Genetic Factors Contribute to the Phenotypic Variability in GJB2-Related Hearing Impairment

Abstract

Recessive variants in GJB2 are the most important genetic cause of sensorineural hearing impairment (SNHI) worldwide. Phenotypes vary significantly in GJB2-related SNHI, even in patients with identical variants. For instance, patients homozygous for the GJB2 p.V37I variant, which is highly prevalent in the Asian populations, usually present with mild-to-moderate SNHI; yet severe-to-profound SNHI is occasionally observed in approximately 10% of p.V37I homozygotes. To investigate the genomic underpinnings of the phenotypic variability, we performed next-generation sequencing of GJB2 and other deafness genes in 63 p.V37I homozygotes with extreme phenotypic severities. Additional pathogenic variants of other deafness genes were identified in five of the 35 patients with severe-to-profound SNHI. Furthermore, case-control association analyses were conducted for 30 unrelated p.V37I homozygotes with severe-to-profound SNHI against 28 p.V37I homozygotes with mild-to-moderate SNHI, and 120 population controls from the Taiwan Biobank. The severe-to-profound group exhibited a higher frequency of the crystallin lambda 1 (CRYL1) variant (rs14236), located upstream of GJB2, than the mild-to-moderate and Taiwan Biobank groups. Our results demonstrated that pathogenic variants in other deafness genes and a possible modifier, the CRYL1 rs14236 variant, may contribute to phenotypic variability in GJB2-realted SNHI, highlighting the importance of comprehensive genomic surveys to delineate the genotype-phenotype correlations. Recessive variants in GJB2 are the most important genetic cause of sensorineural hearing impairment (SNHI) worldwide. Phenotypes vary significantly in GJB2-related SNHI, even in patients with identical variants. For instance, patients homozygous for the GJB2 p.V37I variant, which is highly prevalent in the Asian populations, usually present with mild-to-moderate SNHI; yet severe-to-profound SNHI is occasionally observed in approximately 10% of p.V37I homozygotes. To investigate the genomic underpinnings of the phenotypic variability, we performed next-generation sequencing of GJB2 and other deafness genes in 63 p.V37I homozygotes with extreme phenotypic severities. Additional pathogenic variants of other deafness genes were identified in five of the 35 patients with severe-to-profound SNHI. Furthermore, case-control association analyses were conducted for 30 unrelated p.V37I homozygotes with severe-to-profound SNHI against 28 p.V37I homozygotes with mild-to-moderate SNHI, and 120 population controls from the Taiwan Biobank. The severe-to-profound group exhibited a higher frequency of the crystallin lambda 1 (CRYL1) variant (rs14236), located upstream of GJB2, than the mild-to-moderate and Taiwan Biobank groups. Our results demonstrated that pathogenic variants in other deafness genes and a possible modifier, the CRYL1 rs14236 variant, may contribute to phenotypic variability in GJB2-realted SNHI, highlighting the importance of comprehensive genomic surveys to delineate the genotype-phenotype correlations. Hearing impairment is the most common inherited sensory disorder in the world. Approximately 2% of children worldwide experience bilateral sensorineural hearing impairment (SNHI),1Morton C.C. Nance W.E. Newborn hearing screening--a silent revolution.N Engl J Med. 2006; 354: 2151-2164Crossref PubMed Scopus (1202) Google Scholar two-thirds of which are attributed to genetic causes.2Hilgert N. Smith R.J.H. Van Camp G. Forty-six genes causing nonsyndromic hearing impairment: which ones should be analyzed in DNA diagnostics?.Mutat Res. 2009; 681: 189-196Crossref PubMed Scopus (391) Google Scholar Of the >200 genes that have been linked to hereditary hearing impairment, recessive variants in the gap junction protein β 2 (GJB2) gene [Online Mendelian Inheritance in Man (OMIM) number 220290] are the most important,3Kenna M.A. Feldman H.A. Neault M.W. Frangulov A. Wu B.L. Fligor B. Rehm H.L. Audiologic phenotype and progression in GJB2 (connexin 26) hearing loss.Arch Otolaryngol Head Neck Surg. 2010; 136: 81-87Crossref PubMed Scopus (77) Google Scholar possibly accounting for approximately 20% of children with SNHI globally.4Chan D.K. Chang K.W. GJB2-associated hearing loss: systematic review of worldwide prevalence, genotype, and auditory phenotype.Laryngoscope. 