title: A novel KCNQ4 mutation and a private IMMP2L-DOCK4 duplication segregating with nonsyndromic hearing loss in a Brazilian family.
abstract: Here we describe a novel missense variant in the KCNQ4 gene and a private duplication at 7q31.1 partially involving two genes (IMMP2L and DOCK4). Both mutations segregated with nonsyndromic hearing loss in a family with three affected individuals. Initially, we identified the duplication in a screening of 132 unrelated cases of hearing loss with a multiplex ligation-dependent probe amplification panel of genes that are candidates to have a role in hearing, including IMMP2L. Mapping of the duplication by array-CGH revealed that the duplication also encompassed the 3'-end of DOCK4. Subsequently, whole-exome sequencing identified the breakpoint of the rearrangement, thereby confirming the existence of a fusion IMMP2L-DOCK4 gene. Transcription products of the fusion gene were identified, indicating that they escaped nonsense-mediated messenger RNA decay. A missense substitution (c.701A>T) in KCNQ4 (a gene at the DFNA2A locus) was also identified by whole-exome sequencing. Because the substitution is predicted to be probably damaging and KCNQ4 has been implicated in hearing loss, this mutation might explain the deafness in the affected individuals, although a hypothetical effect of the product of the fusion gene on hearing cannot be completely ruled out.
authors.affiliation: Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo , São Paulo, Brazil.
authors.forename: Daniela T
authors.initials: DT
authors.lastname: Uehara
authors.affiliation: Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo , São Paulo, Brazil.
authors.forename: Érika L
authors.initials: ÉL
authors.lastname: Freitas
authors.affiliation: Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo , São Paulo, Brazil.
authors.forename: Leandro U
authors.initials: LU
authors.lastname: Alves
authors.affiliation: Faculty of Medicine, University of Brasilia , Brasília, Brazil.
authors.forename: Juliana F
authors.initials: JF
authors.lastname: Mazzeu
authors.affiliation: Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo , São Paulo, Brazil.
authors.forename: Maria Tbm
authors.initials: MT
authors.lastname: Auricchio
authors.affiliation: DERDIC, Pontifical Catholic University of São Paulo , São Paulo, Brazil.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Tabith
authors.affiliation: Department of Ophthalmology and Otorhinolaryngology, Faculty of Medicine, University of São Paulo , São Paulo, Brazil.
authors.forename: Mário Lr
authors.initials: ML
authors.lastname: Monteiro
authors.affiliation: Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo , São Paulo, Brazil.
authors.forename: Carla
authors.initials: C
authors.lastname: Rosenberg
authors.affiliation: Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo , São Paulo, Brazil.
authors.forename: Regina C
authors.initials: RC
authors.lastname: Mingroni-Netto