The mutation spectrum of the GJB2 and SLC26A4 genes, the 2 most common genes causing deafness, are known to be ethnic specific. In this study, the spectrum of the reported GJB2 and SLC26A4 mutations in different populations are reviewed and considered from a human migration perspective.
Methods:
Fifty-two and 17 articles on GJB2 and SLC26A4 mutations, respectively, were reviewed through the PubMed database from April 1996 to September 2014. The 4 most prevalent mutations were selected and compared. A cluster analysis was subsequently performed for these selected mutations.
Results:
The present review of frequent mutations shows the ethnic-specific GJB2 and SLC26A4 gene mutation spectrum. A cluster analysis of the GJB2 and SLC26A4 genes revealed similarities between ethnic populations.
Conclusion:
The mutation spectrum reviewed in this study clearly indicated that the frequent mutations in the GJB2 and SLC26A4 genes are consistent with the founder mutation hypothesis. A comparison with the Y-chromosome phylogenetic tree indicated that these mutations may have occurred during human migration.
MortonNE. Genetic epidemiology of hearing impairment. Ann N Y Acad Sci. 1991;630:16-31.
2.
AzaiezHChamberlinGPFischerSM, et al. GJB2: the spectrum of deafness-causing allele variants and their phenotype. Hum Mutat. 2004;24:305-311.
3.
DaiPYuFHanB, et al. GJB2 mutation spectrum in 2,063 Chinese patients with nonsyndromic hearing impairment. J Transl Med. 2009;7:26.
4.
TsukadaKNishioSUsamiS; Deafness Gene Study Consortium. A large cohort study of GJB2 mutations in Japanese hearing loss patients. Clin Genet. 2010;78:464-470.
5.
ChanDKChangKW. GJB2-associated hearing loss: systematic review of worldwide prevalence, genotype, and auditory phenotype. Laryngoscope. 2014;124:E34-E53.
6.
SnoeckxRLHuygenPLFeldmannD, et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005;77:945-957.
7.
MiyagawaMNishioSYUsamiS; Deafness Gene Study Consortium. Mutation spectrum and genotype-phenotype correlation of hearing loss patients caused by SLC26A4 mutations in the Japanese: a large cohort study. J Hum Genet. 2014;59:262-268.
8.
ShinJWLeeSCLeeHKParkHJ. Genetic screening of GJB2 and SLC26A4 in Korean cochlear implantees: experience of Soree Ear Clinic. Clin Exp Otorhinolaryngol. 2012;5(suppl 1):S10-S13.
9.
WuCCHungCCLinSY, et al. Newborn genetic screening for hearing impairment: a preliminary study at a tertiary center. PLoS One. 2011;6:e22314.
10.
TekinMXiaXJErdenetungalagR, et al. GJB2 mutations in Mongolia: complex alleles, low frequency, and reduced fitness of the deaf. Ann Hum Genet. 2010;74:155-164.
11.
SnoeckxRLDjelantikBVan LaerLVan de HeyningPVan CampG. GJB2 (connexin 26) mutations are not a major cause of hearing loss in the Indonesian population. Am J Med Genet A. 2005;135:126-129.
12.
ZainalSAMd DaudMKAbd RahmanNZainuddinZAlwiZ. Mutation detection in GJB2 gene among Malays with non-syndromic hearing loss. Int J Pediatr Otorhinolaryngol. 2012;76:1175-1179.
13.
WattanasirichaigoonDLimwongseCJariengprasertC, et al. High prevalence of V37I genetic variant in the connexin-26 (GJB2) gene among non-syndromic hearing-impaired and control Thai individuals. Clin Genet. 2004;66:452-460.
14.
PadmaGRamchanderPVNandurUVPadmaT. GJB2 and GJB6 gene mutations found in Indian probands with congenital hearing impairment. J Genet. 2009;88:267-272.
15.
SantosRLWajidMPhamTL, et al. Low prevalence of connexin 26 (GJB2) variants in Pakistani families with autosomal recessive non-syndromic hearing impairment. Clin Genet. 2005;67:61-68.
16.
BajajYSirimannaTAlbertDMQadirPJenkinsLBitner-GlindziczM. Spectrum of GJB2 mutations causing deafness in the British Bangladeshi population. Clin Otolaryngol. 2008;33:313-318.
17.
DahlHHChingTYHutchisonWHouSSeetoMSjahalam-KingJ. Etiology and audiological outcomes at 3 years for 364 children in Australia. PLoS One. 2013;8:e59624.
