients and all asymptomatic parents were heterozygous, 15 siblings were heterozygous and asymptomatic except for a moderate increase in Serum CK in some

CasePreviousTesting: Duchenne-like clinical presentation, Males and females equally affected, Normal dystrophin and decreased level of α- and γ-SG in muscle specimens

CaseGenotypingMethod: DNA was isolated from peripheral blood leukocytes and subject to PCR amplification for linkage analysis. Total RNA was extracted from muscle biopsies and cDNA synthesis was performed and amplified. This was sequenced and analyzed for mutations.

Variant: NM_000231.2(SGCG):c.848G>A (p.Cys283Tyr)

ClinVar: 2006 https://www.ncbi.nlm.nih.gov/clinvar/variation/2006/

gnomAD: 0.000008796, https://gnomad.broadinstitute.org/variant/13-23898652-G-A

Affected: 18

Unaffected: At least 29

Segregations: N/A

SegregationAddInfo: Candidate Gene Sequencing

Proband 1: male, Dx at 18 years, LV septal wall thickness = 30mm, family history of HCM with father and brother affected

HP:0001639, HP:0001670

Hypertrophic cardiomyopathy, asymmetric septal hypertrophy

Variant: NM_145046.4(CALR3):c.218G>A (p.Arg73Gln).

Not in ClinVar

ExAC Score: Overall 1.624e-5

http://gnomad.broadinstitute.org/variant/19-16601357-C-T

Proband KH9 was 11yo at report, has the Hurler phenotype, and has this variant in compound heterozygosity with 704ins5 (CTGCT)

Proband KH4 was 6yo at report, has the Hurler phenotype, and has this variant in compound heterozygosity with 704ins5 (CTGCT)

Case2: Female, Birth onset, Germany

CasePresentingHPOs: HP:0003552, HP:0001558, HP:0002375, HP:0002747, HP:0004887, HP:0001385, HP:0001537, HP:0000023, HP:0012418, HP:0000278, HP:0000347, HP:0000470, HP:0001276, HP:0002808, HP:0001376, HP:0002063, HP:0011968, HP:0000975, HP:0003236, HP:0000938, HP:0009803, HP:0030084, HP:0001561, HP:0002828, HP:0005949, HP:0001284, HP:0003198, HP:0003557, HP:0003687, HP:0010602 (Muscle stiffness, Decreased fetal movement, Hypokinesia, Respiratory insufficiency due to muscle weakness, Respiratory failure requiring assisted ventilation, Hip dysplasia, Umbilical hernia, Inguinal hernia, Hypoxemia, Retrognathia, Micrognathia, Short neck, Hypertonia, Kyphosis, Limited joint motion, Rigidity, Feeding difficulties, Profuse sweating, Elevated serum creatine phosphokinase, Osteopenia, Shortened phalanges, Clinodactyly, Polyhydramnios, Multiple joint contractures, Apneic episodes in infancy, Areflexia, Myopathic changes, Increased variability in muscle fiber diameter, Centrally nucleated skeletal muscle fibers, Type 2 muscle fiber predominance)

HPOsFreeText: Tracheostomy performed, Bladder catheter required, Inability to sit or roll, Increased echogenicity on muscle ultrasound, Treatment with carbamazepine, benzodiazepines, and baclofen reportedly provided no substantial benefit, Difficulty sitting due to hyperactivity of hip extensors, Mini rods and z-band broadening were seen in atrophic fibers

CaseNotHPOs: HP:0100543, HP:0003730, HP:0002486, HP:0002353, HP:0002363, HP:0000496, HP:0003202, HP:0003798 (Cognitive impairment, EMG: myotonic runs, Myotonia, EEG abnormality, Abnormality of brainstem morphology, Abnormality of eye movement, Skeletal muscle atrophy, Nemaline bodies)

NotHPOsFreeText: Abnormal metabolic screening, Muscle fiber type grouping

CaseAddInfo: Case is de novo and confirmed via parental testing

CasePreviousTesting: Negative ACTA1 and CRYAB

CaseGenotypingMethod: Based on the Patient 1 results, the same region of TPM3 (Exon 6) was PCR amplified and sequenced in the proband and her parents via bidirectional Sanger sequencing.

Variant: NM_152263.4(TPM3):c.654_656AGA[1] (p.Glu219del)

ClinVar: 235144 https://www.ncbi.nlm.nih.gov/clinvar/variation/235144/

gnomAD: Not in gnomAD

Article is a PDF, so annotating here.

