Forty-six genes causing nonsyndromic hearing impairment: Which ones should be analyzed in DNA diagnostics?

doi:10.1016/j.mrrev.2008.08.002

Mutation Research/Reviews in Mutation Research

Volume 681, Issues 2–3, March–June 2009, Pages 189-196

https://doi.org/10.1016/j.mrrev.2008.08.002 Get rights and content

Abstract

Hearing impairment is the most common sensory disorder, present in 1 of every 500 newborns. With 46 genes implicated in nonsyndromic hearing loss, it is also an extremely heterogeneous trait. Here, we categorize for the first time all mutations reported in nonsyndromic deafness genes, both worldwide and more specifically in Caucasians. The most frequent genes implicated in autosomal recessive nonsyndromic hearing loss are GJB2, which is responsible for more than half of cases, followed by SLC26A4, MYO15A, OTOF, CDH23 and TMC1. None of the genes associated with autosomal dominant nonsyndromic hearing loss accounts for a preponderance of cases, although mutations are somewhat more frequently reported in WFS1, KCNQ4, COCH and GJB2. Only a minority of these genes is currently included in genetic diagnostics, the selection criteria typically reflecting: (1) high frequency as a cause of deafness (i.e. GJB2); (2) association with another recognisable feature (i.e. SLC26A4 and enlarged vestibular aqueduct); or (3) a recognisable audioprofile (i.e. WFS1). New and powerful DNA sequencing technologies have been developed over the past few years, but have not yet found their way into DNA diagnostics. Implementing these technologies is likely to happen within the next 5 years, and will cause a breakthrough in terms of power and cost efficiency. It will become possible to analyze most – if not all – deafness genes, as opposed to one or a few genes currently. This ability will greatly improve DNA diagnostics, provide epidemiological data on gene-based mutation frequencies, and reveal novel genotype–phenotype correlations.

Introduction

Hearing loss (HL) is the most common birth defect in industrialized countries and the most prevalent sensorineural disorder. One of every 500 newborns has bilateral permanent sensorineural hearing loss ≥40 dBHL. Before the age of 5, the prevalence increases to 2.7 per 1000 and to 3.5 per 1000 during adolescence [1]. HL is categorized in several ways: conductive HL typically implies a defect of the outer or middle ear while sensorineural HL refers to a defect of the inner ear. The co-occurrence of both conductive and sensorineural hearing loss is referred to as a mixed hearing loss. Based on the age of onset, HL can also be described as prelingual (before speech development, sometimes referred to as congenital although not all prelingual cases are congenital) or postlingual (after speech development). It is estimated that in developed countries, genetic causes of HL can be found in at least two-thirds of prelingual cases. The remaining one-third of cases can be ascribed to environmental factors and unidentified genetic factors.

The most common environmental (non-genetic) cause of congenital hearing loss is congenital cytomegaloviral (CMV) infection. Its overall birth prevalence is 0.64%, with only about 10% of this number having symptomatic CMV. Of asymptomatic cases, 0–4.4% develops unilateral or bilateral HL before the age of 6 years. These figures generally apply to developed countries, although there is wide ethnic variation [2]. In addition, the diagnosis of congenital CMV is often difficult to make, especially in children over 3 weeks of age. As PCR-based techniques using dried bloodspot cards become widely available, reliable screening for in utero CMV exposure will be possible. Other environmental causes of hearing loss in the newborn period include bacterial infection, hyperbilirubinemia, anoxia and the use of ototoxic medications.

In most cases, inherited HL is monogenic. In 70% of neonates who fail newborn hearing screens (NBHS) and are presumed to have inherited HL, there are no other distinguishing physical findings and the HL is classified as nonsyndromic. In the remaining 30%, the HL is accompanied by other physical findings and is said to be syndromic [3]. Of the more than 400 syndromes in which HL is a recognized feature, Usher syndrome, Pendred syndrome and Jervell and Lange-Nielsen syndrome are the most frequent [4].

