Audioprofile-Directed Successful Mutation Analysis in a DFNA2/ KCNQ4 (p.Leu274His) Family

Abstract

Objectives:

We undertook to show that in a family with nonsyndromic autosomal dominant sensorineural hearing loss, genetic analysis can be successful when there is a match with a specific DFNA audioprofile. We also provide an update of relevant DFNA2/KCNQ4 audioprofiles and report the results of automatic audioprofile analysis using the Internet program AudioGene.

Methods:

Audiometric data and blood samples were obtained from the family W08-0384. Based on the audiograms of the affected participants, mutation analysis of KCNQ4 was started. Original audiometric threshold data were collected for all identified KCNQ4-related DFNA2 families. The Internet computer program AudioGene, recently developed for automatic audioprofile analysis, was accessed.

Results:

The family's audioprofile and the program AudioGene predicted the DFNA2/KCNQ4 locus. Mutation analysis of KCNQ4 revealed a c.821T>A (p.Leu274His) mutation of the KCNQ4 gene. This mutation has been previously identified in a Dutch family. Genetic analysis revealed a common haplotype in these two families over a region including the KCNQ4 gene.

Conclusions:

Familiarity with the audioprofiles of DFNA traits may lead to successful mutation analysis of the gene involved, even in a small family in which genetic linkage analysis is not an option. Alternatively, the specially developed program AudioGene can be accessed on the Internet to perform automatic audioprofile analysis of a family's (audiological) phenotype.

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References

Van Camp

Smith

RJH

. Hereditary hearing loss homepage. http://hereditaryhearingloss.org. Accessed September 13, 2010.

Ruel

Emery

Nouvian

. Impairment of SLC17A8 encoding vesicular glutamate transporter—3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dys function in null mice. Am J Hum Genet 2008;83:278–92.

Smith

RJH

Huygen

PLM

. Making sense of nonsyndromic deafness. Arch Otolaryngol Head Neck Surg 2003;129:405–6.

Huygen

PLM

Pennings

RJE

Cremers

CWRJ

. Characterizing and distinguishing progressive phenotypes in nonsyndromic autosomal dominant hearing impairment. Audiol Med 2003;1:37–46.

Huygen

PLM

Pauw

Cremers

CWRJ

. Audiometric profiles associated with genetic non-syndromal hearing impairment: A review and phenotype analysis. In: Martini

Stephens

Read

, eds. Genes, hearing and deafness: From molecular biology to clinical practice. London, England: Informa Healthcare, 2007:185–204.

Topsakal

Pennings

RJE

te Brinke

. Phenotype determination guides swift genotyping of a DFNA2/KCNQ4 family with a hot spot mutation (W276S). Otol Neurotol 2005;26:52–8.

Hildebrand

Tack

McMordie

. Audioprofile-directed screening identifies novel mutations in KCNQ4 causing hearing loss at the DFNA2 locus. Genet Med 2008;10:797–804.

Hildebrand

DeLuca

Taylor

. A contemporary review of AudioGene audioprofiling: A machine-based candidate gene prediction tool for autosomal dominant nonsyndromic hearing loss. Laryngoscope 2009;119:2211–5.

Talebizadeh

Kelley

Askew

Beisel

Smith

. Novel mutation in the KCNQ4 gene in a large kindred with dominant progressive hearing loss. Hum Mutat 1999;14:493–501.

10.

Coucke

Van Hauwe

Kelley

. Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. Hum Mol Genet 1999;8:1321–8.

11.

De Leenheer

EMR

Ensink

RJH

Kunst

HPM

. DFNA2/KCNQ4 and its manifestations. In: Cremers

CWRJ

Smith

, eds. Genetic hearing impairment: Its clinical presentations. Basel, Switzerland: Karger, 2002:41–6.

12.

Van Camp

Coucke

Akita

. A mutational hot spot in the KCNQ4 gene responsible for autosomal dominant hearing impairment. Hum Mutat 2002;20:15–9.

13.

Marres

van Ewijk

Huygen

. Inherited nonsyndromic hearing loss. An audiovestibular study in a large family with autosomal dominant progressive hearing loss related to DFNA2. Arch Otolaryngol Head Neck Surg 1997;123:573–7.

14.

Van Camp

Willems

Smith

RJH

. Nonsyndromic hearing impairment: Unparalleled heterogeneity. Am J Hum Genet 1997;60:758–64.

15.

Van Hauwe

Coucke

Ensink

Huygen

Cremers

Van Camp

. Mutations in the KCNQ4 K⁺ channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region. Am J Med Genet 2000;93:184–7.

16.

Akita

Abe

Shinkawa

Kimberling

Usami

. Clinical and genetic features of nonsyndromic autosomal dominant sensorineural hearing loss: KCNQ4 is a gene responsible in Japanese. J Hum Genet 2001;46:355–61.

17.

Kunst

Marres

Huygen

. Nonsyndromic autosomal dominant progressive sensorineural hearing loss: Audiologic analysis of a pedigree linked to DFNA2. Laryngoscope 1998;108:74–80.

18.

De Leenheer

EMR

Huygen

PLM

Coucke

Admiraal

RJC

Van Camp

Cremers

CWRJ

. Longitudinal and cross-sectional phenotype analysis in a new, large Dutch DFNA2/KCNQ4 family. Ann Otol Rhinol Laryngol 2002;111:267–74.

19.

Kubisch

Schroeder

Friedrich

. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell 1999;96:437–46.

20.

Yang

Shieh

. Identification of novel mutations in the KCNQ4 gene of patients with nonsyndromic deafness from Taiwan. Audiol Neurootol 2007;12:20–6.

21.

Mencía

González-Nieto

Modamio-Høybjør

. A novel KCNQ4 pore-region mutation (p.G296S) causes deafness by impairing cell-surface channel expression. Hum Genet 2008;123:41–53.

22.

Kamada

Kure

Kudo

. A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: Implication for the genotype-phenotype correlation. J Hum Genet 2006;51:455–60.

23.

Ensink

RJH

Huygen

PLM

Van Hauwe

Coucke

Cremers

CWRJ

Van Camp

. A Dutch family with progressive sensorineural hearing impairment linked to the DFNA2 region. Eur Arch Otorhinolaryngol 2000;257:62–7.

24.

Petit

. Genes responsible for human hereditary deafness: Symphony of a thousand. Nat Genet 1996;14:385–91.

25.

Cremers

. Hearing: Cracking the code. J Laryngol Otol 2000;114:6–16.

26.

Beisel

Nelson

Delimont

Fritzsch

. Longitudinal gradients of KCNQ4 expression in spiral ganglion and cochlear hair cells correlate with progressive hearing loss in DFNA2. Brain Res Mol Brain Res 2000;82:137–49.

27.

Beisel

Rocha-Sanchez

Morris

. Differential expression of KCNQ4 in inner hair cells and sensory neurons is the basis of progressive high-frequency hearing loss. J Neurosci 2005;25:9285–93.

28.

Bom

SJH

De Leenheer

EMR

Lemaire

. Speech recognition scores related to age and degree of hearing impairment in DFNA2/KCNQ4 and DFNA9/COCH. Arch Otolaryngol Head Neck Surg 2001;127:1045–8.

29.

Cremers

CWRJ

Smith

, eds. Genetic hearing impairment: Its clinical presentations. Basel, Switzerland: Karger, 2002.