Deafness, Autosomal Recessive 111

A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-111 (DFNB111) is caused by homozygous mutation in the MPZL2 gene (604873) on chromosome 11q23.

Description

DFNB111 is characterized by early-onset, moderate to severe sensorineural hearing loss with no vestibular involvement (Wesdorp et al., 2018; Bademci et al., 2018).

Clinical Features

Wesdorp et al. (2018) reported 8 patients from 3 consanguineous families, 1 Dutch (W05-682) and 2 Turkish (W16-0195, W16-0451), with autosomal recessive nonsyndromic hearing loss. All affected individuals had symmetric, slowly progressive, moderate to severe hearing loss. Onset occurred in the first decade, and high frequency hearing was more severely affected. There was no vestibular involvement.

Bademci et al. (2018) reported 8 patients from 3 unrelated consanguineous families, 2 Turkish and 1 Iranian, with autosomal recessive nonsyndromic sensorineural hearing loss. Seven patients had bilateral, symmetric, moderate hearing loss, whereas 1 patient had more severe hearing loss. Congenital or prelingual onset was suspected based on patient report; no previous audiograms were available.

Molecular Genetics

By homozygosity mapping and whole-exome sequencing in a consanguineous Dutch family (W05-682) segregating autosomal recessive nonsyndromic hearing loss, Wesdorp et al. (2018) identified homozygosity for a 1-bp deletion (c.72del; 604873.0001) in the MPZL2 gene. By subsequent screening of a phenotype-matched cohort and analysis of whole-exome sequencing data of genetically undiagnosed individuals with nonsyndromic hearing loss, they identified 2 Turkish families (W16-0195 and W16-0451) with homozygous or compound heterozygous MPZL2 mutations comprising c.72del and a nonsense mutation (Q74X; 604873.0002). The mutations segregated with the phenotype in all families. All c.72del alleles shared a halotype of at least 0.5 Mb, suggesting that it is a founder variant of ancient origin.

In affected members of 3 consanguineous families from Turkey and Iran with DFNB111, Bademci et al. (2018) identified homozygosity for the previously identified c.72delA founder mutation in the MPZL2 gene. The mutation segregated with the phenotype in all families.

Animal Model

Wesdorp et al. (2018) showed that Mpzl2 mutant mice displayed early-onset progressive sensorineural hearing loss that was more pronounced at high frequencies. Histologic analysis of adult mutant mice demonstrated altered organization of outer hair cells and supporting cells and degeneration of the organ of Corti.