Case#: Single case; 37-year-old male construction worker; sudden unexplained death (SUD); found dead in bed ~1 hr after lunch, August 2005; molecular autopsy via WES in 2019 from autopsy tissue

DiseaseAssertion: Sudden unexplained death (SUD); no structural cardiac cause at autopsy; MYBPC3/TTN/ACADVL/RYR2-related per WES reevaluation

FamilyInfo: No family history or segregation data reported. The paper is a single molecular autopsy; no relatives were genotyped or phenotyped. No pedigree assessment performed.

ParentalTesting: Not performed, no family members tested.

CasePresentingHPOs: HP:0001698 (Sudden cardiac death); HP:0004756 (Ventricular tachycardia), the latter only as a speculative arrhythmic mechanism, not a documented clinical event

CaseHPOFreeText: Found dead in bed ~1 hr after lunch in August 2005. External examination showed no traumatic injury; toxicological blood screen negative. Clinical history unremarkable. Heart weighed 350 g (reference 331±57 g in men) with regular morphology and volume. Microscopy showed small foci of interstitial fibrosis, deemed not significant. No other organ showed significant abnormality. Case dismissed as SUD, reevaluated in 2019.

CaseNotHPOs: HP:0001639; HP:0001644; HP:0004308; HP:0001279

CaseNotHPOFreeText: No structural cardiac disease at autopsy, no hypertrophy, no dilation, normal heart morphology and volume. No evidence of any cardiomyopathy phenotype. No documented arrhythmia or syncope in life.

CasePreviousTesting: Autopsy (2005) with toxicology, histology. WES (2019) on DNA from FFPE left ventricular tissue; 562-gene cardiac panel (234 SCD/heart-disease genes + 328 heart-expressed genes); filtering against gnomAD (rare = MAF <0.1%); in silico prediction with DANN, MutationTaster, FATHMM, MutationAssessor, PolyPhen-2, SIFT, PROVEAN; ACMG 2015 classification; WebGestalt enrichment analysis.

Genotyping Method: WES on Illumina 500 (TruSeq library prep, xGen exome capture), SeqMule pipeline, ENLIS Genome Research annotation; variants confirmed by Sanger sequencing. Aligned to GRCh37.

FunctionalAnalysis: None performed by the authors, no functional assays in this paper. (ACADVL p.V383A residual activity ~20% is cited from a 2007 external study, not performed here.)

Variant: Four heterozygous missense variants, one per gene

ClinVar:926037

CAID: CA221696968

gnomAD: N/A

AdditionalInfo:N/A

PatientID: None

KindredID: 67

Case: M, 25Y0M, Spanish

DiseaseAssertion: VHL

FamilyInfo: No familial antecedents. No known familial tumors.

CohortInfo: Probands belonging to 18 unrelated Spanish VHL families carrying germline VHL deletions.

CasePresentingHPOs: HP:0006880; HP:0001737; HP:0009711 (Cerebellar hemangioblastoma, Pancreatic cysts, Retinal capillary hemangioma)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 1-2 Deletion (c.1-?_464+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Germline HSPC300, ENST197804 and FANCD2 (unclear if partial or complete) gene deletion. Study provides evidence to show that loss of HSPC300 highly correlates with the absence of ccRCC in VHL patients.

MutationType: exon_loss_variant

CivicName: Exon 1-2 Deletion

MultipleGeneVariants: Germline, HSPC300, Deletion MultipleGeneVariants: Germline, ENST197804, Deletion MultipleGeneVariants: Germline, FANCD2, Deletion

GroupID: 38

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0000107; HP:0009711; HP:0010797; HP:0009713; HP:0030393; HP:0001737; HP:0030424 (Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Spinal hemangioblastoma, Endolymphatic sac tumor, Pancreatic cysts, Epididymal cyst)

GroupHPOFreeText: # of affected individuals: Renal cyst (1), Retinal capillary hemangioma (1), Hemangioblastoma/brain/cerebellum (2), Spinal hemangioblastoma (2), Endolymphatic sac tumor (1), Pancreatic cysts (2), Epididymal cyst (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 1-3 Deletion (c.1-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: Germline, HSPC300, partial deletion

MultipleGeneVariants: Germline, ENST197804, deletion

GroupID: 45

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0005584; HP:0000107; HP:0009711; HP:0010797; HP:0009713; HP:0030393; HP:0001737; HP:0030424 (Renal cell carcinoma, Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Spinal hemangioblastoma, Endolymphatic sac tumor, Pancreatic cysts, Epididymal cyst)

GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Renal cyst (1), Retinal capillary hemangioma (1), Hemangioblastoma/brain/cerebellum (1), Spinal hemangioblastoma (1), Endolymphatic sac tumor (1), Pancreatic cysts/single cyst (1), Epididymal cyst (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 1-3 Deletion (c.1-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: Germline, HSPC300, partial deletion

MultipleGeneVariants: Germline, ENST197804, deletion

MultipleGeneVariants: Germline, IRAK2, deletion

MultipleGeneVariants: Germline, TATDN2, partial deletion

GroupID: 51

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0005584; HP:0010797; HP:0030393; HP:0030424 (Renal cell carcinoma, Hemangioblastoma, Endolymphatic sac tumor, Epididymal cysts)

GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Hemangioblastoma/brain/cerebellum (1), Endolymphatic sac tumor (1), Epididymal cysts (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 1-3 Deletion (c.1-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: Germline, IRAK2, deletion

MultipleGeneVariants: Germline, FANCD2, deletion

Case UZ090: 4 year old female (row 91 in supplemental table)

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370

CaseHPOFreeRext: vWF:Ag (%) = 15; vWF:GPIbR (%) = 14.1; Act/Ag ratio = 0.94; FVIII:C (%) = 9.1; Platelets (x10^9/L) = 395

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)

GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants

PreviouslyPublished:

Gene: VWF

Variant: c.2573G>T p.Cys858Phe

HGVS:

ClinVarID: 100229

CAID:

gnomAD: absent

MultipleGeneVariants:

Gene: VWF

Variant: c.7437+5G>A

ClinVarID: not found

gnomAD: 0.000001859 (3 in 1613728) no homozygotes https://gnomad.broadinstitute.org/variant/12-5976106-C-T?dataset=gnomad_r4

CasePT-110: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.

