Late‐onset hearing loss case associated with a heterozygous truncating variant of DIAPH1

Diaphanous-related formin 1 (DIAPH1) is a formin homology F-actin elongating protein encoded by DIAPH1. Homozygous recessive variants resulting in the loss of DIAPH1 function cause seizures, cortical blindness, and microcephaly syndrome (SCBMS), but hearing loss has not been reported. In contrast, dominant variants of human DIAPH1 are associated with DFNA1 non-syndromic sensorineural hearing loss. The deafness phenotype is due partly to abnormal F-actin elongation activity caused by disruption of the DIAPH1 autoinhibitory mechanism. We report an elderly female heterozygous for the c.3145C>T: p.R1049X variant who showed late-onset sensorineural hearing loss in her fifth decade. p.R1049X lacks F-actin elongation activity because this variant truncates one-third of the FH2 domain, which is vital for DIAPH1 dimerization and processive F-actin elongation activity. Concordantly, no increase of F-actin or processive F-actin elongation activity was observed after overexpression of p.R1049X DIAPH1 in HeLa cells or by single-molecule microscopy using Xenopus XTC cells. However, overexpression of the p.R1049X variant impairs formation of cell-cell junctions and mitosis. We speculate that late-onset hearing loss is a long-term consequence of heterozygosity for the recessive p.R1049X variant, a phenotype that may have been overlooked among carriers of other recessive alleles of DIAPH1.