Case#: OAK 96

DiseaseAssertion: clinical dx of adOA based on ophthalmological examination

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: All 30 coding exons of the OPA1 gene were amplified from genomic DNA by means of PCR. PCR and RT-PCR products were sequenced employing BigDyeTerminator Chemistry (Applied Biosystems, Darmstadt, Germany) and separated on an ABI 3100 DNA Sequencer

PreviouslyPublished: n/a

Variant: c.1705+1G>T (p.V556fsX596)

CAID: CA10576007

SupplementalData:

AdditionalInfo: Generation of minigene constructs and heterologous expression in COS7 cells allowed for cDNA analysis of the c.1705+1G>T mutation. This revealed a deletion of the last 40 nucleotides in exon 17 resulting from a splicing event that involves a cryptic splice donor site within exon 17 resulting in a frameshift and premature translation termination (p.V556fsX596).

Case3: Male, 27 years report, 20 years diagnosis, Germany

CasePresentingHPOs: HP:0002878 (Respiratory failure)

HPOsFreeText: 6-min walk test at 201 (m)

CaseNotHPOs:

NotHPOsFreeText: Not wheelchair bound

CaseAddInfo: 7 years on ERT

PatientCell CL:0000057 (fibroblast)

GeneFunction GO:0070131 (positive regulation of mitochondrial translation)

GeneAlteration n/a

FunctionalEvidence (Figure 2D) Labelling patient fibroblast proteins with EasyTag EXPRESS35S Protein Labeling Mix showed decreased assembly of complex I (NDUFB8) and IV (COXI) which corroborates the reduced mean enzyme activity and mitochondrial translation in Table 1.

FAVariants NM_017819.3(TRMT10C):c.814A>G (p.Thr272Ala)

ClinVar: 224317

and

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

ClinVar: 224316

NM_017819.3(TRMT10C):c.814A>G (p.Thr272Ala)

ClinVar 224317

CAID CA10575895

gnamAD n/a

Case: Zampieri SD9, 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.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.

Family CL-16: FamilyInfo: Japanese and German ancestry Proband II.2: had large aneurysm of sinuses of Valsalva and ascending aorta at ae 38 skin laxity on lower face and submandibular area during childhood but not noticeable in adulthood single palmar crease bilateral limited ability to supinate forearms inguinal hernia

II.3: died at age 26 of aortic dissection, no skin laxity

I.1, III.1: mildly dilated aortic root, mild aortic insufficiency, cutis laxa (face, submandibular, trunk, extremities) III.1: overall normal pulmonary function, prolonged wound healing I.1: inguinal hernia III.1: 12 year old male

VariantInfo: Direct sequence analysis of ELN in CL‐16, III.1 uncovered a 25 bp deletion in exon 30, 2114_2138del. This defect was present in all affected members of the family available for testing, including I.1 and II.2. The mutation was not found in II.1. CAID: CA322210

Family CL-13: Singaporean girl of chinese decent with no family history of cutis laxa.

MonDO: MONDO:0008504

Case: CL-13, II.1: 6 year old Asian female, Singaporean of Chinese decent with de novo variant.

DiseaseAssertion: Cutis Laxa

FamilyInfo: Parents do not harbor variant and are asymptomatic. No family history of cutis laxa.

CasePresentingHPOs: HP:0000973, HP:0001582, HP:0008070, HP:0040080, HP:0000343, HP:0005280, HP:0002616 (Cutis laxa, Redundant skin, Sparse hair, Anteverted ears, Depressed nasal bridge, Aortic root aneurysm)

CaseHPOFreeText: tear shaped eyes

CaseNOTHPOs: HP:0001659 (Aortic regurgitation)

CasePreviousTesting: At the age of 5 years 9 months an echocardiogram showed significant dilatation of the aortic root at the level of the sinuses of Valsalva with a measured diameter of 2.47 cm (normal <2.2 cm for her body surface area).

GenotypingMethod: DNA extracted from whole blood was amplified using PCR for each exon of ELN gene. Amplified products were sequenced bidirectionally using Sanger sequencing. A panel of 121 normal control individuals was genotyped for mutations 2114_2138del and 2159delC using denaturing high performance liquid chromatography.