Variant: NM_000257.3:c.5326A>G (p.Ser1776Gly)

ClinVar: 177629 https://www.ncbi.nlm.nih.gov/clinvar/variation/177629/

gnomAD: East Asian 3.007e-4, Overall 4.595e-5 https://gnomad.broadinstitute.org/variant/14-23884437-T-C

Multiple Gene Variants:

MYBPC3 Variant:

Variant is reported as below, but the nucleotide sequence is incorrect. Unable to register

Variant: NM_000256.3:c.76A>G (p.Ser236Gly)

Case#: 33 year-old female; first cardiologic evaluation at age 24 (LV wall thickness 13 mm); re-evaluated at 33 after recurrent palpitations

DiseaseAssertion: Noonan syndrome (PTPN11) with sarcomeric hypertrophic cardiomyopathy (MYBPC3); non-obstructive HCM, mild phenotype

FamilyInfo: Father carries the MYBPC3 c.1790G>A variant and has HCM; the PTPN11 variant was absent in both parents, consistent with de novo. Both parents and the proband's brothers underwent full cardiologic evaluation, no cardiovascular disease in the other family members. Parents declined genetic testing of the underage siblings. Grandparents (I-1, I-2) and II-2, II-3 have unknown phenotypes (pedigree Fig. 2).

ParentalTesting: Both parents genotyped for the two proband variants (Table 1). Father heterozygous for MYBPC3 c.1790G>A; neither parent carries PTPN11 c.1510A>G, supporting de novo status. Phase between the two variants therefore established as in trans (different genes).

CasePresentingHPOs: HP:0001639; HP:0001962; HP:0004322; HP:0000271; HP:0001647; HP:0000508

CaseHPOFreeText: Regular psychophysical development. First echo at 24 showed mild increase in LV wall thickness (13 mm). At 33, presented with several episodes of palpitations; exam showed mild facial dysmorphisms (wide mouth, sloping forehead, prominent nasal bridge, prominent nose, low-set ears), short stature, and a systolic heart murmur. Echo: asymmetric LV hypertrophy, maximum wall thickness 16 mm at the anterior interventricular septum, mild mitral regurgitation, non-obstructive. No other cardiovascular signs.

CaseNotHPOs: HP:0001635; HP:0001650; HP:0001642; HP:0001250

CaseNotHPOFreeText: No heart failure, no LV outflow obstruction, no pulmonary stenosis, no other congenital heart defect. No intellectual disability; psychophysical development was regular. No other signs of cardiovascular disease on examination.

CasePreviousTesting: NGS panel of 325 cardiomyopathy-associated genes (Supplementary Table S1); MAF threshold 5%; variants validated by Sanger sequencing; cascade testing restricted to the two proband variants.

Genotyping Method: NGS targeted panel (Maxwell 16 DNA extraction, Agilent Alyssa analysis, Illumina Variant Interpreter, in-house pipeline) with Sanger validation; parental Sanger genotyping for the same two variants.

FunctionalAnalysis: None performed by the authors. They cite prior HeLa cell work showing the MYBPC3 c.1790G>A change causes exon 18 inclusion in the transcript and an almost undetectable 248 bp product.

Variant 1: PTPN11 NM_002834.3:c.1510A>G (p.Met504Val); heterozygous missense; de novo; classified pathogenic, explains Noonan syndrome

ClinVar: Not stated in the paper; verify the current record before submitting.

CAID: N/A

gnomAD: Not reported in the paper; I have not checked gnomAD for this variant.

Variant 2: MYBPC3 NM_000256.3:c.1790G>A (p.Arg597Gln); heterozygous missense; exon 18, last nucleotide of the exon, affecting a highly conserved residue and causing a splicing variation; inherited from the father

ClinVar: Not stated in the paper; authors note it is classified pathogenic/likely pathogenic for HCM in several genetic databases.

CAID: N/A

gnomAD: N/A

PMID: 32824488

Gene: MYBPC3

AdditionalInfo: Authors describe this as the first reported young adult with HCM and mild NS carrying variants in both PTPN11 and MYBPC3. Note the terminology problem: the abstract calls them "compound heterozygous," but the variants are in different genes on different chromosomes, so this is digenic (double heterozygosity), not compound heterozygosity. The authors argue the mild phenotype contrasts with the usual expectation that multiple sarcomeric hits worsen the disease, and that red flags justified the broad panel.

Case#: 64-year-old male, non-smoker, first admitted June 2014; Russian family; died 2019 at age 69

DiseaseAssertion: MYBPC3-related cardiomyopathy with a predominantly restrictive phenotype in combination with left ventricular noncompaction (LVNC) and cardiac sarcoidosis

FamilyInfo: Son (39) and daughter (35) both heterozygous for the same variant and both have non-obstructive asymmetric HCM, with no LVNC on cardiac CT; both essentially asymptomatic on beta-blocker monotherapy. Five-year SCD risk 4.82% (son) and 2.07% (daughter); ICD implanted in the son, no shocks in three years. Authors mention another family of theirs with a father who died suddenly young and children with HCM and LVNC.

