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

Hypertrophic cardiomyopathy is the most common genetic cardiovascular disease and is predominantly inherited in an autosomal dominant pattern. In this study, genetic analysis of a family affected by hypertrophic cardiomyopathy with three patients was done using whole-exome sequencing.

Whole-exome sequencing was performed on two affected individuals and one healthy family member. The candidate variant was evaluated using Sanger sequencing on other family members. Given the novelty of the candidate variant, it was also studied in 200 healthy individuals. Different bioinformatics analyses were performed to evaluate variant pathogenicity.

The candidate variant was present in two affected patients as well as in two apparently healthy siblings. This variant was novel and did not exist in any databases. An echocardiographic result on family members showed that another proband’s brother was affected and did not have a candidate variant. Also, this variant was not found in a population of 200 healthy individuals. Bioinformatics analysis revealed the pathogenicity of the variant.

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, concluding that the results of exome sequencing should be analyzed carefully, and necessitating further study in a pedigree with more affected individuals and functional studies to prove the variant as pathogenic.