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 2 Structured representation of data from curation of channelopathy gene-disease pairs (LQTS, SQTS, CPVT, BrS)

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

Channelopathy
Gene	Gene-disease validity^a	Inheritance	Allelic requirement	Disease-associated variant consequence	Variant classes reported with evidence of pathogenicity
Long QT syndrome (LQTS)
Familial long QT syndrome
KCNQ1	Definitive	AD; AR^b	Monoallelic autosomal; biallelic autosomal	Decreased gene product level; altered gene product sequence	Missense; inframe indels; NMD truncating^d; structural variants (multi exon deletions and a duplication)
KCNH2	Definitive	AD^b	Monoallelic autosomal	Decreased gene product level; altered gene product sequence	Missense; inframe indels; NMD truncating^d; structural variants (whole exon deletions and duplications)
SCN5A	Definitive	AD^b	Monoallelic autosomal	Altered gene product sequence	Missense; inframe indels
Long QT Syndrome with atypical features
CALM1	Definitive	AD^c	Monoallelic autosomal	Altered gene product sequence	Missense
CALM2	Definitive	AD^c	Monoallelic autosomal	Altered gene product sequence	Missense
CALM3	Definitive	AD^c	Monoallelic autosomal	Altered gene product sequence	Missense
TRDN	Strong	AR^c	Biallelic autosomal	Absent gene product level; altered gene product sequence	NMD truncating^d; missense
Syndrome with QT prolongation and cardiac arrhythmias
KCNQ1 (JLNS)	Definitive	AR	Biallelic autosomal	Absent gene product level; altered gene product sequence	Missense; inframe indels; NMD truncating^d; structural variants (whole exon deletions); complex rearrangements
KCNE1 (JLNS)	Moderate	AR	Biallelic autosomal	Altered gene product sequence	Missense; inframe indels; stop gained NMD escaping
KCNJ2 (ATS)	Definitive	AD	Monoallelic autosomal	Altered gene product sequence	Missense; inframe indels; stop gained NMD escaping
CACNA1C (TS)	Definitive	AD^c	Monoallelic autosomal	Altered gene product sequence	Missense
Brugada Syndrome (BrS)
SCN5A	Definitive	AD^b	Monoallelic autosomal	Decreased gene product level; altered gene product sequence	Missense; inframe indels; NMD truncating^d
Catecholaminergic polymorphic ventricular tachycardiac (CPVT)
Classic CPVT phenotype
RYR2	Definitive	AD^b	Monoallelic autosomal	Altered gene product sequence	Missense; structural variants (exon 3 deletion)
CASQ2	Definitive	AR	Biallelic autosomal	Absent gene product level; altered gene product sequence	Missense; NMD truncating^d
CASQ2	Moderate	AD^b	Monoallelic autosomal	Decreased gene product level; altered gene product sequence	Missense; NMD truncating^d
Atypical CPVT Phenotype
CALM1	Moderate	AD^c	Monoallelic autosomal	Altered gene product sequence	Missense
CALM2	Moderate	AD^c	Monoallelic autosomal	Altered gene product sequence	Missense
CALM3	Moderate	AD^c	Monoallelic autosomal	Altered gene product sequence	Missense
TRDN	Definitive	AR	Biallelic autosomal	Absent gene product level; altered gene product sequence	Missense; NMD truncating^d; structural variants (exon 2 deletion)
TECRL	Definitive	AR	Biallelic autosomal	Absent gene product level; altered gene product sequence	Missense; NMD truncating^d; structural variants (exon 2 deletion)
Short QT syndrome (SQTS)
Classic SQTS
KCNH2	Definitive	AD	Monoallelic autosomal	Altered gene product sequence	Missense
KCNQ1	Strong	AD^c	Monoallelic autosomal	Altered gene product sequence	Missense
SLC4A3	Moderate	AD	Monoallelic autosomal	Altered gene product sequence	Missense
KCNJ2	Moderate	AD	Monoallelic autosomal	Altered gene product sequence	Missense
Syndrome including shortened QT and cardiac arrhythmias
SLC22A5 (PSCD)	Definitive	AR	Biallelic autosomal	Altered gene product sequence	Missense

^aGene-disease validity—ClinGen classification (https://clinicalgenome.org/)
^bTypified by incomplete penetrance
^cTypically de novo
AD Autosomal dominant, AR Autosomal recessive, ATS Andersen-Tawil Syndrome, indels Insertions or deletions, JLNS, Jervell and Lange-Nielsen Syndrome, NMD Nonsense-mediated decay, PSCD Primary systemic carnitine deficiency, TS Timothy Syndrome
^dNMD truncating = truncating variants nonsense-mediated decay (NMD) triggering: frameshift, stop gained, splice acceptor/donor, splice region/intronic variants with proven effect on splicing

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ISSN: 1756-994X

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