ParentalTesting: Not performed; the proband is the index case; his parents were not evaluated. Transmission to both children confirmed by Sanger.

CasePresentingHPOs:HP:0001639

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Genotyping Method: Next-generation sequencing panel; variants confirmed by Sanger.

FunctionalAnalysis: N/A

Variant 1: MYBPC3 NM_000256.3:c.278delA; heterozygous frameshift

Variant 2: KCNJ5 c.464G>A; heterozygous missense

ClinVar: N/A

CAID:N/A

gnomAD: N/A

Gene:MYBPC3

PMID:36011256

Case#: Pedigree III:2; male; HCM diagnosed clinically at age 39 (1998); heart transplant after progression to end-stage heart failure

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM), progressed to end-stage heart failure with systolic dysfunction

FamilyInfo: No family history of heart disease reported at diagnosis; no known consanguinity. Parents deceased and unavailable for testing. 12 relatives genotyped: one brother (III:3) homozygous, seven first- and second-degree relatives heterozygous. All heterozygotes have normal ECG, normal echo, and no cardiac symptoms. Three children of generation IV (IV:7, IV:8, IV:9) still awaiting results.⁠

ParentalTesting: Not performed; both parents deceased. Absence of consanguinity stated but not genetically confirmed; parental phase therefore inferred rather than tested.

CasePresentingHPOs: HP:0001639; HP:0002094 (Dyspnea); HP:0001658; HP:0001678

CaseHPOFreeText: Exertional dyspnea at age 39 with systolic murmur; IVS 26 mm, posterior wall >16 mm, LVOT peak velocity 2.8 m/s. Pacemaker 1999, extracted 2010 for infection. 2013 circumflex occlusion treated with stent (cholesterol 6.8 mmol/L, LDL 4.6 mmol/L; former smoker). Septum 27 mm, moderate systolic dysfunction, NSVT on Holter → ICD. 2014 AF with severe dyspnea; on beta-blocker, ACE inhibitor, and aldosterone antagonist. 2016 VO₂max 14 mL/kg/min; LVEDP 24 mmHg rising to 38 with exercise, pulmonary pressure 56/27 rising to 70/… systolic. Biopsy: moderate interstitial fibrosis, focal hypertrophy and atrophy, no infiltrative disease.

CaseNotHPOs: HP:0000822; HP:0000819

CaseNotHPOFreeText: BP normal throughout, no hypertension. No storage or infiltrative disease on biopsy. Spirometry normal. Narrow QRS, so CRT not indicated.

CasePreviousTesting: 84-gene cardiomyopathy NGS panel (MYBPC3 100% coverage); MLPA confirmed true homozygosity rather than hemizygous deletion; Sanger cascade in 12 relatives.

Genotyping Method: NGS panel followed by MLPA confirmation of homozygosity; Sanger for family cascade.

FunctionalAnalysis: None performed. Biopsy showed interstitial fibrosis with hypertrophy and atrophy, no infiltrative disease. Dominant-negative mechanism proposed, untested.

Variant: MYBPC3 NM_000256.3:c.2618C>A (p.Pro873His); homozygous missense; C7 domain. (Paper writes "c.2618 G>A" once, C>A is correct.)

ClinVar: Not stated; conflicting interpretations noted in the literature. Pepper please verifiy for me!

CAID: N/A

gnomAD: AF 0.00006781 (14/206,446; 13/97,288 European non-Finnish) per the authors.

AdditionalInfo: ACMG Class 2 (likely pathogenic) heterozygous. Authors argue homozygosity drove progression to end-stage failure; alternative triggers considered, prior myocarditis (1989) and the 2013 infarct; but judged insufficient to explain severity.

PMID: 29663722 Gene: MYBPC3 HGNC: HGNC:7551

PatientID: None

KindredID: 1

Case: F, 24Y0M, Ethnicity Unknown

DiseaseAssertion: Assumed VHL

FamilyInfo: Third child of healthy unrelated parents; she has two healthy older sisters.

CasePresentingHPOs: HP:0001511; HP:0001999; HP:0000952; HP:0001943; HP:0001508; HP:0000851; HP:0001250; HP:0002650; HP:0001332; HP:0001263; HP:0006880 (Intrauterine growth retardation, Abnormal facial shape, Jaundice, Hypoglycemia, Failure to thrive, Congenital hypothyroidism, Seizure, Scoliosis, Dystonia, Global developmental delay, Cerebellar hemangioblastoma)

CaseHPOFreeText: Normally born after 37 weeks pregnancy. During the prenatal period, she showed intrauterine growth retardation of unknown cause. At birth, dysmorphic features were noted (full list in table 1). After birth, she was treated for physiological jaundice and hypoglycemia. In addition, she has problem for failure to thrive and feeding difficulties associated with poor sucking and regurgitation. Furthermore, she was diagnosed with a congenital hypothyroidism in the neonatal screening. At 26 months old, she developed epilepsy. At 7Y, was considered to have Rett syndrome because of stereotypic hand movements since 2 years old, scoliosis and dystonia. Her psychomotor development was severely delayed: she had no ability to move by herself, visual contact, or social interaction. Brain MRI was performed at 1 year old and 6 years old. Both of these showed no abnormal findings. At 16 years old, follow-up MRI unexpectedly demonstrated a solid tumor with peritumoral edema at right cerebellum; diagnosed a cerebellar hemangioblastoma and confirmed through histopathology.

CaseNotHPOs: HP:0002012 (Abnormality of the abdominal organs)

CaseNotHPOFreeText: Repeat brain MRI, fundoscopy, abdominal echography and CT, blood and urine testing revealed no other tumors associated with VHL.

