A C-terminal nonsense mutation links PTPRQ with autosomal-dominant hearing loss, DFNA73

Purpose Hearing loss is genetically extremely heterogeneous, making it suitable for next-generation sequencing (NGS). We identified a four-generation family with nonsyndromic mild to severe hearing loss of the mid- to high frequencies and onset from early childhood to second decade in seven members. Methods NGS of 66 deafness genes, Sanger sequencing, genome-wide linkage analysis, whole-exome sequencing (WES), semiquantitative reverse-transcriptase polymerase chain reaction. Results We identified a heterozygous nonsense mutation, c.6881G>A (p.Trp2294*), in the last coding exon of PTPRQ . PTPRQ has been linked with recessive ( DFNB84A ), but not dominant deafness. NGS and Sanger sequencing of all exons (including alternatively spliced 5′ and N-scan-predicted exons of a putative “extended” transcript) did not identify a second mutation. The highest logarithm of the odds score was in the PTPRQ -containing region on chromosome 12, and p.Trp2294* cosegregated with hearing loss. WES did not identify other cosegregating candidate variants from the mapped region. PTPRQ expression in patient fibroblasts indicated that the mutant allele escapes nonsense-mediated decay (NMD). Conclusion Known PTPRQ mutations are recessive and do not affect the C-terminal exon. In contrast to recessive loss-of-function mutations, c.6881G>A transcripts may escape NMD. PTPRQ Trp2294* protein would lack only six terminal residues and could exert a dominant-negative effect, a possible explanation for allelic deafness, DFNA73 , clinically and genetically distinct from DFNB84A .