Paediatric or syndromic cardiomyopathy

Gene: SCN8A

Red List (low evidence)

Comment on list classification: There is only one case available in support of the association of monoallelic SCN8A variants with cardiomyopathy from UK 100,000 genomes cohort. The cardiomyopathy phenotype is not explained by the genotype in this patient.

Hence, there is no reliable evidence for this association and this gene should be rated red on this panel.

Created: 1 Sep 2025, 1:33 p.m. | Last Modified: 1 Sep 2025, 1:33 p.m.

Panel Version: 7.56

Comment on phenotypes: OMIM phenotypes accessed on 01 September 2025.

Created: 1 Sep 2025, 1:30 p.m. | Last Modified: 1 Sep 2025, 1:30 p.m.

Panel Version: 7.55

SCN8A is a well-established gene for complex neurodevelopmental disorder including early-onset epilepsy and developmental impairments. SCN8A has been associated with relevant phenotypes in OMIM (MIMs #614306, #614558, #617080 & #618364), Gene2Phenotype (with 'definitive' rating on the DD panel) and ClinGen ('definitive' rating for complex neurodevelopmental disorder (MONDO:0100038) by Epilepsy GCEP). There is significant evidence that SCN8A variants can lead to cardiac arrhythmias (e.g. bradycardia) during epileptic seizures and increase risk for Sudden Unexpected Death in Epilepsy.

However, there is no published evidence associating SCN8A variants to cardiomyopathy except for a single patient reported in PMID:39472908 (2024). This publication reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with heterozygous missense variant in SCN8A gene (c.3967G>A/ p.Ala1323Thr) via reanalysis of data from trio genome sequencing. This variant is reported to be likely pathogenic in the publication. However, the publication states that the cardiomyopathy phenotype is not explained by the genotype.

In addition, no cardiac presentations have been recorded as clinical manifestations for the OMIM phenotypes.
Sources: Literature

Created: 1 Sep 2025, 1:29 p.m. | Last Modified: 1 Sep 2025, 1:30 p.m.

Panel Version: 7.54

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Cognitive impairment with or without cerebellar ataxia, OMIM:614306; Developmental and epileptic encephalopathy 13, OMIM:614558; Seizures, benign familial infantile, 5, OMIM:617080; ?Myoclonus, familial, 2, OMIM:618364

Publications

• 3947290