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Complete Deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: No mutation was detected in MECP2 on chromosome Xq28. At 5 months old, her chromosome analysis of the white blood cells revealed a distal deletion of the short arm of chromosome 3. Genomic DNA from the patient and her parents revealed a de novo 11.0-Mb deletion at 3p26.3-25.3 that included VHL and a paternally inherited 740-kb gain at Xp22.2-22.13, which was predicted to be a benign copy number variation. Unfortunately, since the mutation analysis of VHL was not performed using resected tumor tissues in the present case, “the second hit” could not be confirmed. Thus, the reason remains unclear why a cerebellar hemangioblastoma developed in her.

MutationType: deletion

CivicName: 3p26.3-25.3 11Mb del

MultipleGeneVariants: see VariantEvidence.

PatientID: None

KindredID: 36

Case: M, 31Y0M, Spanish

DiseaseAssertion: VHL

FamilyInfo: Positive for familial antecedents. No known familial tumors.

CohortInfo: Probands belonging to 18 unrelated Spanish VHL families carrying germline VHL deletions.

CasePresentingHPOs: HP:0006880; HP:0001737 (Cerebellar hemangioblastoma, Pancreatic cysts)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: Exon 1 Deletion (c.1-?_340+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: Germline HSPC300, ENST197804 and FANCD2 (unclear if partial or complete) gene deletions. Study provides evidence to show that loss of HSPC300 highly correlates with the absence of ccRCC in VHL patients.

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: Germline, HSPC300, Deletion MultipleGeneVariants: Germline, ENST197804, Deletion MultipleGeneVariants: Germline, FANCD2, Deletion

Case1: Male, Infant, ethnicity not stated

DiseaseAssertion: congenital fiber-type disproportion (CFTD) and fatal infantile cardiomyopathy

FamilyInfo: The father was a healthy 20-yr old with no particular medical concerns, and there was no family history of neuromuscular or genetic disorders on either side. Both parents confirmed as heterozygous carriers of the MYL2 c.188del variant by Sanger sequencing

ParentalTesting: Both parents were confirmed as heterozygous carriers of MYL2 c.188del p.(Asn63Metfs7) by Sanger sequencing. Father confirmed as heterozygous carrier of NEB c.25435C>T p.(Gln8479)

CasePresentingHPOs: HP:0001290, HP:0001252, HP:0001640, HP:0001638, HP:0001639

CaseHPOFreeText: Newborn exam revealed normal first and second heart sound with gallop rhythm and palpable liver at the right costal margin, as well as generalized hypotonia and diminished reflexes. Echocardiogram was performed at 11 d of age and revealed patent foramen ovale with left to right shunt and right atrial enlargement. At age 5 mo, the proband was admitted to hospital in decompensated heart failure and intubated on inotropic support. Echocardiography revealed left ventricular dilatation, mild to moderate mitral valve regurgitation, and left atrial enlargement, with left ventricular function moderately to severely decreased with shortening fraction of 12% and ejection fraction of 23%. A vastus lateralis biopsy performed at 5 mo of age because of persistent muscle weakness and hypotonia revealed variability in fiber size with checkerboard pattern of 1:1 ratio of type 1 and type 2 fibers exhibiting hypotrophy of type 1 fiber size in comparison to the type 2 fibers. high lactate level (7.8 mmol/L)

CaseNotHPOs: NR

CaseNotHPOFreeText: Gomori trichrome–stained light micrographs and electron microscopy (EM) showed no evidence of ragged red fiber or nemaline rods, and oxidative stains revealed no evidence of cores, targetoid, or target fibers. Normal serum creatine kinase level. Normal birth weight, length, and head circumference. There was no histopathologic evidence of Pompe disease and GAA enzyme-level testing was normal. Genetic testing for POLG and Noonan syndrome genes normal

CasePreviousTesting: Genetic testing was performed for DNA polymerase γ, catalytic subunit (POLG) and Noonan syndrome genes (PTPN11, SOS1, KRAS, RAF1, BRAF, MAP2K1, MAP2K2, and HRAS), all of which were normal. There was no histopathologic evidence of Pompe disease and GAA enzyme-level testing was normal. Muscular dystrophy was considered unlikely given the histopathologic findings and normal serum creatine kinase level.

Genotyping Method: Next-generation sequencing was performed by the Laboratory for Molecular Medicine (LMM) of Partners Healthcare Personalized Medicine using the Agilent SureSelect Design process. The gene panel utilized an all exon approach for 43 genes of interest for neuromuscular and cardiac conditions by targeting coding exons with bait out to coding sequence (CDS) ±65 bases. The complete coding regions of all genes were sequenced to average depth of 316 reads

FunctionalAnalysis: No functional analysis of the variant was performed

Variant: NM_000432.3:c.188del

ClinVar: NR

CAID: UnregisteredVariant

gnomAD: NR

AdditionalInfo: This case also has a heterozygous pathogenic NEB variant c.25435C>T p.(Gln8479*) inherited from the father, classified as pathogenic but considered unlikely to be a significant contributor to disease as no second NEB allele was identified.

PatientID: 3

KindredID: 3

Case: F, 27Y0M, Bulgarian

DiseaseAssertion: VHL

FamilyInfo: Positive family history of retinal HB and CNS HB - father was operated on for both; he was not available for performing molecular genetic testing thus no genotype was confirmed.

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

CaseHPOFreeText: retinal capillary hemangioma was found in this patient; and an infratentorial tumour, initially considered on MRI to be ependymoma or haemangiopericytoma, but having the typical characteristics of cHB - after operation, HB of the cerebellum was histologically proven.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: N/A

Variant: p.E173Sfs*4 (c.516_517dupGTCAAGCCT; 532_542delCTGGACATCGTinsATTA)

LegacyVariant: N/A

CaseProblemVariantFreeText: A duplication and deletion-insertion are both involved in this protein change.