Variant: ELN:c.2159delC, in exon30 ClinVarID: 16736 CAID: CA2580077344 gnomAD: Not found in gnomAD v.4.1

Case: Dawidziuk Proband, female, Polish, Caucasian, 10yo at report, onset at 22wks

CasePresentingHPOs: HP:0033044, HP:0034332, HP:0000817, HP:0002540, HP:0001263, HP:0002273, HP:0001252, HP:0000508, HP:0001272, HP:0002470, HP:0001298, HP:0004322, HP:0001344, HP:0100710, HP:5200044, HP:0000252, HP:0002061, HP:0000767

CasePresentingHPOsFreeText: lack of smile, “rounded” back, protruding shoulder blades, tendency to open the mouth and tilt the head back, cortico-subcortical atrophy of the cerebellum on MRI, enlargement of the 4th ventricle and widening of cerebellar sulci. Low COQ10 level tests showing 0.6 mg/l (normal range >0.67 mg/l); after 2-month treatment: 0.7 mg/l

Cardiac echocardiogram, complete blood count, electrolyte levels, CPK, liver and renal function tests, carnitine and acyl-carnitine, copper, thyroid function tests, lactate, blood amino acid profile, homocysteine, as well as urine for protein and organic acids, were within normal limits.

CaseNOTHPOs: HP:0025190, HP:0010865, HP:0001336, HP:0001250, HP:0000639, HP:0000514, HP:0000570, HP:0000657, HP:0001310, HP:0002174, HP:0002080, HP:0002353,

CaseNOTHPOSFreeText: family history of neurodevelopmental disorders. The supratentorial structures are normal. Echocardiogram, abdominal ultrasonography, and ophthalmologic investigation were also uneventful. Encephalomyopathy

CasePreviousTesting: The aCGH analysis did not show any pathogenic copy number variations. Genetic panel excluded congenital Rett, Rett-like and Angelman's syndromes, microdeletion / microduplication syndromes and genetically based lysosomal diseases

CaseGenotypingMethod: Exome sequencing, Sanger sequencing of parents to confirm biallelic origin

Variant: c.681+1G>A; c.352G>A (p.Gly118Ser) confirmed in trans

ClinVarID: or CAID: CA386577420; CA244466459

gnomAD: The splice-site variant, c.681+1G>A in exon /7, is present in gnomAD v4.1.0 with a MAF=0.00002229 (1/44868 alleles) in the East Asian population and 0 homozygotes. The missense variant, p.Gly118Ser, is present in gnomAD v4.1.0 with a MAF=0.0001650 (1/6062 alleles) in the Middle Eastern population and 0 homozygotes.

AddCaseInfo: healthy, non-consanguineous parents

PreviouslyPublished: n/a

VariantEvidence: COQ5 mRNA (Supp.Fig.3) showed that its level is markedly diminished

Case# UW-AP:III-3, 60yo reported

CasePresentingHPOs HP:0001251, HP:0001310, HP:0001260, HP:0000639, HP:0007256

Variant NM_152703.4(SAMD9L):c.2640C>A (p.His880Gln)

ClinVar 242372

CaseAddInfo only genotyping methods described are for extended Family 1 or in a previous study. Is this UW family also from another study?

CaseFSIP2_4 male, 43yo report, Tunisian

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

(male infertility, asthenospermia, sperm tail anomaly)

HPOsFreeText Sperm volume: 1.7mL, sperm concentration: 49.5 million/mL, total motility: 5h, vitality: 52%, normal spermatozoa: 0%, absent flagella: 6%, short flagella: 70%, coiled flagella: 14%, flagella of irregular caliber: 80%

CaseNotHPOs n/a

CasePreviousTesting Previous genetic analysis of DNAH1, CFAP43, and CFAP44 did not end in diagnosis. "Normal somatic karyotypes 46,XY and were negative for Y chromosome microdeletions."

