title: Broadening the phenotype of DFNB28: Mutations in TRIOBP are associated with moderate, stable hereditary hearing impairment.
abstract: DFNB28 is characterized by prelingual, severe to profound sensorineural hearing impairment (HI). It is associated with mutations in exon 6 and 7 of TRIOBP and has not been reported in the European population. Here, we describe two isolated cases of Dutch origin with congenital, moderate HI and compound heterozygous mutations in TRIOBP. Three of the mutations are novel, one nonsense mutation (c.5014G>T (p.Gly1672*)) and two frameshift mutations (c.2653del (p.Arg885Alafs*120) and c.3460_3461del (p.Leu1154Alafs*29)). The fourth mutation is the known c.3232dup (p.Arg1078Profs*6) mutation. Longitudinal audiometric analyses in one of the subjects revealed that HI was stable over a period of 15 years. Vestibular function was normal. Predicted effects of the mutations do not explain the relatively mild phenotype in the presented subjects, whereas location of the mutation might well contribute to the milder HI in one of the subjects. It is known that isoform classes TRIOBP-4 and TRIOBP-5 are important for stereocilia stability and rigidity. To our knowledge, p.Gly1672* is the first pathogenic variant identified in DFNB28 that does not affect isoform class TRIOBP-4. This suggests that a single TRIOBP copy to encode wildtype TRIOBP-4 is insufficient for normal hearing, and that at least one TRIOBP copy to encode TRIOBP-5 is indispensable for normal inner ear function. Furthermore, this study demonstrates that DFNB28 can be milder than reported so far and that mutations in TRIOBP are thus associated with a heterogeneous phenotype.
authors.affiliation: Department of Otorhinolaryngology, Hearing & Genes, Radboud University Medical Center, Nijmegen, The Netherlands; The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: mieke.wesdorp@radboudumc.nl.
authors.forename: Mieke
authors.initials: M
authors.lastname: Wesdorp
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Jiddeke M
authors.initials: JM
authors.lastname: van de Kamp
authors.affiliation: Department of Otolaryngology- Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Erik F
authors.initials: EF
authors.lastname: Hensen
authors.affiliation: Department of Otorhinolaryngology, Hearing & Genes, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Margit
authors.initials: M
authors.lastname: Schraders
authors.affiliation: Department of Otorhinolaryngology, Hearing & Genes, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Oostrik
authors.affiliation: Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Helger G
authors.initials: HG
authors.lastname: Yntema
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ilse
authors.initials: I
authors.lastname: Feenstra
authors.affiliation: Department of Otorhinolaryngology, Hearing & Genes, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ronald J C
authors.initials: RJC
authors.lastname: Admiraal
authors.affiliation: Department of Otorhinolaryngology, Hearing & Genes, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Henricus P M
authors.initials: HPM
authors.lastname: Kunst
authors.affiliation: Hussman Institute for Human Genetics and Departments of Human Genetics and Otolaryngology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
authors.affiliation: Department of Biological Sciences, Bethlehem University, Bethlehem, Palestine.
authors.forename: Moien
authors.initials: M
authors.lastname: Kanaan
authors.affiliation: Department of Otorhinolaryngology, Hearing & Genes, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
authors.affiliation: Department of Otorhinolaryngology, Hearing & Genes, Radboud University Medical Center, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ronald J E
authors.initials: RJE
authors.lastname: Pennings
mesh_terms: D001309:Auditory Threshold; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D016368:Frameshift Mutation; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006309:Hearing / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D006320:Hearing Tests; D040941:Heredity; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012307:Risk Factors; D012720:Severity of Illness Index
chemical_list: D018389:Codon, Nonsense; D005819:Genetic Markers; D008840:Microfilament Proteins; C425471:TRIOBP protein, human
keywords: DFNB28; Genotype–phenotype correlations; Hereditary hearing impairment; TRIOBP