Extension of the clinical and molecular phenotype of DIAPH1-associated autosomal dominant hearing loss (DFNA1).
In about 20% of non-syndromic hearing loss (NSHL) cases, inheritance is autosomal dominant (ADNSHL). DIAPH1 mutations define the ADNSHL locus DFNA1. We identified two new families with heterozygous truncating DIAPH1 mutations (p.Ala1210Serfs*31 and p.Arg1213*). In contrast to the extensively studied original DFNA1 family, hearing loss was not confined to low frequencies, but congenital manifestation and rapid progression were confirmed. In line with a recent unrelated study, we identified an association with thrombocytopenia, reclassifying DFNA1 as a syndrome. Consequently, we suggest to include the blood count into the initial clinical workup of patients with autosomal dominant hearing loss to guide the genetic diagnosis. We provide the first data on DIAPH1 expression in the organ of Corti, where it localizes to the inner pillar cells, at the base of the outer hair cells. Homozygous truncating DIAPH1 mutations located N-terminally to the DFNA1 mutations have recently been identified in autosomal recessive microcephaly. It is therefore noteworthy that we found DIAPH1 expression also in spiral ganglion neurons and in the barrier between the myelinating glia of the peripheral nervous system and oligodendrocytes that form the myelinating glia of the central nervous system (CNS).
Bioscientia Center for Human Genetics, Ingelheim, Germany.
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C
Neuhaus
Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, Cologne, Germany.
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Lang-Roth
Molecular Physiology of Hearing, Hearing Research Centre Tübingen (THRC), Department of Otolaryngology, University of Tübingen, Tübingen, Germany.
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U
Zimmermann
Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
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R
Heller
Bioscientia Center for Human Genetics, Ingelheim, Germany.
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T
Eisenberger
Gemeinschaftspraxis für Phoniatrie, Pädaudiologie und Hals-Nasen-Ohrenheilkunde, Regensburg, Germany.
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M
Weikert
Kompetenzzentrum für Humangenetik, Gynäkologie und Laboratoriumsmedizin, Regensburg, Germany.
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S
Markus
Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne, Cologne, Germany.
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M
Knipper
Bioscientia Center for Human Genetics, Ingelheim, Germany.|Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
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Bolz
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D002490:Central Nervous System / Q000473:pathology; D002648:Child; D005260:Female; D000080865:Formins; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009457:Neuroglia / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D013136:Spiral Ganglion / Q000378:metabolism / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; C108962:DIAPH1 protein, human; D000080865:Formins
DFNA1; DIAPH1; deafness; hearing loss; thrombocytopenia