Variant NM_173651.3(FSIP2):c.16393_16396del (p.Asn5465Glufs)

ClinVar 586971

gnomAD not in gnomAD

CaseAddInfo Consanguineous parents

CasePMIDs 29449551

Variant 1. NM_000512.5:c.901G>T 2. NM_000512.5:c.1156C>T 3. NM_000512.5:c.120+1G>A 4. NM_000512.5:c.346G>A 5. NM_000512.5:c.1171A>G 6. NM_000512.5:c.860C>T 7. NM_000512.5:c.139G>A 8. NM_000512.5:c.280C>T 9. NM_000512.5:c.1019G>A 10. NM_000512.5:c.1168del

Italics highlight common variants with table 2

This proband was "described and recently published by Vazna et al." (PMID: 19396826). Patient is compound heterozygous for c.1882C>T (p.Arg628Ter) and c.208C>T (p.Gln70Ter) (P based on classification by the ClinGen Lysosomal Diseases VCEP); phase confirmed in trans. PM3=0 points

Case#: Pedigree OA-16, North of England

DiseaseAssertion: optic atrophy

FamilyInfo: 2 additional affected individuals

CasePresentingHPOs: HP:0000648

CaseHPOFreeText: Snellen BCVA 20/200 - hand movement, mean age of onset= 3.7yrs

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: Cautious that they may overlap with the individuals from Hudson et al since both are from England, but the author notes that they "checked against the eOPA1 database (http://lbbma.univ-angers.fr/eOPA1/, Accessed 10-12-09) to determine whether they had been described in previous mutational reports."

GenotypingMethod: The entire coding region of the OPA1 and OPA3 genes was amplified by PCR and sequenced. Variants were confirmed by reverse sequencing.

Variant: c.1635C>G; p.S545R

ClinVar: 30461

CAID: CA10575554

SupplementalData:

Case# B4, Male, UK

CasePreviousTesting re-sequenicing of genome

CaseGenotypingMethod genotyped for five microsatellite markers spanning TMEM43 on chromosome 3p25

Variant NM_024334.2(TMEM43):c.424G>A (p.Glu142Lys)

ClinVar 46147

gnomAD 0.001121 link

FamilyLabel R07-429

Family#PresentingHPOs HP:0001263, HP:0003072, HP:0003015, HP:0003300, HP:0000978, HP:0002099, HP:0003193, HP:0002721, HP:0002007, HP:0000316, HP:0000218, HP:0000767, HP:0008905, HP:0003027, HP:0002987, HP:0003049, HP:0001156, HP:0004209, HP:0006380, HP:0006460, HP:0002694, HP:0005930, HP:0011844, HP:0008788, HP:0003155, HP:0002850

(GDD, Hypercalcemia, Flared metaphyses, Ovoid vertebral bodies, Easy bruising, Asthma, Allergic rhinitis, Immunodeficiency, Frontal bossing, Hypertelorism, High arched palate, Pectus excavatum, Rhizomelia, Mesomelia, Contractures of elbows, Ulnar deviation of the wrist, Brachydactyly, Fifth finger clinodactyly, Knee contractures, Increased laxity of ankles, Sclerosis of skull base, Epiphyseal abnormality, Abnormal appendicular skeleton morphology, Delayed pubic bone ossification, elevated alkaline phosphatase, decreased IgM)

HPOsFreeText Born at term, significant developmental delay/special education, abnormal brain MRI, severe unclassified immunodeficiency, normal PTH concentration, mild hypercalcemia. Radiographic findings: widened/flared metaphyses with irregular ossification, moth-eaten long bones, fragmentation of the proximal metacarpals, and a distinctive transverse gap seen in the tibias. From table: eczema or atrophoderma, wheel chair bound-unable to bear weight on lower extremities, flattened supraorbital ridges, normal formed and positioned ears, mild pectus excavatum, Mesomelia with significant anterior bowing in the upper and lower extremities, Ulnar deviation at the wrists with laxity, telescoping fingers, Mild knee contractures, Significant laxity at the ankles with positional equinovarus, 2-3 syndactyly, Delayed ossification of the fontanel, Delayed ossification of the basal occipital bone, Delayed ossification of the posterior elements of the spine, Significant metaphyseal irregularities, Epiphyseal delay with irregular epiphyses, Subjectively large distance from the epiphyses to the metaphyseal edge, Ossification defect or gaps in the appendicular skeleton, Brachydactyly with metaphyseal irregularities and epiphyseal delay, IgE <1 (normal <20 IU/ml), CD3 T-lymphocytes 82% (normal 60-76%), Parathyroid hormone intact 19 (normal 11-51 pg/ml). Radiograph additionally showed widened/flared metaphyses with irregular ossifications and irregular ossification front, brachydactyly with irregular metacarpal and phalangeal metaphyses and delayed epiphyseal ossification, absence of pubic bone ossification, and delayed ossification of the basal occipital bone and subjectively increased density of the skull.