Monogenic hearing loss can be inherited in different ways. Autosomal recessive HL (ARNSHL) occurs in 80% of cases and is typically prelingual, while autosomal dominant HL (ADNSHL) accounts for about 20% of cases and is most often postlingual. In less than 1% of cases, the inheritance occurs through the X-chromosome or the mitochondria [5]. Monogenic hearing loss is an extremely heterogeneous trait, with over 100 mapped loci and 46 causally implicated genes (Hereditary Hearing Loss Homepage; http://webh01.ua.ac.be/hhh/). For over half of these loci, specific ‘deafness-causing’ genes have not yet been found. Their identification will provide further knowledge about the pathways involved in the hearing process and will allow for better genetic diagnostics. The ultimate goal is to provide better and/or new habilitation for hearing impaired persons.

Over the past decade, universal newborn hearing screening programs have been developed and implemented in many developed countries. The rationale for this initiative is based on the premise that early detection and intervention for children with hearing loss maximizes opportunities for language and speech development, thereby facilitating the acquisition of normal social, cognitive and motor skills. Stimulation of the auditory cortex before the age of 6 months is crucial for normal development of the auditory tracts. Screening is most often performed by automated auditory brainstem response (ABR) or otoacoustic emission (OAE) testing.

Section snippets

Frequency of mutations causing monogenic hearing loss

To date, 46 genes have been identified as causally related to nonsyndromic HL. Mutations in these genes do not occur at the same frequencies across ethnicities. In addition, although families with ARNSHL are found around the world, the majority of families reported with ARNSHL originate from the ‘consanguinity belt’, a region ranging from North Africa, through the Middle East to India. These consanguineous families have a large power for linkage mapping and allow locus identification on the

Clinical diagnostics for hearing impairment

Diagnosing the cause of HL can be challenging. In many cases, making an accurate diagnosis requires a multidisciplinary team, with involvement of a paediatrician, otolaryngologist, medical geneticist, ophthalmologist, and often additional specialists. Recognizing congenital HL has been facilitated by the implementation of newborn hearing screening in most developed countries. NBHS should be performed just after birth, preferably before hospital discharge and certainly before the age of 1 month.

Genetic diagnostics for hearing loss

Universal NBHS has lowered the age of detection of HL. In babies who are diagnosed with severe-to-profound HL in the absence of other abnormal findings on physical examination, the single best next diagnostic test is mutation screening for deafness at the DFNB1 locus. This screening should include DNA sequencing of GJB2 and mutation testing for the two large GJB6-containing deletions, as GJB2 mutations cause about half of all genetic hearing loss cases. Table 2 lists all genes that are

Evolution of molecular diagnostics

During the last 15 years, major achievements have been made in detecting new deafness genes. These achievements have far outpaced translation of this knowledge to improved clinical care. The gap created reflects the fact that diagnostic tests are still performed using the classical sequencing technology based on the Sanger method. These automatic DNA sequencers are very useful but are limited by slow throughput, which makes extensive sequencing of all known deafness-causing genes very expensive

Conflict of interest

None.

Acknowledgements

This study was supported by grants from EUROHEAR (LSHG-CT-2004-512063) and the Fund for Scientific Research Flanders (FWO-F, Grant G.0138.07). Nele Hilgert is a fellow of the Fund for Scientific Research Flanders (FWO-F). RJHS is the Sterba Hearing Research Professor, University of Iowa College of Medicine, who supported the project with National Institutes of Health (NIH)-National Institute on Deafness and Other Communication Disorders (NIDCD) grants DC02842 and DC03544.

References (47)

A. Kenneson et al.
GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: a HuGE review
Genet. Med.
(2002)
R.L. Snoeckx et al.
GJB2 mutations and degree of hearing loss: a multicenter study
Am. J. Hum. Genet.
(2005)
T. Yang et al.
Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4)
Am. J. Hum. Genet.
(2007)
M. Gomez-Zaera et al.
Presence of a major WFS1 mutation in Spanish Wolfram syndrome pedigrees
Mol. Genet. Metab.
(2001)
G. Richard et al.
Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis–ichthyosis–deafness syndrome
Am. J. Hum. Genet.
(2002)
L. Jin et al.
Mitochondrial tRNASer(UCN) gene is the hot spot for mutations associated with aminoglycoside-induced and non-syndromic hearing loss
Biochem. Biophys. Res. Commun.
(2007)
S.S. Connell et al.
Performance after cochlear implantation in DFNB1 patients
Otolaryngol. Head Neck Surg.
(2007)
F. Alasti et al.
A novel TECTA mutation confirms the recognizable phenotype among autosomal recessive hearing impairment families
Int. J. Pediatr. Otorhinolaryngol.
(2008)
C.C. Morton et al.
Newborn hearing screening—a silent revolution
N. Engl. J. Med.
(2006)
A. Kenneson et al.
Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection
Rev. Med. Virol.
(2007)

G. Van Camp et al.

Nonsyndromic hearing impairment: unparalleled heterogeneity

Am. J. Hum. Genet.

