Audiometric Characteristics of a Dutch DFNA10 Family With Mid-Frequency Hearing Impairment.
OBJECTIVE
Mutations in EYA4 can cause nonsyndromic autosomal dominant sensorineural hearing impairment (DFNA10) or a syndromic variant with hearing impairment and dilated cardiomyopathy. A mutation in EYA4 was found in a Dutch family, causing DFNA10. This study is focused on characterizing the hearing impairment in this family.


METHODS
Whole exome sequencing was performed in the proband. In addition, peripheral blood samples were collected from 23 family members, and segregation analyses were performed. All participants underwent otorhinolaryngological examinations and pure-tone audiometry, and 12 participants underwent speech audiometry. In addition, an extended set of audiometric measurements was performed in five family members to evaluate the functional status of the cochlea. Vestibular testing was performed in three family members. Two individuals underwent echocardiography to evaluate the nonsyndromic phenotype.


RESULTS
The authors present a Dutch family with a truncating mutation in EYA4 causing a mid-frequency hearing impairment. This mutation (c.464del) leads to a frameshift and a premature stop codon (p.Pro155fsX). This mutation is the most N-terminal mutation in EYA4 found to date. In addition, a missense mutation, predicted to be deleterious, was found in EYA4 in two family members. Echocardiography in two family members revealed no signs of dilated cardiomyopathy. Results of caloric and velocity step tests in three family members showed no abnormalities. Hearing impairment was found to be symmetric and progressive, beginning as a mid-frequency hearing impairment in childhood and developing into a high-frequency, moderate hearing impairment later in life. Furthermore, an extended set of audiometric measurements was performed in five family members. The results were comparable to those obtained in patients with other sensory types of hearing impairments, such as patients with Usher syndrome type IIA and presbyacusis, and not to those obtained in patients with (cochlear) conductive types of hearing impairment, such as DFNA8/12 and DFNA13.


CONCLUSIONS
The mid-frequency hearing impairment in the present family was found to be symmetric and progressive, with a predominantly childhood onset. The results of psychophysical measurements revealed similarities to other conditions involving a sensory type of hearing impairment, such as Usher syndrome type IIA and presbyacusis. The study results suggest that EYA4 is expressed in the sensory cells of the cochlea. This phenotypic description will facilitate counseling for hearing impairment in DFNA10 patients.
1Department of Otorhinolaryngology, Head and Neck Surgery, Radboud university medical center, Nijmegen, The Netherlands; 2Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands; 3Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; 4Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, The Netherlands; 5Department of Cardiology, Radboud university medical center, Nijmegen, The Netherlands; and 6Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.
Eline
E
van Beelen
Anne M M
AM
Oonk
Joop M
JM
Leijendeckers
Elisabeth H
EH
Hoefsloot
Ronald J E
RJ
Pennings
Ilse
I
Feenstra
Hendrik-Jan
HJ
Dieker
Patrick L M
PL
Huygen
Ad F M
AF
Snik
Hannie
H
Kremer
Henricus P M
HP
Kunst
D000293:Adolescent; D000328:Adult; D000368:Aged; D001302:Audiometry, Speech; D002648:Child; D018450:Disease Progression; D005190:Family; D005260:Female; D006319:Hearing Loss, Sensorineural / Q000235:genetics / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D013067:Speech Perception; D015534:Trans-Activators / Q000235:genetics; D014724:Vestibular Function Tests; D044465:White People / Q000235:genetics*
C117736:EYA4 protein, human; D015534:Trans-Activators