FamilyNotHPOs n/a

NotHPOsFreeText fixed equinovarus, walked with or without assistance

CountryOrigin n/a

Ethnicity n/a

Race n/a

Family#PreviousTesting PTH1R coding exons sequenced due to phenotype overlap with JMC. No variants identified.

ProbandLabel R07-429A

Variant NM_025164.4(SIK3):c.559C>T (p.Arg187Cys)

ClinVar 587366

gnomAD not in gnomAD

FamilyAddInfo consanguineous

FamilyPMIDs n/a

PatientID: 82

KindredID: 82

Case: Sex Unknown, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711; HP:0010797 (retinal capillary hemangioma, hemangioblastoma)

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0006770; HP:0100634; HP:0030405; HP:0030421 (clear cell renal cell carcinoma; Neuroendocrine neoplasm, pancreatic neuroendocrine neoplasm, Epididymal neoplasm)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 29437867 (likely family 17 - see here for more info)

SupplementalData: Yes; see table S1 for VHL subject genetic and manifestation information.

Variant: p.V166Sfs*4 (c.496_506del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 223229 https://www.ncbi.nlm.nih.gov/clinvar/variation/223229/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: minus_2_frameshift_variant

CivicName: V166Sfs*4 (c.496_506del)

MultipleGeneVariants: N/A

PatientID: 1

KindredID: 1

Case: M, 41Y0M, Ethnicity Unknown

DiseaseAssertion: assumed VHL

FamilyInfo: No family history of VHL disease.

CasePresentingHPOs: HP:0030393; HP:0009711; HP:0010797; HP:0002666; HP:0009726; HP:0001737 (endolymphatic sac tumor, retinal capillary hemangioma, hemangioblastoma, pheochromocytoma, renal neoplasm, pancreatic cysts)

CaseHPOFreeText: patient was 21 years old when he experienced a sudden right hearing loss (cophosis). During a follow-up, the patient suffered from other manifestations of VHL disease mentioned above.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R113* (c.337C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 220414 https://www.ncbi.nlm.nih.gov/clinvar/variation/220414/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: stop_gained

CivicName: R113*(c.337C>T)

MultipleGeneVariants: N/A

PatientID: 9

KindredID: 9

Case: F, 16Y0M, Korean

DiseaseAssertion: VHL

FamilyInfo: No family history of VHL.

CohortInfo: 26 Korean patients with more than one HAB in the CNS or eye, a single HAB in the CNS or retina plus a visceral manifestation (multiple renal, pancreatic or hepatic cysts, pheochromocytoma and RCC) and positive family history plus any one of the above manifestations.

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: Diagnosed with VHL Type 1.

CaseNotHPOs: HP:0002666; HP:0005584; HP:0010797 (Pheochromocytoma, Renal cell carcinoma, Hemangioblastoma)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E70K (c.208G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 43598, https://www.ncbi.nlm.nih.gov/clinvar/variation/43598/

CAID: N/A

gnomAD: 0.000004365, https://gnomad.broadinstitute.org/variant/3-10183739-G-A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: E70K (c.208G>A)

MultipleGeneVariants: N/A

PatientID: 431

KindredID: 431

Case: Sex Unknown, 15Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797; HP:0009711 (Hemangioblastoma, Retinal capillary hemangioma)

CaseHPOFreeText: CNS and retinal hemangioblastoma.

CaseNotHPOs: HP:0002666; HP:0006770; HP:0001732; HP:0000107 (Pheochromocytoma, Clear cell renal cell carcinoma, Abnormality of the pancreas, Renal cyst)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

Variant: Exon 3 Deletion (c.464-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant; deletion

CivicName: Exon 3 Deletion

MultipleGeneVariants: N/A

In a study of 426 unrelated VHL patients, 111 were discovered to have alterations in the VHL gene. 18 novel variants were identified in VHL patients, but none were present in 200 unaffected control individuals. DNA samples from peripheral blood leukocytes underwent polymerase chain reaction (PCR) amplification, denaturing high-performance liquid chromatography (DHPLC), and direct sequence analysis of the entire coding sequence and intron-exon boundaries. The L153P (c.458T>C) germline missense mutation of the VHL gene was found in a 36 yr old VHL patient with renal cysts as well as central nervous system and retinal hemangioblastoma (index case 191).

PatientID: 83

KindredID: 83

Case: Sex Unknown, 11Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0010797 (Hemangioblastoma)

CaseHPOFreeText: CNS hemangioblastoma.