ClinVarID: N/A

CAID: Two CAIDs are associated with the cDNA changes, just note that together they result in one protein change, which is not registered. - CA2499306821 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499306821 (c.516_517dupGTCAAGCCT) - CA2499306820 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2499306820 (c.532_542delCTGGACATCGTinsATTA) - p.E173Sfs4 NOT* registered with associating p.s

gnomAD: N/A

VariantEvidence: N/A

MutationType: duplication AND delins

CivicName: c.516_517dupGTCAAGCCT and c.532_542delCTGGACATCGTinsATTA

MultipleGeneVariants: SNP c.870A>G in CCND1 gene (A>G)

GroupID/ KindredID: 7

DiseaseAssertion: VHL

GroupSize: Unknown

GroupNumberMales: N/A

GroupNumberFemales: N/A

GroupEthnicity: Brazilian

GroupAgeRange: N/A

GroupInfo: Family VHL type 1 - did not exhibit any renal lesions - unclear how many members were involved

GroupPresentingHPOs: N/A

GroupHPOFreeText: N/A

GroupNotHPOs: N/A

GroupNotHPOFreeText: No renal lesions

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Yes

Variant: VHL partial deletion

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: deletion also encompassed the FANCD2 gene and predictably the neighbouring C3orf10 gene

MutationType: deletion

CivicName: Deletion

MultipleGeneVariants: N/A

GroupID: 50

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: 0 GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0010797 (Hemangioblastoma)

GroupHPOFreeText: # of affected individuals: Hemangioblastoma/brain/cerebellum (2)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 1-3 Deletion (c.1-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: Germline, FANCD2, partial deletion

MultipleGeneVariants: Germline, ENST197804, deletion

MultipleGeneVariants: Germline, HSPC300, deletion

MultipleGeneVariants: Germline, IRAK2, deletion

MultipleGeneVariants: Germline, TATDN2, partial deletion

GroupID: 44

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0009711 (Retinal capillary hemangioma)

GroupHPOFreeText: # of affected individuals: Retinal capillary hemangioma (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 1-3 Deletion (c.1-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: Germline, IRAK2, deletion

GroupID: 43

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0005584; HP:0000107; HP:0009711; HP:0010797; HP:0030393; HP:0001737; HP:0030405 (Renal cell carcinoma, Renal cyst, Retinal capillary hemangioma, Hemangioblastoma, Endolymphatic sac tumor, Pancreatic cysts, Pancreatic endocrine tumor)

GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Renal cyst (2), Retinal capillary hemangioma (4), Hemangioblastoma/brain/cerebellum (3), Endolymphatic sac tumor (2), Pancreatic cysts (3), Pancreatic endocrine tumor (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 1-3 Deletion (c.1-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: Germline, IRAK2, partial deletion

MultipleGeneVariants: Germline, ENST197804, partial deletion

GroupID: 49

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0000107; HP:0010797; HP:0009713; HP:0001737 (Renal cyst, Hemangioblastoma, Spinal hemangioblastoma, Pancreatic cysts)

GroupHPOFreeText: # of affected individuals: Renal cyst (1), Hemangioblastoma/brain/cerebellum (4), Spinal hemangioblastoma (3), Pancreatic cysts (2)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 1-3 Deletion (c.1-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1-3 Deletion

MultipleGeneVariants: Germline, FANCD2, partial deletion

MultipleGeneVariants: Germline, IRAK2, deletion

GroupID: 24

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0005584; HP:0000107; HP:0009711; HP:0010797 (Renal cell carcinoma, Renal cyst, Retinal capillary hemangioma, Hemangioblastoma)

GroupHPOFreeText: # of affected individuals: Renal cell carcinoma (1), Renal cyst (1), Retinal capillary hemangioma (1), Hemangioblastoma/brain/cerebellum (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 2-3 Deletion (c.341-?_642+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 2-3 Deletion

MultipleGeneVariants: Germline, IRAK2, partial deletion

GroupID: 2

DiseaseAssertion: VHL

GroupSize: N/A GroupNumberMales: N/A GroupNumberFemales: N/A GroupEthnicity: N/A GroupAgeRange: N/A

GroupInfo: 54 VHL deletion families from the Freiburg registry were selected in order to assist in the correlation of VHL deletions to clinical phenotypes.

GroupPresentingHPOs: HP:0009711; HP:0009713; HP:0030393; HP:0030424 (Retinal capillary hemangioma, Spinal hemangioblastoma, Endolymphatic sac tumor, Epididymal cyst)

GroupHPOFreeText: # of affected individuals: Retinal capillary hemangioma (1), Spinal hemangioblastoma (1), Endolymphatic sac tumor (1), Epididymal cyst (1)

GroupNotHPOs: N/A

GroupNotHPOFreeText: N/A

GroupPreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Supplemental Table 2, Table 1, Table 3

Variant: Exon 1 Deletion (c.1-?_340+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: Germline, ENST197804, partial deletion

PatientID: 1

KindredID: 1

Case: M, 31Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Mother with the same variant and presented with breast cancer at age 46 and cerebellar hemangioblastoma and renal cell carcinoma both at age 54. Maternal grandfather (id: 3) presented with cerebellar hemangioblastoma at age 65. Maternal great-uncle (id: 4) presented with prostate cancer at age 65. Maternal great-grandfather (id: 5) presented with cerebellar hemangioblastomas at age 69. Maternal grandmother and sister did not have the mutation. His maternal grandfather was not tested. No family history of retinal capillary hemangiomas or pheochromocytoma.