(1997)

H.V. Toriello et al.

Hereditary Hearing Loss and its Syndromes

(2004)

K. Cryns et al.

Deafness genes and their diagnostic applications

Audiol. Neurootol.

(2004)

P. Gasparini et al.

High carrier frequency of the 35delG deafness mutation in European populations. Genetic Analysis Consortium of GJB2 35delG

Eur. J. Hum. Genet.

(2000)

R.J. Morell et al.

Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness

N. Engl. J. Med.

(1998)

A. Ohtsuka et al.

GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation

Hum. Genet.

(2003)

I. del Castillo et al.

A deletion involving the connexin 30 gene in nonsyndromic hearing impairment

N. Engl. J. Med.

(2002)

F.J. del Castillo et al.

A novel deletion involving the connexin-30 gene, del(GJB6-d13s1854), found in trans with mutations in the GJB2 gene (connexin-26) in subjects with DFNB1 non-syndromic hearing impairment

J. Med. Genet.

(2005)

J.E. Common et al.

Specific loss of connexin 26 expression in ductal sweat gland epithelium associated with the deletion mutation del(GJB6-D13S1830)

Clin. Exp. Dermatol.

(2005)

W. Reardon et al.

Enlarged vestibular aqueduct: a radiological marker of pendred syndrome, and mutation of the PDS gene

QJM

(2000)

B. Coyle et al.

Molecular analysis of the PDS gene in Pendred syndrome

Hum. Mol. Genet.

(1998)

H. Azaiez et al.

Genotype–phenotype correlations for SLC26A4-related deafness

Hum. Genet.

(2007)

N. Nal et al.

Mutational spectrum of MYO15A: the large N-terminal extension of myosin XVA is required for hearing

Hum. Mutat.

(2007)

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ReviewForty-six genes causing nonsyndromic hearing impairment: Which ones should be analyzed in DNA diagnostics?

Abstract

Introduction

Section snippets

Frequency of mutations causing monogenic hearing loss

Clinical diagnostics for hearing impairment

Genetic diagnostics for hearing loss

Evolution of molecular diagnostics

Conflict of interest

Acknowledgements

Genet. Med.

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Mol. Genet. Metab.

Am. J. Hum. Genet.

Biochem. Biophys. Res. Commun.

Otolaryngol. Head Neck Surg.

Int. J. Pediatr. Otorhinolaryngol.

Newborn hearing screening—a silent revolution

N. Engl. J. Med.

Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection

Rev. Med. Virol.

Nonsyndromic hearing impairment: unparalleled heterogeneity

Am. J. Hum. Genet.

Hereditary Hearing Loss and its Syndromes

Deafness genes and their diagnostic applications

Audiol. Neurootol.

High carrier frequency of the 35delG deafness mutation in European populations. Genetic Analysis Consortium of GJB2 35delG

Eur. J. Hum. Genet.

Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness

N. Engl. J. Med.

GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation

Hum. Genet.

A deletion involving the connexin 30 gene in nonsyndromic hearing impairment

N. Engl. J. Med.

A novel deletion involving the connexin-30 gene, del(GJB6-d13s1854), found in trans with mutations in the GJB2 gene (connexin-26) in subjects with DFNB1 non-syndromic hearing impairment

J. Med. Genet.

Specific loss of connexin 26 expression in ductal sweat gland epithelium associated with the deletion mutation del(GJB6-D13S1830)

Clin. Exp. Dermatol.

Enlarged vestibular aqueduct: a radiological marker of pendred syndrome, and mutation of the PDS gene

QJM

Molecular analysis of the PDS gene in Pendred syndrome

Hum. Mol. Genet.

Genotype–phenotype correlations for SLC26A4-related deafness

Hum. Genet.

Mutational spectrum of MYO15A: the large N-terminal extension of myosin XVA is required for hearing

Hum. Mutat.

Review
Forty-six genes causing nonsyndromic hearing impairment: Which ones should be analyzed in DNA diagnostics?