CaseNotHPOs: HP:0009711; HP:0006770; HP:0002666; HP:0000107; HP:0001732 (Retinal capillary hemangioma, Clear cell renal cell carcinoma, Pheochromocytoma, Renal cyst, Abnormality of the pancreas)

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished:N/A

SupplementalData: Table S1, S2 and S3

Variant: Partial Deletion (4.6kb)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: deletion

CivicName: Null (Partial deletion of 4.6kb)

MultipleGeneVariants: N/A

PatientID: IV

KindredID: 3

Case: Sex Unknown, 21Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: 3 other family members presented with his VHL mutation. Patient 3-I was asymptomatic. Patients 3-II and 3-III both presented with pheochromocytoma at 15Y.

CasePresentingHPOs: HP:0002666; HP:0009711 (Pheochromocytoma, Retinal capillary hemangioma)

CaseHPOFreeText: Diagnosed with VHL at age 10Y. Presented with pheochromocytoma at 12Y and retinal hemangioblastoma at 10Y. Age at the end of study: 21Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.G93D (c.278G>A)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496054, https://www.ncbi.nlm.nih.gov/clinvar/variation/496054/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: G93D (c.278G>A)

MultipleGeneVariants: N/A

PatientID: I

KindredID: 4

Case: Sex Unknown, 53Y0M, Danish

DiseaseAssertion: VHL

FamilyInfo: N/A

CasePresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

CaseHPOFreeText: Diagnosed with VHL at age 7Y. Presented with retinal hemangioblastoma at 7Y and 14Y. Age of death: 53Y.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.F136S (c.407T>C)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 496064, https://www.ncbi.nlm.nih.gov/clinvar/variation/496064/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: F136S (c.407T>C)

MultipleGeneVariants: N/A

GroupID/ KindredID: 18

DiseaseAssertion: VHL

GroupSize: 14

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: 14 registrants belonging to the same family (18) have the germline VHL mutation.

GroupPresentingHPOs:HP:0009711; HP:0010797; HP:0001737; HP:0005584; HP:0000107; HP:0002666; HP:0030393; HP:0001407 (retinal capillary hemangioma, hemangioblastoma, pancreatic cysts, renal cell carcinoma, renal cyst, pheochromocytoma, endolymphatic sac tumor, hepatic cysts)

GroupHPOFreeText: 6 had retinal hemangioblastoma, 9 had CNS hemangioblastoma, 7 had renal cell carcinoma, 8 had renal cysts, 4 had pheochromocytoma, 5 had pancreatic cysts, 2 had endolymphatic sac tumors, 1 with adnexal papillary tumor of probably mesonephric origin, and 5 had hepatic cysts.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: Previously reported, HGMD (Human Gene Mutation Database: http://uwcmml1s.uwcm.ac.uk/uwcm/mg/search/120488.html)

SupplementalData: N/A

Variant: p.V170D (c.509T>A)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: 625256 https://www.ncbi.nlm.nih.gov/clinvar/variation/625256/

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant;transversion

CivicName: V170D (c.509T>A)

MultipleGeneVariants: N/A

Between 1994 and 2001, the Dutch VHL working group conducted DNA analysis on 146 probands with VHL-associated manifestations. DNA of probands was extracted from peripheral blood samples. Exons 1, 2 and 3 of the VHL gene and their flanking untranslated and intronic coding sequences were amplified by PCR and subjected to semi-automated sequence analysis. Screening for structural rearrangements, including deletions, involving the VHL gene was performed by Southern blot analysis and the multiplex ligation-dependent probe amplification (MLPA) assay. Deletions encompassing the entire VHL gene were confirmed by FISH analysis on lymphocytes from affected individuals. VHL mutations were identified in 43 families. This mutation (c.452T>C) was detected in a VHL patient with CNS hemangioblastomas and renal cell carcinoma (family no. 11). This was published in a future publication: PMID: 32179488.

