New mutation in the NEBL gene in a family with Hypertrophic cardiomyopathy: Complexity of whole exome sequencing results interpretation

Objective: Hypertrophic cardiomyopathy is a most common genetic cardiovascular disease which is predominantly inherited with autosomal dominant pattern. In this study, Genetic analysis of a family affected by Hypertrophic cardiomyopathy with three patients was done using whole exome sequencing. Materials and Methods: whole exome sequencing was performed on two affected individuals and one healthy family member. Candidate variant was evaluated using sanger sequencing on other family members. Given the novelity of candidate variant, it was also studied in 200 healthy individuals. Different bioinformatics analyzes were performed to evaluate variant pathogenicity. Results: The candidate variant was present in two affected patients as well as in a two apparently healthy sibling. This variant was novel and did not exist in any databases. Echocardiographic results on family members showed that another proband’s brother was affected and didn’t have a candidate variant. Also, this variant was not found in a 200 healthy population. Bioinformatic analysis revealed the pathogenicity of the variant. Conclusion: Although all the early studies of the candidate variant showed it as a causative variant , further studies on more individuals of the family rejected its causality alone and from these results it can be concluded that the results of exome sequencing should be analyzed carefully and it need further study in a pedigrees with more affected individuals and functional studies to prove the variant as a pathogenic.