CasePresentingHPOs: HP:0006880; HP:0009713; HP:0005562 (Cerebellar hemangioblastoma, Spinal hemangioblastoma, Multiple renal cysts)

CaseHPOFreeText: N/A

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1 (pedigree) and Table 1 (phenotype and age of onset data).

Variant: Exon 1 Deletion (c.1-?_340+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: Germline, FANCD2, Partial Deletion

PatientID: 2

KindredID: 1

Case: F, 54Y0M, Ethnicity Unknown

DiseaseAssertion: VHL

FamilyInfo: Son (id:1) with the same variant, presenting with cerebellar hemangioblastoma at age 18, spinal hemangioblastomas at ages 19 and 31 and renal cysts but the age of onset for these is not noted. Father (id: 3) presented with cerebellar hemangioblastoma at age 65. Paternal uncle (id: 4) presented with prostate cancer at age 65. Paternal grandfather (id: 5) presented with cerebellar hemangioblastomas at age 69. Mother and daughter did not have the mutation. Her father was not tested. No family history of retinal capillary hemangiomas or pheochromocytoma.

CasePresentingHPOs: HP:0006880; HP:0005584; HP:0003002 (Cerebellar hemangioblastoma, Renal cell carcinoma, Breast carcinoma)

CaseHPOFreeText: Bilateral breast cancer at age 46 and 49. First cancer was diagnosed at the age of 46 in her right breast. The patient was treated by mastectomy with postoperative chemotherapy (CMF). Histopathological examination revealed invasive ductal breast carcinoma. A metastasis in 1 axillary lymph node was found. There was no evidence of distant metastases. Three years later, at the age of 49, she was diagnosed with cancer of her left breast. It was an invasive ductal carcinoma. There was no evidence for lymph-node or distant metastases. At present, 9 and 6 years after treatment of the breast cancers there is no evidence of breast cancer recurrence. However at age of 54, lesions typical for VHL disease including cerebellar haemangioblastoma and renal cell carcinoma were diagnosed in the patient.

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

CaseNotHPOFreeText: N/A

CasePreviousTesting: N/A

PreviouslyPublished: N/A

SupplementalData: Figure 1 (pedigree) and Table 1 (phenotype and age of onset data).

Variant: Exon 1 Deletion (c.1-?_340+?del)

LegacyVariant: N/A

CaseProblemVariantFreeText: N/A

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

VariantEvidence: N/A

MutationType: exon_loss_variant

CivicName: Exon 1 Deletion

MultipleGeneVariants: Germline, FANCD2, Partial Deletion

Case III.4: Female, age 30

DiseaseAssertion: Distal myopathy

FamilyInfo: Figure 1, similar distal muscle weakness in four relatives. Patients I.2 and II.2 experienced foot drop while walking. Patient III.2 muscle biopsy findings suggestive of core myopathy suggested a disorder similar to his youngest sister. Patient IV.1 displayed a less progressive muscular phenotype than her older relatives and tested negative for the mutation in RYR1

CasePresentingHPOs: HP:0001761, HP:0008994, HP:0002650

"Pes cavus, Proximal muscle weakness in lower limbs, Scoliosis"

CaseHPOFreeText: stepping gait

CasePreviousTesting: muscle biopsy showed fiber size variability, increased internal nuclei and histochemical evidence of eccentric core-like lesions, Analysis of RYR1 revealed a heterozygous c.880G > A:p.(Glu294Lys) mutation

GenotypingMethod: Amplicon-based Sanger sequencing, MotorPlex used to analyze a large set of genes that cause known forms of non-syndromic muscle disorders

MultipleGeneVariants:

(1) MHY7Variant: Novel

Variant: NM_000257.4:c.4303T>C

ClinVar: not found

CAID: CA389040164

gnomAD: not found

(2) RYR1Variant:

Variant: NM_000540.2:c.880G>A

ClinVar: 590621

CAID: CA072725

gnomAD: https://gnomad.broadinstitute.org/variant/19-38939074-G-A?dataset=gnomad_r2_1

Total allele frequency: 0.00006159 European (non-Finnish)

Supplementary Data Table S3

Case: 152

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)

CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing

Variant: NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)

ClinVar: 155814 https://www.ncbi.nlm.nih.gov/clinvar/variation/155814/

gnomAD: 0.0006368, https://gnomad.broadinstitute.org/variant/14-23891476-C-T

MultipleGeneVariants:

(1) CRYAB Variant

Variant as listed does not exist on any transcript

Variant: c.331G>A (p.Gly111Ser)

ClinVar: N/A

gnomAD: N/A

(2) DSP Variant

Variant: NM_004415.4(DSP):c.4372C>G (p.Arg1458Gly)

ClinVar: 44906 https://www.ncbi.nlm.nih.gov/clinvar/variation/44906/

gnomAD: 0.003556, https://gnomad.broadinstitute.org/variant/6-7580795-C-G

Supplementary Data Table S3

Case: 296

DiseaseEntity: HCM

HPOsFreeText: left ventricular hypertrophy (LVH) ≥15 mm

InheritancePattern: n/a

CasePreviousTesting: MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1 (59 genes total tested)

CaseGenotypingMethod: NGS of 59 genes (Supplemental Table S1), pathogenic and likely pathogenic variants confirmed via Sanger Sequencing

Variant: NM_000257.4(MYH7):c.2539_2541del (p.Lys847del)

ClinVar: 42913 https://www.ncbi.nlm.nih.gov/clinvar/variation/42913/

gnomAD: Not in gnomAD

MultipleGeneVariants:

(1) DOLK Variant

Current transcript of DOLK has a C at location 17 and a Pro rather than an Ala

Variant: c.17G>C (p.Gly6Ala)

