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In this case report, we characterize a novel inherited frameshift mutation c.4700_4701del (p.Phe1567Cysfs*221) in a single copy of the SCN5A gene and its association with Brugada syndrome (BrS). The proband experienced a life-threatening ventricular arrhythmia successfully treated with DC-shock and he also suffered from supraventricular tachycardia. Ajmaline test confirmed the BrS diagnosis. No other mutation nor low frequency variants in the other 23 analyzed genes were detected. The same mutation was found in the father and sister, who were both diagnosed with BrS. We hypothesize that this mutation could be responsible for BrS and potentially linked to supraventricular tachycardias. Further studies are needed to confirm this observation and to assess the clinical relevance of this mutation, in terms of risk-stratification.

Brugada syndrome (BrS) is a known cause of sudden cardiac death. The genetic basis of BrS is not well understood, and no one single gene is linked to even a majority of BrS cases. However, mutations in the gene SCN5A are the most common, although the high amount of phenotypic variability prevents a clear correlation between genotype and phenotype. Research techniques are limited, as most BrS cases still remain without a genetic diagnosis, thus impairing the implementation of experimental models representative of a general pathogenetic mechanism. In the present study, we report the largest family to-date with the segregation of the heterozygous variant NM_198056:c.4894C>T (p.Arg1632Cys) in the SCN5A gene. The genotype-phenotype relationship observed suggests a likely pathogenic effect of this variant. Functional studies to better understand the molecular effects of this variant are warranted.

In this case series, we report for the first time a family in which the inherited nonsense mutation [c. 3946C > T (p.Arg1316*)] in the SCN5A gene segregates in association with Brugada syndrome (BrS). Moreover, we also report, for the first time, the frameshift mutation [c.7686delG (p.Ile2563fsX40)] in the NF1 gene, as well as its association with type 1 neurofibromatosis (NF1), characterized by pigmentary lesions (café au lait spots, Lisch nodules, freckling) and cutaneous neurofibromas. Both of these mutations and associated phenotypes were discovered in the same family. This genetic association may identify a subset of patients at higher risk of sudden cardiac death who require the appropriate electrophysiological evaluation. This case series highlights the importance of genetic testing not only to molecularly confirm the pathology but also to identify asymptomatic family members who need clinical examinations and preventive interventions, as well as to advise about the possibility of avoiding recurrence risk with medically assisted reproduction.