A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct

Parna Chattaraj; Tina Munjal; Keiji Honda; Nanna D. Rendtorff; Jessica S. Ratay; Julie A. Muskett; Davide S. Risso; Isabelle Roux; E. Michael Gertz; Alejandro A. Schäffer; Thomas B. Friedman; Robert J. Morell; Lisbeth Tranebjærg; Andrew J. Griffith

doi:10.1136/jmedgenet-2017-104721

A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct

Parna Chattaraj, Tina Munjal, Keiji Honda, Nanna D. Rendtorff, Jessica S. Ratay, Julie A. Muskett, Davide S. Risso, Isabelle Roux, E. Michael Gertz, Alejandro A. Schäffer, Thomas B. Friedman, Robert J. Morell, Lisbeth Tranebjærg, Andrew J. Griffith^*

^*Corresponding author for this work

Department of Clinical Medicine

16 Citations (Scopus)

Abstract

Background E nlargement of the vestibular aqueduct (EVA) is the most common radiological abnormality in children with sensorineural hearing loss. Mutations in coding regions and splice sites of the SLC26A4 gene are often detected in Caucasians with EVA. Approximately one-fourth of patients with EVA have two mutant alleles (M2), one-fourth have one mutant allele (M1) and onehalf have no mutant alleles (M0). The M2 genotype is correlated with a more severe phenotype. Methods We performed genotype-haplotype analysis and massively parallel sequencing of the SLC26A4 region in patients with M1 EVA and their families. Results We identified a shared novel haplotype, termed CEVA (Caucasian EVA), composed of 12 uncommon variants upstream of SLC26A4. The presence of the CEVA haplotype on seven of ten 'mutation-negative' chromosomes in a National Institutes of Health M1 EVA discovery cohort and six of six mutation-negative chromosomes in a Danish M1 EVA replication cohort is higher than the observed prevalence of 28 of 1006 Caucasian control chromosomes (p<0.0001 for each EVA cohort). The corresponding heterozygous carrier rate is 28/503 (5.6%). The prevalence of CEVA (11 of 126) is also increased among M0 EVA chromosomes (p=0.0042). Conclusions T he CEVA haplotype causally contributes to most cases of Caucasian M1 EVA and, possibly, some cases of M0 EVA. The CEVA haplotype of SLC26A4 defines the most common allele associated with hereditary hearing loss in Caucasians. The diagnostic yield and prognostic utility of sequence analysis of SLC26A4 exons and splice sites will be markedly increased by addition of testing for the CEVA haplotype.

Original language	English
Journal	Journal of Medical Genetics
Volume	54
Issue number	10
Pages (from-to)	665-673
Number of pages	9
ISSN	0022-2593
DOIs	https://doi.org/10.1136/jmedgenet-2017-104721
Publication status	Published - 2017

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Chattaraj, P., Munjal, T., Honda, K., Rendtorff, N. D., Ratay, J. S., Muskett, J. A., Risso, D. S., Roux, I., Gertz, E. M., Schäffer, A. A., Friedman, T. B., Morell, R. J., Tranebjærg, L., & Griffith, A. J. (2017). A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct. Journal of Medical Genetics, 54(10), 665-673. https://doi.org/10.1136/jmedgenet-2017-104721

Chattaraj, P, Munjal, T, Honda, K, Rendtorff, ND, Ratay, JS, Muskett, JA, Risso, DS, Roux, I, Gertz, EM, Schäffer, AA, Friedman, TB, Morell, RJ, Tranebjærg, L & Griffith, AJ 2017, 'A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct', Journal of Medical Genetics, vol. 54, no. 10, pp. 665-673. https://doi.org/10.1136/jmedgenet-2017-104721

@article{55a56322696e4a769969e4bbec5d3774,

title = "A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct",

abstract = "Background E nlargement of the vestibular aqueduct (EVA) is the most common radiological abnormality in children with sensorineural hearing loss. Mutations in coding regions and splice sites of the SLC26A4 gene are often detected in Caucasians with EVA. Approximately one-fourth of patients with EVA have two mutant alleles (M2), one-fourth have one mutant allele (M1) and onehalf have no mutant alleles (M0). The M2 genotype is correlated with a more severe phenotype. Methods We performed genotype-haplotype analysis and massively parallel sequencing of the SLC26A4 region in patients with M1 EVA and their families. Results We identified a shared novel haplotype, termed CEVA (Caucasian EVA), composed of 12 uncommon variants upstream of SLC26A4. The presence of the CEVA haplotype on seven of ten 'mutation-negative' chromosomes in a National Institutes of Health M1 EVA discovery cohort and six of six mutation-negative chromosomes in a Danish M1 EVA replication cohort is higher than the observed prevalence of 28 of 1006 Caucasian control chromosomes (p<0.0001 for each EVA cohort). The corresponding heterozygous carrier rate is 28/503 (5.6%). The prevalence of CEVA (11 of 126) is also increased among M0 EVA chromosomes (p=0.0042). Conclusions T he CEVA haplotype causally contributes to most cases of Caucasian M1 EVA and, possibly, some cases of M0 EVA. The CEVA haplotype of SLC26A4 defines the most common allele associated with hereditary hearing loss in Caucasians. The diagnostic yield and prognostic utility of sequence analysis of SLC26A4 exons and splice sites will be markedly increased by addition of testing for the CEVA haplotype.",

