title: Phenotypic variability in a seven-generation Swedish family segregating autosomal dominant hearing impairment due to a novel EYA4 frameshift mutation.
abstract: Linkage to an interval overlapping the DFNA10 locus on chromosome 6q22-23 was found through genome wide linkage analysis in a seven-generation Swedish family segregating postlingual, autosomal dominant nonsyndromic sensorineural hearing impairment. A novel heterozygous frame-shift mutation (c.579_580insTACC, p.(Asp194Tyrfs*52)) in EYA4 was identified that truncates the so-called variable region of the protein. The mutation is predicted to result in haploinsufficiency of the EYA4 product. No evidence for dilated cardiomyopathy was found in the family, contrasting to a previous family with a deletion resulting in a similar truncation in the variable region. A highly variable age of onset was seen in the mutation carriers. For assessment of the aetiology of this variability, clinical and audiometric data analyses were performed. The affected family members all had similar cross-sectional and longitudinal deterioration of pure tone average (PTA) once the process of hearing deterioration had started, and no gender, parent-of-origin or family branch differences on PTA could be found. Age at onset varied between the family branches. In summary, this is the ninth published genetically verified DFNA10 family. The results imply that unidentified factors, genetic or environmental, other than the EYA4 mutation, are of importance for the age at onset of DFNA10, and that mutation early in the variable region of the EYA4 protein can occur in the absence of dilated cardiomyopathy.
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Carina
authors: C
authors: Frykholm
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Joakim
authors: J
authors: Klar
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Hanna
authors: H
authors: Arnesson
authors: Department of Special Education, Stockholm University, Stockholm, Sweden.
authors: Anna-Carin
authors: AC
authors: Rehnman
authors: Department of Cellular and Molecular Medicine, University of Copenhagen, Denmark.
authors: Marianne
authors: M
authors: Lodahl
authors: Department of Cardiology, Karolinska University Hospital, Huddinge, Sweden.
authors: Ulla
authors: U
authors: Wedén
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Niklas
authors: N
authors: Dahl
authors: Department of Cellular and Molecular Medicine, University of Copenhagen, Denmark; Department of Otorhinolaryngology, Head & Neck Surgery and Audiology, Bispebjerg Hospital/Rigshospitalet, DK-2400 Copenhagen NV, Denmark. Electronic address: tranebjaerg@sund.ku.dk.
authors: Lisbeth
authors: L
authors: Tranebjærg
authors: Department of Cellular and Molecular Medicine, University of Copenhagen, Denmark; Department of Otorhinolaryngology, Head & Neck Surgery and Audiology, Bispebjerg Hospital/Rigshospitalet, DK-2400 Copenhagen NV, Denmark.
authors: Nanna D
authors: ND
authors: Rendtorff
mesh_terms: D000293:Adolescent; D000328:Adult; D009202:Cardiomyopathies / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D016368:Frameshift Mutation; D005799:Genes, Dominant; D008040:Genetic Linkage; D034381:Hearing Loss / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D006801:Humans; D008297:Male; D010375:Pedigree; D010641:Phenotype; D013548:Sweden; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C117736:EYA4 protein, human; D015534:Trans-Activators
keywords: Autosomal dominant; DFNA10; EYA4; Genome-wide linkage; Hearing impairment; Mutation