2014; 124: E34-E53Crossref PubMed Scopus (205) Google Scholar GJB2 encodes connexin 26,5Kelsell D.P. Dunlop J. Stevens H.P. Lench N.J. Liang J.N. Parry G. Mueller R.F. Leigh I.M. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.Nature. 1997; 387: 80-83Crossref PubMed Scopus (1258) Google Scholar which is mainly expressed in the supporting cells of the inner ear.6Chen Y. Hu L. Wang X. Sun C. Lin X. Li L. Mei L. Huang Z. Yang T. Wu H. Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2.Sci Rep. 2016; 633279Google Scholar Connexin 26 is a transmembrane protein that forms cell-cell gap junctions that maintain potassium recycling and intercellular signaling in the inner ear.7Jagger D.J. Forge A. Connexins and gap junctions in the inner ear--it's not just about K⁺ recycling.Cell Tissue Res. 2015; 360: 633-644Crossref PubMed Scopus (75) Google Scholar,8Wingard J.C. Zhao H.B. Cellular and deafness mechanisms underlying connexin mutation-induced hearing loss - a common hereditary deafness.Front Cell Neurosci. 2015; 9: 202Crossref PubMed Scopus (108) Google Scholar More than 400 GJB2 variants have been reported as pathogenic or likely pathogenic in the Deafness Variation Database (University of Iowa, Iowa City, IA, http://deafnessvariationdatabase.org, last accessed January 13, 2023). Several pathogenic GJB2 variants are particularly prevalent in certain ethnic groups, such as NM_004004.6:c.101T>C (p.Met34Thr) and NM_004004.6:c.35delG (p.Gly12ValfsTer2) in White individuals,9Gürtler N. Kim Y. Mhatre A. Müller R. Probst R. Lalwani A.K. GJB2 mutations in the Swiss hearing impaired.Ear Hear. 2003; 24: 440-447Crossref PubMed Scopus (26) Google Scholar,10Gasparini P. Rabionet R. Barbujani G. Melçhionda S. Petersen M. Brøndum-Nielsen K. Metspalu A. Oitmaa E. Pisano M. Fortina P. Zelante L. Estivill X. High carrier frequency of the 35delG deafness mutation in European populations: Genetic Analysis Consortium of GJB2 35delG.Eur J Hum Genet. 2000; 8: 19-23Crossref PubMed Scopus (352) Google Scholar NM_004004.6:c.167delT (p.Leu56ArgfsTer26) in Ashkenazi Jews,11Morell R.J. Kim H.J. Hood L.J. Goforth L. Friderici K. Fisher R. Van Camp G, Berlin CI, Oddoux C, Ostrer H, Keats B, Friedman TB: Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness.N Engl J Med. 1998; 339: 1500-1505Crossref PubMed Scopus (482) Google Scholar and NM_004004.6:c.109G>A (p.Val37Ile), usually abbreviated as p.V37I, and NM_004004.6:c.235delC (p.Leu79CysfsTer3) in East Asian populations.12Hwa H.L. Ko T.M. Hsu C.J. Huang C.H. Chiang Y.L. Oong J.L. Chen C.C. Hsu C.K. Mutation spectrum of the connexin 26 (GJB2) gene in Taiwanese patients with prelingual deafness.Genet Med. 2003; 5: 161-165Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 13Oguchi T. Ohtsuka A. Hashimoto S. Oshima A. Abe S. Kobayashi Y. Nagai K. Matsunaga T. Iwasaki S. Nakagawa T. Usami S.I. Clinical features of patients with GJB2 (connexin 26) mutations: severity of hearing loss is correlated with genotypes and protein expression patterns.J Hum Genet. 2005; 50: 76-83Crossref PubMed Scopus (79) Google Scholar, 14Dai P. Yu F. Han B. Yuan Y. Li Q. Wang G. Liu X. He J. Huang D. Kang D. Zhang X. Yuan H. Schmitt E. Han D. Wong L.J. The prevalence of the 235delC GJB2 mutation in a Chinese deaf population.Genet Med. 2007; 9: Full Text Full Text PDF PubMed Scopus (77) Google Scholar, Kim Han Kim hearing in deafness and in a 2015; Scholar The severity of GJB2-related SNHI is correlated with of such as and to hearing with of such as (p.Met34Thr) and (p.Val37Ile), usually mild-to-moderate hearing T. Ohtsuka A. Hashimoto S. Oshima A. Abe S. Kobayashi Y. Nagai K. Matsunaga T. Iwasaki S. Nakagawa T. Usami S.I. Clinical features of patients with GJB2 (connexin 26) mutations: severity of hearing loss is correlated with genotypes and protein expression patterns.J Hum Genet. 2005; 50: 76-83Crossref PubMed Scopus (79) Google Lin Liu Lin Yang Chen Wu C.C. Hsu C.J. model for in patients with GJB2 Hear. PubMed Scopus Google D. S. F. J. mutations and of hearing loss: a J Hum Genet. