MITF variants cause nonsyndromic sensorineural hearing loss with autosomal recessive inheritance

MITF variants cause nonsyndromic sensorineural hearing loss with autosomal recessive inheritance

Thongpradit, S., Jinawath, N., Javed, A., Noojarern, S., Khongkraparn, A., Tim-Aroon, T., Lertsukprasert, K., Suktitipat, B., Jensen, L. T., Wattanasirichaigoon, D.

Sci Reports (2020) 10, 12712, doi: 10.1038/s41598-020-69633-4

     MITF is a known gene underlying autosomal dominant hearing loss, Waardenburg syndrome (WS).  Using whole exome sequencing, we identified a homozygous c.1022G>A: p.Arg341His variant of MITF, which co-segregated with the hearing loss in five affected children of a consanguineous hearing couple.  Targeted exome sequencing in a cohort of 130 Nonsyndromic sensorineural hearing loss (NSHL) individuals, using our in-house gene panel revealed a second family with c.1021C>T: p.Arg341Cys MITF variant. Functional studies confirmed that the Arg341His and Arg341Cys alleles yielded a normal sized MITF protein, with aberrant cytosolic localization as supported by the molecular modeling and the reporter assays.  In conclusion, we demonstrate MITF as a new cause of autosomal recessive NSHL (ARNSHL), with heterozygous individuals free of symptoms. MITF should be included in clinical testing for NSHL, even though it is rare causing of hearing loss.