PatientID: None (XIII)

KindredID: 7

Case: Sex and Ethnicity unknown; Age >18Y0M

DiseaseAssertion: asymptomatic

FamilyInfo: Total of 13 family members belonging to Family 7 (see Table 2; or follow KindredID 7)

CasePresentingHPOs: None

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: 16572651

SupplementalData: N/A

Variant: p.G34Rfs*98 (c.99_100insA)

CaseProblemVariantFreeText: N/A

LegacyVariant: N/A

ClinVarID: N/A

CAID: CA2018007671 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2018007671

gnomAD: N/A

VariantEvidence: N/A

MutationType: plus_1_frameshift_variant

CivicName: G34Rfs (c.99_100insA)

MultipleGeneVariants: N/A

PatientID: None

KindredID: 16

Case: M, Age Unknown, Chinese

DiseaseAssertion:Asymptomatic

FamilyInfo: Positive. The patient's uncle was the proband and presented with hemangioblastoma, renal cell carcinoma, and abnormality of the pancreas. The patient's mother and cousin also had the mutation but were asymptomatic.

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: HP:0010797, HP:0009711, HP:0002666, HP:0005584, HP:0001732 (hemangioblastoma, retinal capillary hemangioma, pheochromocytoma, renal cell carcinoma, abnormality of the pancreas)

CaseNotHPOFreeText: The patient did not present with epididymal or ovarian cystadenomas.

CasePreviousTesting: N/A

PreviouslyPublished:29330336

Variant: Exon 1 deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVar: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: N/A

Using polymerase chain reaction (PCR)-direct sequencing and universal primer quantitative fluorescent multiplex–PCR, mutations in VHL gene in 19 VHL disease families recruited from the Department of Urology, Peking University First Hospital in the period from 2009 to 2012 were examined. One proband and their sister (family 1) were found to carry the mutation c.292T>A in exon 1 of the VHL gene. The proband presented with hemangioblastoma at age 35, retinal angioma and pancreatic cysts or tumours at age 37, and renal cell carcinoma at age 39. The patient had positive VHL family history and their first sister also carried this germline mutation but was asympromatic. Patient's mother did not undergo genetic testing but had a hemangioblastoma at age 50 and a pancreatic cyst or tumour at age 62. Another one of the patient's sisters presented with hemangioblastoma (age 40), renal cell carcinoma (age 43), and pancreatic cysts or tumours (age 43). This patient died before diagnosis. The proband's brother also died before diagnosis and presented with hemangioblastoma and retinal angioma at age 27.This family was previously published in 29330336.

216 patients with clinically expected VHL disease due to family history or presence of VHL typical tumours were routinely examined in an eye centre in Germany between January 2019 and January 2020, majority of which were of European descent (~95%). Since data on the genotype–phenotype correlation of the onset of Retinal Hemangioblastoma (RH) is scarce in relation to VHL disease, this study wanted to inversitage the relationship between VHL gene variants (truncating vs single amino acid substitutions) and the ocular phenotype of the disease. 42 different rare VHL gene variants in 148 patients were detected - some of whom had RH and some who did not. Although date of onset of RH, as well as data on central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renalcell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected, it was not reported on a per patient basis and therefore could not be discussed per variant. There was 1 patient reported with the c.461C>T (p.P154L) mutation. This member presented with retinal hemangiomas. No family information was provided.

GroupID: 37

DiseaseAssertion: VHL

GroupSize: 2

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: N/A

GroupAgeRange: N/A

GroupInfo: a retrospective cohort study from an eye centre in Germany involved 148 VHL patients and their genetic data involved in retinal capillary hemangiomas.

GroupPresentingHPOs: HP:0009711 (retinal capillary hemangioma)

GroupHPOFreeText: These 2 patients with a c.463G>C mutation had retinal capillary hemangiomas. Other VHL manifestations were discussed but not per- variant.

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.V155L (c.463G>C)

LegacyVariant: N/A

GroupProblemVariantFreeText: N/A

ClinVarID: 1023631 https://www.ncbi.nlm.nih.gov/clinvar/variation/1023631

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: missense_variant; transversion

CivicName: V155L (c.463G>C)

MultipleGeneVariants: N/A

PatientID: 9

KindredID: 2

Case: F, 29Y0M, African/African American

DiseaseAssertion: VHL

FamilyInfo: She was 23 weeks pregnant at the time of a pheochromocytoma resection. Her 6-year-old daughter screened positive for the mutation; her 8-year-old son was negative. Both mother (although no testing conducted) and daughter were said to be investigated further and monitored long-term.

