A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans

Abstract Deafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses an extended consanguineous family pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as new deafness gene. Homozygosity mapping followed by exome sequencing identified 14.96 Mb locus on chromosome 4p15.32p15.1 containing likely pathogenic missense variant CLRN2 (c.494C > A, NM_001079827.2) segregating disease. Using vitro RNA splicing analysis, we show that c.494C A leads two events: (1) substitution highly conserved threonine (uncharged amino acid) lysine (charged at position 165, p.(Thr165Lys), (2) aberrant splicing, retention intron 2 resulting stop codon after 26 additional acids, p.(Gly146Lysfs*26). Expression studies phenotyping newly produced zebrafish mouse models deficient for clarin further confirm 2, expressed inner ear hair cells, essential normal organization maintenance auditory bundles, function. Together, our findings gene, which will impact future diagnosis treatment deaf patients.