Monogenic hearing loss

Gene: DIAPH3

Comment on list classification: Changing the rating from red to amber as there are now 2 reported cases.

Created: 17 Feb 2019, 11:26 p.m.

Associated with Auditory neuropathy, autosomal dominant, 1 (609129) in OMIM.

PMID: 20624953 - Schoen et al. (2010) - Identified a heterozygous mutation (-172G-A) in the 5-prime untranslated region of the DIAPH3 gene in a large family (33 affected members) with autosomal dominant auditory neuropathy-1. Some individuals are homozygous for the variant. Using genome-wide expression arrays and quantitative RT-PCR, they demonstrate a 2- to 3-fold overexpression of DIAPH3 mRNA in lymphoblastoid cell lines from affected individuals.

PMID: 27658576 - Martinez et al 2017 - 3 family members with progressive bilateral deafness from the age of 20 years. A c.-173C>T variant, located in the regulatory region of DIAPH3 was found in affected family members, but not in 2 unaffected family members.

Created: 17 Feb 2019, 11:25 p.m.

Green List (high evidence)

HGMD c.-172G>A c.-173C>T both pathogenic (Schoen et al 2010 PMID 20624953; Sanchez-Martinez et al 2017 PMID 27658576). Two separate families, 3 affected members have c.-173C>T, 2 unaffected members dont. c.-172G>A v large 4 generation pedigree inc 33 affected family members. Quantitative RT-PCR shows 2-3 fold overexpression of DIAPH3 mRNA in lymphoblastoid cell lines from affected individuals.

Created: 17 Feb 2019, 4:35 p.m.

Publications

• 20624953
• 27658576

Red List (low evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
auditory neuropathy

Publications

• PubMed: 20624953

Mode of pathogenicity
Other

Comment on mode of inheritance: PMID: 20624953 identifies both heterozygotes and homozygotes of the 5'UTR variant they describe with an association with auditory neuropathy.

Created: 23 Feb 2016, 10:45 a.m.

Comment on mode of pathogenicity: PubMed: 20624953 describes a gain-of-function mechanism resulting from the 5'UTR variant.

Created: 23 Feb 2016, 10:44 a.m.

Comment on list classification: Demoted from amber to red. Reported in one family - more evidence required.

Created: 23 Feb 2016, 10:32 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
#609129:Auditory neuropathy, autosomal dominant, 1[Hearing loss, neural typeAbnormal or absent auditory nerve and brainstem responsesAbsent middle ear reflexesAbnormal auditory temporal processesAbnormal gap detectionAbnormal amplitude modulation detectionAbnormal speech discriminationNormal outer hair cell functionsNormal otoacoustic emissionsNormal cochlear microphonics]

Publications

• PMID:14767582
• 15520414
• 18755006
• 19457867
• 20624953