18.
BazazzadeganNNikzatNFattahiZ, et al. The spectrum of GJB2 mutations in the Iranian population with non-syndromic hearing loss—a twelve year study. Int J Pediatr Otorhinolaryngol. 2012;76:1164-1174.
19.
BrownsteinZAvrahamKB. Deafness genes in Israel: implications for diagnostics in the clinic. Pediatr Res. 2009;66:128-134.
20.
TekinMAriciZS. Genetic epidemiological studies of congenital/prelingual deafness in Turkey: population structure and mating type are major determinants of mutation identification. Am J Med Genet A. 2007;143A:1583-1591.
21.
ImtiazFTaibahKRamzanK, et al. A comprehensive introduction to the genetic basis of non-syndromic hearing loss in the Saudi Arabian population. BMC Med Genet. 2011;12:91.
22.
Al-SebeihKAl-KandariMAl-AwadiSA, et al. Connexin 26 gene mutations in non-syndromic hearing loss among Kuwaiti patients. Med Princ Pract. 2014;23:74-79.
23.
Al-AchkarWMoassassFAl-HalabiBAl-AblogA. Mutations of the connexin 26 gene in families with non-syndromic hearing loss. Mol Med Rep. 2011;4:331-335.
24.
PosukhOPallares-RuizNTadinovaVOsipovaLClaustresMRouxAF. First molecular screening of deafness in the Altai Republic population. BMC Med Genet. 2005;6:12.
25.
MinarikGTretinarovaDSzemesTKadasiL. Prevalence of DFNB1 mutations in Slovak patients with non-syndromic hearing loss. Int J Pediatr Otorhinolaryngol. 2012;76:400-403.
26.
DanilenkoNMerkulavaESiniauskayaM, et al. Spectrum of genetic changes in patients with non-syndromic hearing impairment and extremely high carrier frequency of 35delG GJB2 mutation in Belarus. PLoS One. 2012;7:e36354.
27.
TeekRKruustukKZordaniaR, et al. Prevalence of c.35delG and p.M34T mutations in the GJB2 gene in Estonia. Int J Pediatr Otorhinolaryngol. 2010;74:1007-1012.
28.
WiszniewskiWSobieszczanska-RadoszewskaLNowakowska-SzyrwinskaEObersztynEBalJ. High frequency of GJB2 gene mutations in Polish patients with prelingual nonsyndromic deafness. Genet Test. 2001;5:147-148.
29.
SansovićIKnezevićJMusaniVSeemanPBarisićIPavelićJ. GJB2 mutations in patients with nonsyndromic hearing loss from Croatia. Genet Test Mol Biomarkers. 2009;13:693-699.
30.
SeemanPMalikovaMRaskovaD, et al. Spectrum and frequencies of mutations in the GJB2 (Cx26) gene among 156 Czech patients with pre-lingual deafness. Clin Genet. 2004;66:152-157.
31.
PopovaDPKanevaRVarbanovaSPopovTM. Prevalence of GBJ2 mutations in patients with severe to profound congenital nonsyndromic sensorineural hearing loss in Bulgarian population. Eur Arch Otorhinolaryngol. 2012;269:1589-1592.
32.
RadulescuLMartuCBirkenhagerRCozmaSUngureanuLLaszigR. Prevalence of mutations located at the dfnb1 locus in a population of cochlear implanted children in eastern Romania. Int J Pediatr Otorhinolaryngol. 2012;76:90-94.
33.
JaneckeARHirst-StadlmannAGuntherB, et al. Progressive hearing loss, and recurrent sudden sensorineural hearing loss associated with GJB2 mutations—phenotypic spectrum and frequencies of GJB2 mutations in Austria. Hum Genet. 2002;111:145-153.
34.
SantosRLAulchenkoYSHuygenPL, et al. Hearing impairment in Dutch patients with connexin 26 (GJB2) and connexin 30 (GJB6) mutations. Int J Pediatr Otorhinolaryngol. 2005;69:165-174.
35.
MarlinSFeldmannDBlonsH, et al. GJB2 and GJB6 mutations: genotypic and phenotypic correlations in a large cohort of hearing-impaired patients. Arch Otolaryngol Head Neck Surg. 2005;131:481-487.
36.
ZollBPetersenLLangeK, et al. Evaluation of Cx26/GJB2 in German hearing impaired persons: mutation spectrum and detection of disequilibrium between M34T (c.101T>C) and -493del10. Hum Mutat. 2003;21:98.
