The NKX2-5 gene encodes for a transcription factor crucial for cardiac cell differentiation and proliferation. It was the first gene associated with congenital heart disease (CHD) in humans and has been linked to conduction disorders or cardiomyopathies. However, an overlapping phenotype is not frequent in the literature. We describe a family with a novel missense mutation in the NKX2-5 gene (p.Gln181Pro) with numerous antecedents with atrial septal defect (ASD), left ventricular non-compaction (LVNC), conduction disease, and sudden cardiac death (SCD).

Hypertrophic cardiomyopathy (HCM) is a genetic disease characterised by increased left ventricle (LV) wall thickness caused by mutations in sarcomeric genes. Finding a causal mutation can help to better assess the proband’s risk, as it allows the presence of the mutation to be evaluated in relatives and the follow-up to be focused on carriers. We performed an observational study of patients with HCM due to the novel p.Arg652Lys variant in the MYH7 gene. Eight families and 59 patients are described in the follow-up for a median of 63 months, among whom 39 (66%) carry the variant. Twenty-five (64%) of carriers developed HCM. A median maximum LV wall thickness of 16.5 mm was described. The LV hypertrophy was asymmetric septal in 75% of cases, with LV outflow tract obstruction in 28%. The incidence of a composite of serious adverse cardiovascular events (sudden death, aborted sudden death, appropriate implantable cardiac defibrillator discharge, an embolic event, or admission for heart failure) was observed in five (20%) patients. Given the finding of the p.Arg652Lys variant in patients with HCM, but not in controls, with evident segregation in patients with HCM from eight families and the location in an active site of the protein, we can define this variant as likely pathogenic and associated with the development of HCM.

Background/Introduction Hypertrophic cardiomyopathy (HCM) is a genetic disease characterised by increased left ventricle (LV) wall thickness caused by mutations in sarcomeric genes. Finding a causal mutation can help to better assess the proband's risk, as it allows the presence of the mutation to be evaluated in relatives and the follow-up to be focused on carriers. Purpose The objectives of the present study are to assess the genotype-phenotype correlation of a novel variant found in patients with HCM and explore the possibility of a founder effect in the Balearic Islands, Spain. Methods We performed an observational study with phenotype description and genotype correlation of patients with HCM in whom we found a novel variant in the MYH7 gene (NM_000257.4:c.1955G>A) which putatively causes a p.Arg652Lys missense protein change. We did IBD/coalescent-based allele dating analysis of this novel variant. Results This previously non-described variant was found in twelve families with HCM. Out of those, 59 patients corresponding to 8 families were clinically characterized with a median follow-up of 63 months. Among them, 39 (66%) carry the variant. Twenty-five (64%) of carriers developed HCM. A median maximum LV wall thickness of 16.5 mm was described. The LV hypertrophy was asymmetric septal in 75% of cases, with LV outflow tract obstruction in 28%. The incidence of a composite of serious adverse cardiovascular events (sudden death, aborted sudden death, appropriate implantable cardiac defibrillator dis-charge, an embolic event, or admission for heart failure) was observed in five (20%) patients. This p.Arg652Lys variant was classified as likely pathogenic (LP) and associated with the development of HCM for the following reasons: 1) It is found in patients with HCM, but not in controls, 2) There is evident segregation with HCM on the 8 families described, and 3) It is located in an active site of the protein where a variant in the same amino acid has already been clearly established as pathogenic (p.Arg652Gly). Interestingly, the exclusive presence of the variant in our region could correspond to a founder effect in the Balearic Islands, Spain, which we have further investigated. IBD/coalescent-based allele dating analysis reveals that the origin of this allele is 96 generations away which would correspond to 1900–2400 years ago, when the Balearic Islands were already populated. Conclusions We can define the p.Arg652Lys variant in MYH7 as LP in HCM and a founder effect is in the Balearic Islands is highly probable due to the exclusive presence at the region and the dating analysis of it. Funding Acknowledgement Type of funding sources: None.

Introduction: Arrhythmogenic cardiomyopathy (ACM) is an inherited disease characterized by progressive fibroadipose replacement of cardiomyocytes. Its diagnosis is based on imaging, electrocardiographic, histological and genetic/familial criteria. The development of the disease is based mainly on desmosomal genes. Knowledge of the phenotypic expression of each of these genes will help in both diagnosis and prognosis. The objective of this study is to describe the genotype–phenotype association of an unknown PKP2 gene variant in a family diagnosed with ACM. Methods: Clinical and genetic study of a big family carrying the p.Tyr168* variant in the PKP2 gene, in order to demonstrate pathogenicity of this variant, causing ACM. Results: Twenty-two patients (proband and relatives) were evaluated. This variant presented with high arrhythmic load at an early age, but without evidence of structural heart disease after 20 years of follow-up, with low risk in predictive scores. We demonstrate evidence of its pathogenicity. Conclusions: The p.Tyr168* variant in the PKP2 gene causes ACM with a high arrhythmic load and with an absence of structural heart disease. This fact emphasizes the value of knowing the phenotypic expression of each variant.

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