Frequency of GJB2 mutations in patients with nonsyndromic hearing loss from an ethnically characterized Brazilian population

Felix, Felippe; Ribeiro, Marcia Gonçalves; Tomita, Shiro; Zalis, Mariano Gustavo

doi:10.1016/j.bjorl.2017.10.013

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Brazilian Journal of Otorhinolaryngology

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Original articles • Braz. j. otorhinolaryngol. 85 (1) • Jan-Feb 2019 • https://doi.org/10.1016/j.bjorl.2017.10.013 copy

Frequency of GJB2 mutations in patients with nonsyndromic hearing loss from an ethnically characterized Brazilian population^☆ ☆ Please cite this article as: Felix F, Ribeiro MG, Tomita S, Zalis MG. Frequency of GJB2 mutations in patients with nonsyndromic hearing loss from an ethnically characterized Brazilian population. Braz J Otorhinolaryngol. 2019;85:92-8.

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Introduction:

In different parts of the world, mutations in the GJB2 gene are associated with nonsyndromic hearing loss, and the homozygous 35delG mutation (p.Gly12Valfs*2) is a major cause of hereditary hearing loss. However, the 35delG mutation is not equally prevalent across ethnicities, making it important to study other mutations, especially in multiethnic countries such as Brazil.

Objective:

This study aimed to identify different mutations in the GJB2 gene in patients with severe to profound nonsyndromic sensorineural hearing loss of putative genetic origin, and who were negative or heterozygote for the 35delG mutation.

Methods:

Observational study that analyzed 100 ethnically characterized Brazilian patients with nonsyndromic severe to profound sensorineural hearing loss, who were negative or heterozygote for the 35delG mutation. GJB2 mutations were detected by DNA-based sequencing in this population. Participants' ethnicities were identified as Latin European, Non-Latin European, Jewish, Native, Turkish, Afro-American, Asian and Others.

Results:

Sixteen participants were heterozygote for the 35delG mutation; 14 participants, including three 35delG heterozygote's, had nine different alterations in the GJB2 gene. One variant, p.Ser199Glnfs*9, detected in two participants, was previously unreported. Three variants were pathogenic (p.Trp172*, p.Val167Met, and p.Arg75Trp), two were non-pathogenic (p.Val27Ile and p.Ile196Thr), and three variants were indeterminate (p.Met34Thr, p.Arg127Leu, and p.Lys168Arg). Three cases of compound heterozygosity were detected: p.[(Gly12Valfs*2)];[(Trp172*)], p.[(Gly12Valfs*2)](;)[(Met34Thr)], and p.[(Gly12Valfs*2)(;)[(Ser199Glnfs*9)]).

Conclusion:

This study detected previously unclassified variants and one case of previously unreported compound heterozygosity.

KEYWORDS
Hearing loss; Deafness; Genetics

Ethnicity	N (n = 100)
Latin European	35
Afro-American/Latin European	29
Afro-American	23
Native/Latin European	5
Native	3
Native/Afro-American	3
Non-Latin European	1
Afro-American/Non-Latin European	1

Ethnicity	Total (n = 100)		With GJB2 variants (n = 14)		Without GJB2 variants (n = 86)		p
Ethnicity	n	%	n	%	n	%
Latin European	35	35.0	3	21.4	32	37.2
Afro-American	23	23.0	3	21.4		23.3
Afro-American/Latin European	29	29.0	7	50.0	22	25.6	0.35
Others	13	13.0	1	7.1	12	14.0

Case	Variant found	Heterozygous 35delG mutation	Ethnicity	Age (years)	Type of hearing loss
14	p.(Trp172*)	Yes	Afro-American/Latin European	3	Congenital
16	p.[(Val27Ile)(;) [(Arg127Leu)]	No	Afro-American/Latin European	1	Congenital
30	p.(Lys168Arg)	No	Latin European	7	Congenital
35	p.(Val27Ile)	No	Afro-American	5	Congenital
45	p.(Met34Thr)	No	Afro-American	47	Sudden
48	p.(Ser199Glnfs*9)	no	Afro-American/Latin European	4	Congenital
49	p.[(Ile196Thr)(;) [(Lys168Arg)]	No	Afro-American/Latin European	4	Congenital
53	p.(Ser199Glnfs*9)	Yes	Latin European	5	Congenital
62	p.(Val167Met)	No	Afro-American	4	Congenital
64	p.(Lys168Arg)	No	Native/Afro-American	5	Congenital
65	p.(Met34Thr)	Yes	Afro-American/Latin European	47	Progressive
79	p.(Val27Ile)	Yes	Latin European	16	Progressive
82	p.(Arg75Trp)	No	Afro-American/Latin European	3	Congenital
100	p.(Val27Ile)	No	Afro-American/Latin European	2	Congenital

Variant found and annotation	Description	Effect	SIFT	Polyphen-2	Source*	Type of variant
Pathogenic
p.(Trp172*)	Substitution of a guanine by an adenosine at position 516	Substitution of tryptophan by a stop codon at position 172	Not evaluable	Not evaluable	Da Vinci	Non-sense
p.(Arg75Trp) rs28931 593	Substitution of a cytosine by a thymine at position 223	Substitution of arginine by tryptophan at position 75	0.0	1.0	Da Vinci 1000 genomes Deafness Variation	Missense
p. (Val167Met) rs11103 3360	Substitution of a guanine by an adenosine at nucleotide position 499	Substitution of valine by methionine at position 167	0.04	0.168	Deafness Variation 1000 genomes (possibly pathogenic)	Missense
Non-pathogenic
p.(Val27Ile) rs22740 84	Substitution of a guanine by an adenosine at position 79	Substitution of valine by isoleucine at position 27	0.21	1.0	Da Vinci 1000 genomes Deafness Variation	Missense
p.(Ile196Thr)	Substitution of a cytosine by a thymine at position 587	Substitution of isoleucine by threonine at position 196	0.01	0.922	Benign by Deafness Variation	Missense
Variant found and annotation	Description	Effect	SIFT	Polyphen-2	Source*	Type of variant
Indeterminate
p.(Met34Thr) rs3588762 2	Substitution of a thymine by a cytosine at position 101	Substitution of methionine by threonine at position 34	0.01	0.38	DaVinci 1000 genomes Deafness Variation	Missense
p.(Lys168Arg) rs2001043 62	Substitution of an adenosine by a guanine at position 503	Substitution da lysine by arginine at position168	0.29	0.074	Benign by 1000 genomes unknown pathogenicity by Deafness Variation	Missense
p.(Arg127Leu) rs1110331 96	Substitution of a guanine by a thymine at nucleotide position 380	Substitution of arginine by leucine at position 127	0.04	0.277	Pathogenic by Deafness Variation benign by 1000 genomes	Missense
Undescribed
p.(Ser199Glnfs*9)	Duplication of the CAGTG segment at position 596	Substitution of serine by glutamine at position 199 and insertion of a frame shift and stop codon	Not evaluable	Not evaluable	Undescribed	Frame shift

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[1] * Corresponding author. E-mail:fefelix@gmail.com (F. Felix).