37.
D’AndreaPVeronesiVBicegoM, et al. Hearing loss: frequency and functional studies of the most common connexin26 alleles. Biochem Biophys Res Commun. 2002;296:685-691.
38.
RabionetRZelanteLLopez-BigasN, et al. Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene. Hum Genet. 2000;106:40-44.
39.
PampanosAEconomidesJIliadouV, et al. Prevalence of GJB2 mutations in prelingual deafness in the Greek population. Int J Pediatr Otorhinolaryngol. 2002;65:101-108.
40.
NogueiraCCoutinhoMPereiraCTessaASantorelliFMVilarinhoL. Molecular investigation of pediatric Portuguese patients with sensorineural hearing loss [published online September25, 2011]. Genet Res Int. doi:10.4061/2011/587602.
41.
CarlssonPIKarltorpECarlsson-HansenEAhlmanHMollerCVondobelnU. GJB2 (connexin 26) gene mutations among hearing-impaired persons in a Swedish cohort. Acta Otolaryngol. 2012;132:1301-1305.
42.
LöppönenTVäisänenMLLuotonenM, et al. Connexin 26 mutations and nonsyndromic hearing impairment in northern Finland. Laryngoscope. 2003;113:1758-1763.
43.
SiemGFagerheimTJonsrudC, et al. Causes of hearing impairment in the Norwegian paediatric cochlear implant program. Int J Audiol. 2010;49:596-605.
44.
HomøePKochARendtorffND, et al. GJB2 (connexin-26) mutations are not frequent among hearing impaired patients in east Greenland. Int J Audiol. 2012;51:433-436.
45.
PutchaGVBejjaniBABleooS, et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007;9:413-426.
46.
de la Luz Arenas-SordoMMenendezIHernandez-ZamoraE, et al. Unique spectrum of GJB2 mutations in Mexico. Int J Pediatr Otorhinolaryngol. 2012;76:1678-1680.
47.
BatissocoACAbreu-SilvaRSBragaMC, et al. Prevalence of GJB2 (connexin-26) and GJB6 (connexin-30) mutations in a cohort of 300 Brazilian hearing-impaired individuals: implications for diagnosis and genetic counseling. Ear Hear. 2009;30:1-7.
48.
TamayoMLOlarteMGelvezN, et al. Molecular studies in the GJB2 gene (Cx26) among a deaf population from Bogota, Colombia: results of a screening program. Int J Pediatr Otorhinolaryngol. 2009;73:97-101.
49.
GravinaLPFoncubertaMEPrietoMEGarridoJBarreiroCChertkoffL. Prevalence of DFNB1 mutations in Argentinean children with non-syndromic deafness. Report of a novel mutation in GJB2. Int J Pediatr Otorhinolaryngol. 2010;74:250-254.
50.
CifuentesLArancibiaMTorrenteMAcunaMFarfanCRiosC. Prevalence of the 35delG mutation in the GJB2 gene in two samples of non-syndromic deaf subjects from Chile. Biol Res. 2013;46:239-242.
51.
SnoeckxRLHassanDMKamalNMVan Den BogaertKVan CampG. Mutation analysis of the GJB2 (connexin 26) gene in Egypt. Hum Mutat. 2005;26:60-61.
52.
Ammar-KhodjaFFaugereVBauxD, et al. Molecular screening of deafness in Algeria: high genetic heterogeneity involving DFNB1 and the Usher loci, DFNB2/USH1B, DFNB12/USH1D and DFNB23/USH1F. Eur J Med Genet. 2009;52:174-179.
53.
AbidiOBoulouizRNahiliH, et al. GJB2 (connexin 26) gene mutations in Moroccan patients with autosomal recessive non-syndromic hearing loss and carrier frequency of the common GJB2-35delG mutation. Int J Pediatr Otorhinolaryngol. 2007;71:1239-1245.
54.
GasmelseedNMSchmidtMMagzoubMM, et al. Low frequency of deafness-associated GJB2 variants in Kenya and Sudan and novel GJB2 variants. Hum Mutat. 2004;23:206-207.
55.
TrabelsiMBahriWHabibiM, et al. GJB2 and GJB6 screening in Tunisian patients with autosomal recessive deafness. Int J Pediatr Otorhinolaryngol. 2013;77:714-716.
56.
