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20 The role of SCN5A mutations in hypertrophic cardiomyopathy
  1. H Cronin1,
  2. D Kerins1,
  3. G Fahy2,
  4. C Vaughan1
  1. 1Mercy University Hospital, Cork, Ireland
  2. 2Cork University Hospital, Cork, Ireland


Introduction The SCN5A gene encodes the α-subunit of the voltage gated sodium channel (NaV1.5), responsible for regulating inward sodium current. Mutations in the SCN5A gene cause cardiac ion channelopathies with diverse phenotypes including long QT syndrome, Brugada syndrome, familial atrial fibrillation, progressive cardiac conduction disorders and sudden infant death syndrome. SCN5A mutations also cause dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC) and atrial cardiomyopathy causing atrial standstill. To date, no study has confirmed SCN5A mutations as causative in hypertrophic cardiomyopathy (HCM).

Clinical Investigation/Methods A family of four individuals with complex hypertrophic and restrictive cardiomyopathy phenotypes was subjected to genetic screening. Each individual had an ECG, echo, Holter monitor and cardiac MRI performed in advance of the genetic testing. Three individuals (mother, father and son) met diagnostic criteria for HCM. A maternal aunt had restrictive cardiomyopathy. Peripheral blood lymphocytes were used for genomic DNA extraction by standard methods. Samples were analyzed using the Blueprint Genetics Pan Cardiomyopathy Panel Sequence Analysis encompassing 133 genes. A proprietary method was used for targeted sequencing performed using an Illumina sequencing device.

Results The father demonstrated a mutation in the SCN5A gene c.2614G>A, p.(Asp872Asn). His son demonstrated the same mutation. The mother demonstrated a troponin mutation TNNI3 c.422G>A, p.(Arg141Gln). Her sister demonstrated two pathogenic variants, the same troponin mutation as well as a mutation in the sulfonylurea receptor 2 (SUR2) gene ABCC9 c.4103–3C>T, a subunit of ATP-sensitive potassium channels. Figure 1 demonstrates the family pedigree. Troponin I mutations are well documented to cause HCM and restrictive cardiomyopathy however mutations in SCN5A have not yet been confirmed to cause HCM. The mutation demonstrated in the sodium channel-coding gene SCN5A resulted in a heterogeneous missense variant with a substitution of a negatively charged aspartic acid with an uncharged asparagine residue. Mutations in surrounding codons have been reported in association with Brugada syndrome, supporting the functional importance of this region of the protein. The mutation was classified as a variant of uncertain significance by the sequencing database because it has not been observed previously in sufficient numbers.

Abstract 20 Figure 1

Family pedigree

Discussion There is considerable overlap between the clinical presentations associated with SCN5A mutations. This has given rise to the term ‘cardiac sodium channel overlap syndrome’, resulting from the variability of the biophysical defects caused by sodium channel mutations. There is also considerable overlap between various forms of cardiomyopathy caused by the same gene mutations. Reduced penetrance and modifier effects of other genes are postulated to account for this. This report is the first to examine whether an SCN5A mutation is potentially causative in cases of familial hypertrophic cardiomyopathy. The absence of mutations in a comprehensive array of genes encoding myofilament proteins may suggest a wider range of influence of the sodium channel than currently recognised and raises the possibility that mutations in SCN5A may now cause HCM too. Further work needs to be done to confirm this observation.

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