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar variability in hearing severity even in patients with the Lin Liu Lin Yang Chen Wu C.C. Hsu C.J. model for in patients with GJB2 Hear. PubMed Scopus Google J. H. Matsunaga T. A. of the and variants in GJB2 the hearing loss Med. Full Text Full Text PDF PubMed Scopus Google Scholar a of and in and of p.V37I homozygous patients exhibited mild-to-moderate and severe-to-profound SNHI, patients with mild-to-moderate J. H. Matsunaga T. A. of the and variants in GJB2 the hearing loss Med. Full Text Full Text PDF PubMed Scopus Google Scholar Several genetic such as variants in other deafness genes gap junction or of GJB2, have been to the phenotypic variability of GJB2 non-syndromic hearing impairment: of mutations and Neurosci. PubMed Scopus Google S. A. A. C. C. Characterization of GJB2 in the Genet. PubMed Scopus Google Scholar of the and of GJB2 variants in populations, the genetic to phenotypic variability are to delineate and of the prevalence of the GJB2 p.V37I variant and the of genetic in the C.C. C.H. C.C. Lin Lin Huang Y.L. Hsu C.J. Newborn genetic for hearing impairment: a Med. Full Text Full Text PDF PubMed Scopus Google Scholar, Lin Lin C.C. Hsu Huang Wu C.C. Hsu C.J. and in Full Text Full Text PDF PubMed Scopus (26) Google Scholar, C.C. C.C. Lin Hsu C.J. Newborn genetic for hearing impairment: a a Scholar we were to a with a GJB2 homozygous for to investigate the genomic underpinnings for the phenotypic in with the GJB2 next-generation sequencing and case-control genetic association were for Our results that pathogenic variants in other deafness genes and a possible in the crystallin lambda 1 the variant may contribute to the phenotypic variability in GJB2 p.V37I homozygotes. to a of patients with SNHI were to have the homozygous GJB2 p.V37I variant sequencing the Taiwan patients in the present were and with non-syndromic hereditary hearing impairment Taiwan The patients with for SNHI, and to or were patients with SNHI auditory or to and Lin Liu Lin Yang Chen Wu C.C. Hsu C.J. model for in patients with GJB2 Hear. PubMed Scopus Google Hsu C.J. Lin Lin Wu C.C. Liu and of patients with and sensorineural hearing Otolaryngol Head Neck Surg. 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M.A. mutations is the most identified of nonsyndromic hearing PubMed Scopus Google Scholar have been linked to non-syndromic SNHI. the results demonstrated that in approximately GJB2 p.V37I homozygotes with severe-to-profound SNHI, the phenotype may from pathogenic variants in other deafness genes of homozygous GJB2 p.V37I in Deafness from GJB2 p.V37I with pathogenic pathogenic from with deafness with from with deafness with from with deafness with of and Deafness Variation frequency of East Asian population in Database sequencing hearing loss not Mendelian Inheritance in with with supporting with with SNHI, sensorineural hearing frequency in Taiwan Biobank from with deafness with in a of and Deafness Variation frequency of East Asian population in Database sequencing hearing loss not Mendelian Inheritance in with with supporting with with SNHI, sensorineural hearing frequency in Taiwan Biobank association analyses of and population controls identified case-control association analyses of and controls identified variants. the are to be the variants that in with population controls and the of the of variants were the association analyses The variants were to the of the population association in of the from population from variant frequency in Taiwan Biobank in a from variant frequency in Taiwan Biobank the most variant in the population association variant in the association The variant is a variant in CRYL1 located in the upstream of the CRYL1 variant not pathogenic for SNHI, the analyses that the variant with SNHI severity in GJB2 p.V37I homozygotes. The model demonstrated a SNHI severity and CRYL1 rs14236 variant in p.V37I homozygotes variants of with in association analyses were in a The of the and in the Chinese of variants in number have been linked to P. A. A. J. variants and causing recessive the J A. PubMed Scopus Google Scholar the variants in the present are as variants in the Deafness Variation Database and have population in East Asian and Taiwanese that variants not to and the of the phenotype of the with non-syndromic SNHI of and of association and GJB2 variants were from The variants in that were not the were not the most The association may