JavidniaHCarsonNAwubwaMByaruhangaRMackDVaccaniJP. Connexin gene mutations among Ugandan patients with nonsyndromic sensorineural hearing loss. Laryngoscope. 2014;124:E373-E376.
57.
HamelmannCAmedofuGKAlbrechtK, et al. Pattern of connexin 26 (GJB2) mutations causing sensorineural hearing impairment in Ghana. Hum Mutat. 2001;18:84-85.
58.
YuanYGuoWTangJ, et al. Molecular epidemiology and functional assessment of novel allelic variants of SLC26A4 in non-syndromic hearing loss patients with enlarged vestibular aqueduct in China. PLoS One. 2012;7:e49984.
59.
WuCCLuYCChenPJ, et al. Phenotypic analyses and mutation screening of the SLC26A4 and FOXI1 genes in 101 Taiwanese families with bilateral nonsyndromic enlarged vestibular aqueduct (DFNB4) or Pendred syndrome. Audiol Neurootol. 2010;15:57-66.
60.
DaiPYuanYHuangD, et al. Molecular etiology of hearing impairment in Inner Mongolia: mutations in SLC26A4 gene and relevant phenotype analysis. J Transl Med. 2008;6:74.
61.
AnwarSRiazuddinSAhmedZM, et al. SLC26A4 mutation spectrum associated with DFNB4 deafness and Pendred’s syndrome in Pakistanis. J Hum Genet. 2009;54:266-270.
62.
KahriziKMohseniMNishimuraC, et al. Identification of SLC26A4 gene mutations in Iranian families with hereditary hearing impairment. Eur J Pediatr. 2009;168:651-653.
63.
TekinMAkcayozDComakE, et al. Screening the SLC26A4 gene in probands with deafness and goiter (Pendred syndrome) ascertained from a large group of students of the schools for the deaf in Turkey. Clin Genet. 2003;64:371-374.
64.
AlbertSBlonsHJonardL, et al. SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations. Eur J Hum Genet. 2006;14:773-779.
65.
BorckGRothCMartineUWildhardtGPohlenzJ. Mutations in the PDS gene in German families with Pendred’s syndrome: V138F is a founder mutation. J Clin Endocrinol Metab. 2003;88:2916-2921.
66.
CoyleBReardonWHerbrickJA, et al. Molecular analysis of the PDS gene in Pendred syndrome. Hum Mol Genet. 1998;7:1105-1112.
67.
PeraAVillamarMVinuelaA, et al. A mutational analysis of the SLC26A4 gene in Spanish hearing-impaired families provides new insights into the genetic causes of Pendred syndrome and DFNB4 hearing loss. Eur J Hum Genet. 2008;16:888-896.
68.
PourovaRJanousekPJurovcikM, et al. Spectrum and frequency of SLC26A4 mutations among Czech patients with early hearing loss with and without enlarged vestibular aqueduct (EVA). Ann Hum Genet. 2010;74:299-307.
69.
RendtorffNDSchrijverILodahlM, et al. SLC26A4 mutation frequency and spectrum in 109 Danish Pendred syndrome/DFNB4 probands and a report of nine novel mutations. Clin Genet. 2013;84:388-391.
70.
CampbellCCucciRAPrasadS, et al. Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutations and possible genotype-phenotype correlations. Hum Mutat. 2001;17:403-411.
71.
de MoraesVCdos SantosNZRamosPZSvidnickiMCCastilhoAMSartoratoEL. Molecular analysis of SLC26A4 gene in patients with nonsyndromic hearing loss and EVA: identification of two novel mutations in Brazilian patients. Int J Pediatr Otorhinolaryngol. 2013;77:410-413.
72.
Y Chromosome Consortium. A nomenclature system for the tree of human Y-chromosomal binary haplogroups. Genome Res. 2002;12:339-348.
73.
JoblingMATyler-SmithC. The human Y chromosome: an evolutionary marker comes of age. Nat Rev Genet. 2003;4:598-612.
74.
KarafetTMMendezFLMeilermanMBUnderhillPAZeguraSLHammerMF. New binary polymorphisms reshape and increase resolution of the human Y chromosomal haplogroup tree. Genome Res. 2008;18:830-838.
75.
Van LaerLCouckePMuellerRF, et al. A common founder for the 35delG GJB2 gene mutation in connexin 26 hearing impairment. J Med Genet. 2001;38:515-518.
76.