ClinVar: N/A

gnomAD: N/A

(2) MYPN Variant

Variant: NM_032578.3(MYPN):c.2863C>T (p.Arg955Trp)

ClinVar: 192126 https://www.ncbi.nlm.nih.gov/clinvar/variation/192126/

gnomAD: 0.001449, https://gnomad.broadinstitute.org/variant/10-69948821-C-T

(3) PSEN1 Variant

Variant: NM_000021.4(PSEN1):c.953A>G (p.Glu318Gly)

ClinVar: 98094 https://www.ncbi.nlm.nih.gov/clinvar/variation/98094/

gnomAD: 0.03394, https://gnomad.broadinstitute.org/variant/14-73673178-A-G

Case: 8

DiseaseAssertion: hypertrophic cardiomyopathy, Left ventricular hypertrophy

FamilyInfo: Finnish, no family info

CasePresentingHPOs: HP:0001639, HP:0001712

"hypertrophic cardiomyopathy, Left ventricular hypertrophy"

CaseHPOFreeRext:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: 24 h Holter registration and bicycle ergometer test performed in majority of patients. Cardiac magnetic resonance imaging was performed to verify the diagnosis of HCM

GenotypingMethod: Targeted next-generation sequencing of exons, UTRs and 10 bp flanking regions of 59 cardiomyopathy associated genes, filtered variants confirmed by Sanger sequencing

MultipleGeneVariants:

(1) LAMA4 Variant: c.2593C>G (unknown HGVS descriptor)

ClinVarID: unknown

gnomAD: unknown

(2) MYH7 Variant: NM_000257.4:c.3158G>A

ClinVarID: 155814

gnomAD: http://gnomad.broadinstitute.org/variant/14-23891476-C-T

Total Allele Frequency: 0.0000601 European (Finnish): 0.0006368

PreviouslyPublished:

SupplementalData: Table S3: list of all 382 patients with HCM included in the FinHCM Genetic Study, and the rare variants (GMAF <1%) detected in each patient.

Case1: patient 1, 68 years old, male

DiseaseAssertion: HCM

FamilyInfo: positive family history of SCD and end stage heart failure

CasePresentingHPOs: n/a

CaseHPOFreeText: n/a

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: multiplex targeted high‐throughput sequencing, DNA capture assay including all exons from 130 genes involved in cardiovascular Mendelian disorders and analysed simultaneously four samples by multiplexing

VariantMYH7: NM_000257.4:c.4130C>A

ClinVar: not found

CAID: CA389040836

gnomAD: not found

VariantMYBPC3:

ClinVar: 42813

CAID: CA016212

gnomAD: https://gnomad.broadinstitute.org/variant/11-47367871-C-T

0.01364 European (Finnish)

Case280: Male, Birth onset, Japan, Asian

DiseaseAssertion: Left ventricular noncompaction

CasePresentingHPOs: HP:0030682, HP:0025169, HP:0001635 (Left ventricular noncompaction, Left ventricular systolic dysfunction, Heart failure)

HPOsFreeText: Left Ventricular Ejection Fraction at 40%, LVDD-Z score at 2.16

CaseNotHPOs: HP:0011675 (Arrhythmia)

NotHPOsFreeText: Congenital heart disease with significant hemodynamic changes

CaseAddInfo: No family history, Died since publication

CasePreviousTesting: Genes tested include the 8 sarcomere genes as well as 65 more listed in Table S1.

CaseGenotypingMethod: Genomic DNA was extracted from whole blood from each of the probands. Next Generation Sequencing of 73 genes related to cardiac function was performed, incorporating PCR amplification, and any variants found were subjected to filtering for frequency and pathogenicity. Any variants suggested to be pathogenic were confirmed by Sanger sequencing afterwards.

Variant listed as K542N, could be either CA389050168 or CA389050167.

Variant: NP_000248.2:p.Lys542Asn

ClinVar: N/A

gnomAD: N/A

MultipleGeneVariants:

JUP Variant

Variant: NM_002230.2:c.436G>A (p.Glu146Lys)

CAID: CA8565496 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_002230.2:c.436G%3EA

gnomAD: African 6.353e-5, Overall 2.030e-5 https://gnomad.broadinstitute.org/variant/17-39925702-C-T

Case#: II-9, male, Asian, 38 yr, proband

DiseaseAssertion: HCM, LQT1

FamilyInfo: HCM passed on in family (figure 1)

CasePresentingHPOs: HP:0001279, HP:0001712, HP:0001639 (Syncope, Left ventricular hypertrophy, Hypertrophic cardiomyopathy)

CaseHPOFreeText: physical examination; 12-lead ECG (SR, HR 57 bpm, P 80 ms, PR 164 ms, QRS 102 ms, QTc 423 ms); 2D echocardiographic study with S5-1 probe (MLVWT 14 mm, EF 62%, LVMI 94.27 g/m^2);

CaseNotHPOs: HP:0030148 (Heart murmurs)

CaseNotHPOFreeText: No inverted T wave: Normal QTc 440 ms

CasePreviousTesting: Additional Sanger sequencing for KCNQ1, MKLY2, TMEM70

CaseGenotypingMethod: Illumina-SolexaHiSeq 2000 sequencing from peripheral blood leococytes; bi-directional Sanger sequencing;

Variant: absent

ClinVar: absent

CAID: CA389036862 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389036862

gnomAD: absent

MultipleGeneVariants:

(1) KCNQ1 Variant:

Variant: NM_181798.1(KCNQ1):c.187C>T (p.Arg63Trp)

ClinVar: 53070 https://www.ncbi.nlm.nih.gov/clinvar/variation/53070/

CAID: n/a

gnomAD: absent

(2) MKLY2 Variant:

