Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions

Josephs, Katherine S.; Roberts, Angharad M.; Theotokis, Pantazis; Walsh, Roddy; Ostrowski, Philip J.; Edwards, Matthew; Fleming, Andrew; Thaxton, Courtney; Roberts, Jason D.; Care, Melanie; Zareba, Wojciech; Adler, Arnon; Sturm, Amy C.; Tadros, Rafik; Novelli, Valeria; Owens, Emma; Bronicki, Lucas; Jarinova, Olga; Callewaert, Bert; Peters, Stacey; Lumbers, Tom; Jordan, Elizabeth; Asatryan, Babken; Krishnan, Neesha; Hershberger, Ray E.; Chahal, C. Anwar A.; Landstrom, Andrew P.; James, Cynthia; McNally, Elizabeth M.; Judge, Daniel P.; van Tintelen, Peter; Wilde, Arthur; Gollob, Michael; Ingles, Jodie; Ware, James S.

doi:10.1186/s13073-023-01246-8

Table 1 Structured representation of data from curation of core cardiomyopathy gene-disease pairs (HCM, DCM, ARVC)

From: Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions

Cardiomyopathy
Gene	Gene-disease validity^a	Inheritance	Allelic requirement	Disease-associated variant consequence	Variant classes reported with evidence of pathogenicity
Hypertrophic cardiomyopathy
ACTC1	Definitive	AD	Monoallelic autosomal	Altered gene product sequence	Missense; inframe deletion
MYBPC3	Definitive	AD^c	Monoallelic autosomal	Decreased gene product level; altered gene product sequence	Missense; inframe indels; NMD truncating^e; structural variants (whole exon deletions)
MYH7	Definitive	AD^c	Monoallelic autosomal	Altered gene product sequence	Missense; inframe deletion; stop gained NMD escaping
MYL2	Definitive	AD	Monoallelic autosomal	Altered gene product sequence	Missense
MYL3	Definitive	AD	Monoallelic autosomal	Altered gene product sequence	Missense
TNNI3	Definitive	AD^c	Monoallelic autosomal	Altered gene product sequence	Missense; inframe deletion
TNNT2	Definitive	AD^c	Monoallelic autosomal	Altered gene product sequence	Missense; inframe deletion; stop gained NMD escaping; splice donor variant NMD escaping
TPM1	Definitive	AD^c	Monoallelic autosomal	Altered gene product sequence	Missense
Dilated cardiomyopathy
BAG3	Definitive	AD^c	Monoallelic autosomal	Decreased gene product level; altered gene product sequence	Missense; NMD truncating^e; structural variants (whole exon deletions); copy number variants (whole gene deletion)
DES	Definitive	AD^c;d	Monoallelic autosomal	Altered gene product sequence	Missense; splice acceptor variant NMD escaping
DSP	Strong	AD^c	Monoallelic autosomal	Decreased gene product level; altered gene product sequence	Missense; NMD truncating^e;
FLNC	Definitive	AD^c	Monoallelic autosomal	Decreased gene product level	NMD truncating^e
LMNA	Definitive	AD^d	Monoallelic autosomal	Decreased gene product level; altered gene product sequence	Missense; NMD truncating^e; structural variants (whole exon deletions)
MYH7	Definitive	AD^c	Monoallelic autosomal	Altered gene product sequence	Missense
RBM20	Definitive	AD^d	Monoallelic autosomal	Decreased gene product level; altered gene product sequence	Missense; NMD truncating^e
SCN5A	Definitive	AD^d	Monoallelic autosomal	Decreased gene product level; altered gene product sequence	Missense; NMD truncating^e
TNNC1	Definitive	AD	Monoallelic autosomal	Altered gene product sequence	Missense
TNNT2	Definitive	AD^d	Monoallelic autosomal	Altered gene product sequence	Missense
TTN	Definitive	AD^c	Monoallelic autosomal	Decreased gene product level; Altered gene product sequence	NMD truncating^e (variants must impact exons (PSI > 0.9);Limited repertoire of missense variants established as pathogenic
PLN (IC)^b	Definitive	AD^c	Monoallelic autosomal	Decreased gene product level; altered gene product sequence	Missense; inframe indels; NMD truncating^e; structural variants (whole exon deletions)
Arrhythmogenic right ventricular cardiomyopathy
DSC2	Definitive	AD; AR^c	Monoallelic autosomal; biallelic autosomal	Decreased gene product level; altered gene product sequence	Missense; inframe indels; NMD truncating^e
DSG2	Definitive	AD; AR^c	Monoallelic autosomal; biallelic autosomal	Decreased gene product level; altered gene product sequence	Missense; inframe indels; NMD truncating^e
DSP	Definitive	AD; AR^c	Monoallelic autosomal; biallelic autosomal	Decreased gene product level; altered gene product sequence	Missense; inframe indels; NMD truncating^e
PKP2	Definitive	AD^c; AR	Monoallelic autosomal; Biallelic autosomal	Decreased gene product level; altered gene product sequence	Missense; inframe indels; NMD truncating^e; structural variants
TMEM43	Definitive	AD	Monoallelic autosomal	Altered gene product sequence	Missense (S358L)
Rare familial disorder with ARVC
JUP (ND)	Strong	AR	Biallelic autosomal	Altered gene product sequence	Frameshift variant NMD escaping; Missense; inframe deletion

^aGene-disease validity—ClinGen classification (https://clinicalgenome.org/)
^bPLN-related intrinsic cardiomyopathy is also recorded under HCM in Additional file 3: Table S1
^cTypified by incomplete penetrance
^dTypified by age-related onset
^eNMD truncating = truncating variants nonsense mediated decay (NMD) triggering: frameshift, stop gained, splice acceptor/donor, splice region/intronic variants with proven effect on splicing
AD Autosomal dominant, AR Autosomal recessive; indels, insertions or deletions, IC Intrinsic cardiomyopathy, ND Naxos disease, NMD nonsense-mediated decay, PSI Percent spliced in (only variants in TTN that are in or impact exons constitutively expressed in both major adult cardiac isoforms (PSI > 0.9) should be prioritised)

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ISSN: 1756-994X

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