Whole exome sequencing identifies both nuclear and mitochondrial variations in an Iranian family with non-syndromic hearing loss.

Genetic contributing factors to non-syndromic hearing loss (NSHL) are remarkably diverse spanning over autosomal to X-linked to mitochondrial inheritance patterns. Facing a quite unconventional pedigree, here we report implementation of whole exome sequencing (WES) to uncover mitochondrial pathogenic variant in a six-generation Iranian family with four cases affected with hereditary NSHL of variable severity. As a result, heteroplasmic transition of A to G at position 1555 of MT-RNR1 gene was identified in all affected individuals co-existing with nuclear c.28G > T (p.A10S) variant in the TRMU gene, only in some patients. The reliability of WES to infer nuclear as well as mitochondrial variants in hearing loss were discussed. • It was only in 2015 which applicability of off-target reads from exome sequencing to extract mitochondrial single nucleotide variants and heteroplasmy was confirmed (Pan Zhang et al., Brief Bioinform.). • Since then, WES has been applied to detect mitochondrial mutations in a few genetic disorders but not in hearing loss, yet. • As the most common birth defect in almost all populations, hearing impairment could result from both, nuclear and mitochondrial mutations and could appear in almost all the patterns of inheritance. Therefore, identification of causative mutation can be extremely challenging. • In this manuscript we studied genetic cause of the non-syndromic hearing loss in a six-generation Iranian family with multiple affected individuals. • Due to the various disease severities, the certain pattern of inheritance could not be identified, solely based on the pedigree. Therefore, whole exome sequencing was performed. • Through filtration of numerous variations, we successfully captured A1555G variation in MT-RNR1 gene, which had been reported as a rare cause of non-syndromic hearing loss (NSHL). • The mutation was then confirmed with PCR-RFLP, a common method to identify the above-mentioned variation. • In fact here we report, for the first time, that whole exome sequencing could reliably be used for the detection of mitochondrial variants to identify the genetic cause of hearing impairment. • This study provides another evidence for the application of whole exome sequencing in clinical genetics once the nuclear and mitochondrial variations might equally be involved. [ABSTRACT FROM AUTHOR]