AbidiOBoulouizRNahiliH, et al. The analysis of three markers flanking GJB2 gene suggests a single origin of the most common 35delG mutation in the Moroccan population. Biochem Biophys Res Commun. 2008;377:971-974.
77.
KokotasHVan LaerLGrigoriadouM, et al. Strong linkage disequilibrium for the frequent GJB2 35delG mutation in the Greek population. Am J Med Genet A. 2008;146A:2879-2884.
78.
NajmabadiHNishimuraCKahriziK, et al. GJB2 mutations: passage through Iran. Am J Med Genet A. 2005;133A:132-137.
79.
DzhemilevaLUPosukhOLBarashkovNA, et al. Haplotype diversity and reconstruction of ancestral haplotype associated with the c.35delG mutation in the GJB2 (Cx26) gene among the Volgo-Ural populations of Russia. Acta Naturae. 2011;3:52-63.
80.
YanDParkHJOuyangXM, et al. Evidence of a founder effect for the 235delC mutation of GJB2 (connexin 26) in east Asians. Hum Genet. 2003;114:44-50.
81.
OhtsukaAYugeIKimuraS, et al. GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation. Hum Genet. 2003;112:329-333.
82.
DzhemilevaLUBarashkovNAPosukhOL, et al. Carrier frequency of GJB2 gene mutations c.35delG, c.235delC and c.167delT among the populations of Eurasia. J Hum Genet. 2010;55:749-754.
83.
YaoJLuYWeiQCaoXXingG. A systematic review and meta-analysis of 235delC mutation of GJB2 gene. J Transl Med. 2012;10:136.
84.
BarashkovNADzhemilevaLUFedorovaSA, et al. Carrier frequency of GJB2 gene mutations c.35delG, c.235delC and c.167delT among the populations of Eurasia. J Hum Genet. 2010;55:749-754.
85.
SeemanPSakmaryovaI. High prevalence of the IVS 1 + 1 G to A/GJB2 mutation among Czech hearing impaired patients with monoallelic mutation in the coding region ofGJB2. Clin Genet. 2006;69:410-413.
86.
RamShankarMGirirajanSDaganO, et al. Contribution of connexin26 (GJB2) mutations and founder effect to non-syndromic hearing loss in India. J Med Genet. 2003;40:e68.
87.
JosephAYRasoolTJ. High frequency of connexin26 (GJB2) mutations associated with nonsyndromic hearing loss in the population of Kerala, India. Int J Pediatr Otorhinolaryngol. 2009;73:437-443.
88.
HanSHParkHJKangEJ, et al. Carrier frequency of GJB2 (connexin-26) mutations causing inherited deafness in the Korean population. J Hum Genet. 2008;53:1022-1028.
89.
KelleyPMHarrisDJComerBC, et al. Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. Am J Hum Genet. 1998;62:792-799.
90.
BasonLDudleyTLewisK, et al. Homozygosity for the V37I connexin 26 mutation in three unrelated children with sensorineural hearing loss. Clin Genet. 2002;61:459-464.
91.
WilcoxSASaundersKOsbornAH, et al. High frequency hearing loss correlated with mutations in the GJB2 gene. Hum Genet. 2000;106:399-405.
92.
BruzzoneRVeronesiVGomesD, et al. Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness. FEBS Lett. 2003;533:79-88.
93.
HutchinTCoyNNConlonH, et al. Assessment of the genetic causes of recessive childhood non-syndromic deafness in the UK—implications for genetic testing. Clin Genet. 2005;68:506-512.
94.
ParkHJShaukatSLiuXZ, et al. Origins and frequencies of SLC26A4 (PDS) mutations in east and south Asians: global implications for the epidemiology of deafness. J Med Genet. 2003;40:242-248.
95.
DaiPStewartAKChebibF, et al. Distinct and novel SLC26A4/Pendrin mutations in Chinese and U.S. patients with nonsyndromic hearing loss. Physiol Genomics. 2009;38:281-290.
96.
GuoYFLiuXWGuanJ, et al. GJB2, SLC26A4 and mitochondrial DNA A1555G mutations in prelingual deafness in Northern Chinese subjects. Acta Otolaryngol. 2008;128:297-303.
97.
WuCCYehTHChenPJHsuCJ. Prevalent SLC26A4 mutations in patients with enlarged vestibular aqueduct and/or Mondini dysplasia: a unique spectrum of mutations in Taiwan, including a frequent founder mutation. Laryngoscope. 2005;115:1060-1064.