Variant: absent

ClinVar: absent

CAID: CA408526793 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA408526793

gnomAD: African 0.00006453 https://gnomad.broadinstitute.org/variant/20-30412153-A-G

(3) TMEM70 Variant:

Variant: NM_017866.6(TMEM70):c.440T>C (p.Ile147Thr)

ClinVar: 571761 https://www.ncbi.nlm.nih.gov/clinvar/variation/571761/

CAID: n/a

gnomAD: East Asian 0.0004893 https://gnomad.broadinstitute.org/variant/8-74893513-T-C

Case7: Female, 13 years diagnosis, China, Asian

DiseaseAssertion: Hypertrophic Cardiomyopathy

CasePresentingHPOs: HP:0001639, HP:0001667, HP:0001279 (Hypertrophic cardiomyopathy, Right ventricular hypertrophy, Syncope)

HPOsFreeText: 2 SCD risk factors, NYHA class is II, Right ventricular wall thickness 12 mm

CaseNotHPOs: HP:0002092, HP:0001642, HP:0030680, HP:0011675 (Pulmonary arterial hypertension, Pulmonary stenosis, Congenital heart disease, Arrhythmia)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CaseGenotypingMethod: Probands' genomic DNA was extracted from blood samples. WES was performed, with the resulting sequence data mapped to a reference genome and variants filtered for pathogenicity and predicted effects. All variants identified were confirmed via Sanger sequencing of the respective genes.

Variant reported as below, but no SNP corresponds to the variant.

Variant: NP_000248.2:p.R719E

ClinVar: N/A

gnomAD: N/A

MultipleGeneVariants:

MYOM1 Variant:

Variant: NM_003803.3:c.2507G>T (p.Gly836Val)

CAID: CA8874590 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_003803.3:c.2507G%3ET

gnomAD: East Asian 5.044e-4, Overall 3.707e-5 https://gnomad.broadinstitute.org/variant/18-3129517-C-A

AKAP9 Variant:

Variant: NM_005751.4:c.11590T>C (p.Cys3864Arg)

CAID: CA368165252 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_005751.4:c.11590T%3EC

gnomAD: Not in gnomAD

CaseCM007

DiseaseAssertion: DCM

GenotypingMethod: NGS

MultipleGeneVariants:

VariantMYH7: NM_000257.4:c.2645A>G

ClinVar: not found

CAID: CA389047904

gnomAD: not found

VariantRBM20: NM_001134363.3:c.2062C>T

ClinVar: 202065

CAID: CA335555

gnomAD: https://gnomad.broadinstitute.org/variant/10-112572217-C-T?dataset=gnomad_r2_1

0.00006494 European (non Finnish)

Case#:5-year-old girl

DiseaseAssertion: Asymptomatic

FamilyInfo: Mother was diagnosed with STGD1 and She was homozygous for a (severe) splice site mutation, IVS 35+2 T>C, Maternal uncle was diagnosed with STGD1. Father passed down the G1961E variant.

CasePresentingHPOs: HP:0030630, HP:0011504

CaseHPOFreeText: The ELM in the central macula appeared thickened with indistinct borders, particularly along its inner border (Fig. 2C), horizontal diameter for the region of thickened ELM was 1113 μm, FAF revealed Bull’s Eye Maculopathy (BEM) (Fig. 2B),

CaseNotHPOs:

CaseNotHPOFreeText: No retinal, vasculature, pigmentary or optic nerve head abnormalities were detected on clinical examination, no focal abnormality observed in the outer nuclear layer (ONL) or RPE (Fig. 2C), There was no FAF evidence of flecks or GA

Genotyping Method:

PreviouslyPublished: No

Variant:NM_000350.3:c.5882G>,

ClinVar:7888

CAID:CA119132

SupplementalData:

Case#: 1 female, 12 years old.

DiseaseAssertion: bilateral stage 2B Coats disease. ABCA4 gene mutations were found upon genetic analysis but Stargardt disease was not diagnosed.

FamilyInfo: Single affected individual. Past medical history and family history was reported as normal. No additional information about family is provided in text.

CasePresentingHPOs: HP:0007663 - Reduced visual acuity, HP:0001147 - Retinal exudate, HP:0007763 - Retinal telangiectasia, HP:0025355 - Retinal arteriolar macroaneurysms, HP:0011505- Cystoid macular edema, HP:0020032 - Hyperreflective retinal dots on OCT, HP:0001045 - Vitiligo

CaseHPOFreeText: bilateral significant capillary nonperfusion noted mostly in the temporal retinal periphery together with light-bulb-like capillary dilations and staining of telangiectatic vessels. Mild intravitreal hemorrhage

CaseNotHPOs: HP:0012045 - Retinal flecks, HP:0025010 - Foveal atrophy, HP:0000603 - Central scotoma, HP:0000556 - Retinal dystrophy, HP:0000512 - Abnormal electroretinogram

CaseNotHPOFreeText: Relatively normal foveal architecture.

Genotyping Method: Genetic analysis was performed using Sanger sequencing for the NDP gene, which revealed no pathogenic variants. Exome sequencing was then used with the Illumina HiSeq 2500 platform, which identified two compound heterozygous variants in the ABCA4 gene. Lastly, no mutations were found in the TINF2 gene.

PreviouslyPublished: N/A

Variant: NM_000350.3(ABCA4):c.1373C>T (p.Arg458Cys), NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)

ClinVar: Variation ID: 7888 ( for p.Arg458Cys variant however I believe this is mislabeled for this variant NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu), no variantion ID found for NM_000350.3(ABCA4):c.1373C>T (p.Arg458Cys)

CAID: N/A

SupplementalData: N/A