author = "Parna Chattaraj and Tina Munjal and Keiji Honda and Rendtorff, {Nanna D.} and Ratay, {Jessica S.} and Muskett, {Julie A.} and Risso, {Davide S.} and Isabelle Roux and Gertz, {E. Michael} and Sch{\"a}ffer, {Alejandro A.} and Friedman, {Thomas B.} and Morell, {Robert J.} and Lisbeth Tranebj{\ae}rg and Griffith, {Andrew J.}",

year = "2017",

doi = "10.1136/jmedgenet-2017-104721",

language = "English",

volume = "54",

pages = "665--673",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "B M J Group",

number = "10",

}

TY - JOUR

T1 - A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct

AU - Chattaraj, Parna

AU - Munjal, Tina

AU - Honda, Keiji

AU - Rendtorff, Nanna D.

AU - Ratay, Jessica S.

AU - Muskett, Julie A.

AU - Risso, Davide S.

AU - Roux, Isabelle

AU - Gertz, E. Michael

AU - Schäffer, Alejandro A.

AU - Friedman, Thomas B.

AU - Morell, Robert J.

AU - Tranebjærg, Lisbeth

AU - Griffith, Andrew J.

PY - 2017

Y1 - 2017

N2 - Background E nlargement of the vestibular aqueduct (EVA) is the most common radiological abnormality in children with sensorineural hearing loss. Mutations in coding regions and splice sites of the SLC26A4 gene are often detected in Caucasians with EVA. Approximately one-fourth of patients with EVA have two mutant alleles (M2), one-fourth have one mutant allele (M1) and onehalf have no mutant alleles (M0). The M2 genotype is correlated with a more severe phenotype. Methods We performed genotype-haplotype analysis and massively parallel sequencing of the SLC26A4 region in patients with M1 EVA and their families. Results We identified a shared novel haplotype, termed CEVA (Caucasian EVA), composed of 12 uncommon variants upstream of SLC26A4. The presence of the CEVA haplotype on seven of ten 'mutation-negative' chromosomes in a National Institutes of Health M1 EVA discovery cohort and six of six mutation-negative chromosomes in a Danish M1 EVA replication cohort is higher than the observed prevalence of 28 of 1006 Caucasian control chromosomes (p<0.0001 for each EVA cohort). The corresponding heterozygous carrier rate is 28/503 (5.6%). The prevalence of CEVA (11 of 126) is also increased among M0 EVA chromosomes (p=0.0042). Conclusions T he CEVA haplotype causally contributes to most cases of Caucasian M1 EVA and, possibly, some cases of M0 EVA. The CEVA haplotype of SLC26A4 defines the most common allele associated with hereditary hearing loss in Caucasians. The diagnostic yield and prognostic utility of sequence analysis of SLC26A4 exons and splice sites will be markedly increased by addition of testing for the CEVA haplotype.

AB - Background E nlargement of the vestibular aqueduct (EVA) is the most common radiological abnormality in children with sensorineural hearing loss. Mutations in coding regions and splice sites of the SLC26A4 gene are often detected in Caucasians with EVA. Approximately one-fourth of patients with EVA have two mutant alleles (M2), one-fourth have one mutant allele (M1) and onehalf have no mutant alleles (M0). The M2 genotype is correlated with a more severe phenotype. Methods We performed genotype-haplotype analysis and massively parallel sequencing of the SLC26A4 region in patients with M1 EVA and their families. Results We identified a shared novel haplotype, termed CEVA (Caucasian EVA), composed of 12 uncommon variants upstream of SLC26A4. The presence of the CEVA haplotype on seven of ten 'mutation-negative' chromosomes in a National Institutes of Health M1 EVA discovery cohort and six of six mutation-negative chromosomes in a Danish M1 EVA replication cohort is higher than the observed prevalence of 28 of 1006 Caucasian control chromosomes (p<0.0001 for each EVA cohort). The corresponding heterozygous carrier rate is 28/503 (5.6%). The prevalence of CEVA (11 of 126) is also increased among M0 EVA chromosomes (p=0.0042). Conclusions T he CEVA haplotype causally contributes to most cases of Caucasian M1 EVA and, possibly, some cases of M0 EVA. The CEVA haplotype of SLC26A4 defines the most common allele associated with hereditary hearing loss in Caucasians. The diagnostic yield and prognostic utility of sequence analysis of SLC26A4 exons and splice sites will be markedly increased by addition of testing for the CEVA haplotype.

U2 - 10.1136/jmedgenet-2017-104721

DO - 10.1136/jmedgenet-2017-104721

M3 - Journal article

C2 - 28780564

AN - SCOPUS:85032589075

SN - 0022-2593

VL - 54

SP - 665

EP - 673

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 10

ER -

A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct

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