CasePresentingHPOs: HP:0006748; HP:0009713 (adrenal pheochromocytoma; spinal hemangioblastoma)

CaseHPOFreeText: At the time, the patient was 23 weeks pregnant and had bilateral adrenal phaeochromocytomas removed. There were no clinical features of VHL syndrome; however, MRI showed a haemangioblastoma in the cervical spine.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R167W (c.499C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2218, https://www.ncbi.nlm.nih.gov/clinvar/variation/2218/

CAID: N/A

gnomAD: 0.000007954, https://gnomad.broadinstitute.org/variant/3-10191506-C-T

VariantEvidence: N/A

MutationType: missense_variant;transition

CivicName: R167W (c.499C>T)

MultipleGeneVariants: N/A

PatientID: II.1

KindredID: F10

Case: M, 4Y6M, Ethnicity Unknown

DiseaseAssertion: Polycythemia

FamilyInfo: This patient’s asymptomatic patients were both found to be carriers of the D143= (c.429C>T) germline variant in VHL. Their other child (II.2) also carried the gene. The current patient was the only one who was homozygous for the variant.

CasePresentingHPOs: HP:0001901; HP:0001744 (Polycythemia, Splenomegaly)

CaseHPOFreeText: Diagnosed with erythrocytosis (Polycythemia) and splenomegaly at 4.5 years old (DOB: 2002).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.D143= (c.429C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 416990, https://www.ncbi.nlm.nih.gov/clinvar/variation/416990/

CAID: N/A

gnomAD: 0.000007953, https://gnomad.broadinstitute.org/variant/3-10188286-C-T?dataset=gnomad_r2_1

VariantEvidence: Variant is present in allele 1 and 2 (i.e. homozygous).

MutationType: missense_variant;transition; synonymous_variant

CivicName: D143= (c.429C>T)

MultipleGeneVariants: Germline, Beta Thalassemia

PatientID: II.1

KindredID: F4

Case: M, 7Y0M, Ethnicity Unknown

DiseaseAssertion: Polycythemia

FamilyInfo: Variant c.340+694_340+711dup is inherited from mother (genetically confirmed) and variant R200W (c.598C>T) is assumed to be inherited from father.

CohortInfo: Patients with Chuvash polycythemia for whom VHL R200W had been found in a heterozygous state.

CasePresentingHPOs: HP:0001901; HP:0002625; HP:0001342 (Polycythemia, Deep venous thrombosis, Cerebral hemorrhage)

CaseHPOFreeText: Diagnosed with erythrocytosis (Polycythemia), deep vein thrombosis, intracerebral hemorrhage at age 7 (DOB: 1990).

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.R200W (c.598C>T)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 2232, https://www.ncbi.nlm.nih.gov/clinvar/variation/2232/

CAID: N/A

gnomAD: 0.0002016, https://gnomad.broadinstitute.org/variant/3-10191605-C-T

VariantEvidence: Variants are heterozygous.

MutationType: missense_variant;transition

CivicName: R200W (c.598C>T) and c.340+694_340+711dup

MultipleGeneVariants: Germline, VHL, c.340+694_340+711dup

MultipleGeneVariants: Germline, Factor V Leiden

PatientID: I.2

KindredID: F8

Case: M, Age Unknown, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: 6/10 genetically tested family members across two generations were found to harbor the c.340+648T>C and c.340+617C>G germline mutations of the VHL gene. Patient I.2 presented with retinal capillary hemangioma, pheochromocytoma (pheo) and renal cell carcinoma. Patient I.3 presented with CNS hemangioblastoma and pheo. Patient II.1 presented with pheo. Patients II.2, II.6 and II.7 presented with retinal capillary hemangioma.

CasePresentingHPOs: HP:0005584; HP:0009711; HP:0002666 (Renal cell carcinoma, Retinal capillary hemangioma, Pheochromocytoma)

CaseHPOFreeText: Presented with renal cell carcinoma, retinal capillary hemangioma and pheochromocytoma. Tumors detected at ages 15, 46 and 52.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: c.340+617C>G

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: 827582, https://www.ncbi.nlm.nih.gov/clinvar/variation/827582/

CAID: N/A

gnomAD: N/A

VariantEvidence: These variants segregated in 6 patients of this family who developed VHL disease and were absent in 4 healthy tested descendants, indicating their presence on a single disease-associated allele. Sequencing of tumor DNA did not display loss of heterozygosity, suggesting that a WT VHL deletion (as observed in classic VHL disease) may not be a prerequisite in cells of patients with this specific VHL genotype.

MutationType: missense_variant;transversion; splice_site_variant

CivicName: c.340+617C>G and c.340+648T>C

MultipleGeneVariants: Germline, VHL, c.340+648T>C