Monogenic hearing loss

Gene: DIAPH1

Comment on list classification: Upgrading from red to green after discussion with the GMS hearing loss specialist test group in a Webex and consultation with the Genomics England clinical team

Created: 12 Jun 2019, 11:20 a.m. | Last Modified: 14 Aug 2019, 9:39 a.m.

Panel Version: 1.122

DIAPH1 has a previous gene symbol of DFNA1.
It is associated with Deafness, autosomal dominant 1 (124900) in OMIM

PMID: 9360932 - Lynch et al 1997 - a splice donor mutation in the penultimate exon of the DIAPH1 gene was identified in affected members of a large Costa Rican kindred with autosomal dominant deafness-1

PMID: 26912466 - Stritt et al. 2016 - a heterozygous truncating mutation in the DIAPH1 gene (R1213X) was identified in 8 affected individuals from 2 unrelated families with macrothrombocytopenia and sensorineural hearing loss. It segregated with the disorder in both families. R1213* variant predicting partial truncation of the DIAPH1 diaphanous autoregulatory domain. The R1213* variant was linked to reduced proplatelet formation from cultured MKs, cell clustering, and abnormal cortical filamentous actin. In platelets, there was increased filamentous actin and stable microtubules, indicating constitutive activation of DIAPH1. The authors suggest this is a gain-of-function action.

PMID: 27808407 - Neuhaus et al. (2017) identified two new DFNA1 families with thrombocytopenia as an associated finding each with a heterozygous truncating mutation DIAPH1 gene, (c.3637C>T, p.Arg1213* and a 2-bp deletion c.3624_3625delAG (p.Ala1210Serfs*31).

Created: 18 Feb 2019, 11:04 p.m.

Green List (high evidence)

6 DM variants associated with hearing loss on HGMD, multiple publications. Also pathogenic variants reported in association with microcephaly. OMIM AD deafness 1 #124900. AR variants associated with seizures, cortical blindness microcephaly syndrome #616632

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

Comment on list classification: Evidence for causing deafness has been found in only one family, therefore this should be demoted from green to red.

Created: 23 Feb 2016, 10:20 a.m.

PMID: 1350680 and 9360932 - original studies mapping the cause of autosomal dominant nonsyndromic deafness in the Cost Rican M Kindred to a region on chromosome 5q31 named the DFNA1 gene. All 78 affected members were heterozygous for a mutation found within the gene that caused abberant splicing; PMID: 24781755 - a family study identify a homozygous nonsense alteration as the cause of microcephaly (MCP), severe visual impairment, intellectual disability, and short stature; PMID: 26463574 - describes a case of an affected boy from United Arab Emirates, and a seperate family with 3 affected siblings of Omani ancestry, and identify likely causative homozygous variants in this gene in the individuals affected with microcephaly, blindness and early onset seizures.

Created: 17 Feb 2016, 2:20 p.m.

Comment on list classification: Only one family study for autosomal dominant deafness has been reported. 3 family cases for the association between biallelic mutations and microcephaly, cortical blindness and seizures (and not deafness).

Created: 17 Feb 2016, 2:18 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
#124900:Deafness, autosomal dominant 1[Sensorineural hearing loss; Progressive hearing loss; Low-frequency hearing loss; Childhood onset]; #616632:Seizures, cortical blindness, microcephaly syndrome[Short stature; Poor growth; Microcephaly (up to -10 SD); Cortical blindnessOptic atrophy; Hypotonia (in some patients); Delayed psychomotor development, moderate to severeSeizuresPoor speechHypoplasia of the corpus callosum]

Publications

• PMID:12021256
• 12034774
• 15864301
• 17182868
• 24781755
• 9360932

I don't know

Only one convincing family published

Created: 30 Sep 2015, 1:24 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• PubMed: 9360932