expression to GJB2 is the variants and non-syndromic hereditary hearing impairment the variants in were from in The other variants with are in sequencing performed as the CRYL1 rs14236 variant identified analyses the a for and correlated of possible 2015; PubMed Scopus Google Scholar and Taiwan Biobank Yang H.J. Chang Lin S. A. M.W. Lin Y.L. Liu Li Chen C.H. Wu Genetic of in the Taiwan Biobank the and of Han Med. PubMed Scopus Google Scholar that the GJB2 p.V37I and CRYL1 variants were not in that were and were and the Chinese Han of last accessed January 13, 2023). The rs14236 variant is in with the variant which is from GJB2 p.V37I in the Taiwan Biobank have that the upstream of GJB2, which CRYL1 and gene may a non-syndromic hearing impairment: of mutations and Neurosci. PubMed Scopus Google E. M. M. J.L. Fisher Friderici of GJB2 and is in a J Hum Genet. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar and E. H. Fisher J. A. R. H. T. L. H. C. C. A. E. Van Camp G. Smith R.J. Friderici the of a that controls GJB2 and Genet. 2010; PubMed Scopus Google Scholar a the CRYL1 the expression of the GJB2 gene in patients with SNHI and the The CRYL1 rs14236 variant located is the the of the variant from the features and N. T. The 2015; PubMed Scopus Google N. T. D. M. E. Q. D. D. S. R. B. S. R. A. S. E. P. 2016; PubMed Scopus Google Scholar the rs14236 variant The CRYL1 rs14236 variant the of the The of the rs14236 variant is the among the The is highly among the in protein The rs14236 variant, which the the genomic to the of the the for the the that the CRYL1 variant may as a the expression of the GJB2 p.V37I and case-control association to investigate the genetic that may to SNHI severity in GJB2 p.V37I homozygotes. Approximately of GJB2 p.V37I homozygotes with SNHI severity severe-to-profound were likely attributed to pathogenic variants in genes other than The rs14236 variant in CRYL1 identified as a genetic to SNHI phenotypic variability in GJB2 p.V37I homozygotes. variability of SNHI in patients with GJB2 variants been Lin Liu Lin Yang Chen Wu C.C. Hsu C.J. model for in patients with GJB2 Hear. PubMed Scopus Google D. S. F. J. mutations and of hearing loss: a J Hum Genet. 2005; Full Text Full Text PDF PubMed Scopus Google S. Huang B. Wang G. Yuan Y. P. The the p.V37I mutation in GJB2 and hearing in Chinese 2015; Scholar yet the underlying mechanisms N. E. N. M. variability of patients homozygous for the GJB2 mutation 35delG be the of J Hum Genet. 2009; PubMed Scopus Google Scholar performed a association in White patients homozygous for GJB2 and that phenotypic variability not be the of M. M. K. N. S. T. S. A. N. K. K. Matsunaga T. of the hearing of a GJB2 of genetic J PubMed Scopus Google Scholar hearing in of homozygous for GJB2 and that approximately of that genetic variants may the is supporting the of genetic the most common deafness genetic of GJB2 is in the of patients with SNHI. pathogenic variants in other deafness genes may in patients with GJB2 variants. Our demonstrated that pathogenic variants in other deafness and be in of patients with GJB2 Wu Lin Hsu Lin J. Wu H.P. Hsu C.J. Wu C.C. Chen Hearing impairment with GJB2 a GJB2 cause or Full Text Full Text PDF PubMed Scopus Google Scholar were observed in patients with GJB2 been reported to with GJB2 variants in and Chinese with Y. Sun L. X. Wang X. Chen D. Chen Y. Wu H. Yang T. of and GJB2 mutations in with non-syndromic hearing J 2014; PubMed Scopus Google Scholar The to GJB2 p.V37I homozygotes with the phenotype of severe-to-profound SNHI and identified pathogenic variants of other deafness genes in five results that genetic of GJB2 may be to a of SNHI. for patients with a and such as p.V37I homozygotes with severe-to-profound SNHI, comprehensive genetic is for in other gap junction genes may genetic to phenotypic variability in GJB2-related SNHI. been that connexin 26 may with other of to or gap junctions in the inner J. N. M. connexin 30 and PubMed Scopus Google M. PubMed Scopus Google Scholar the of GJB2 and other gap junction Yuan Y. D. Y. Yuan H. Chang Q. Zhang X. Wang G. S. Kang Lin X. 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Chen Hearing impairment with GJB2 a GJB2 cause or Full Text Full Text PDF PubMed Scopus Google Scholar pathogenic and variants were not observed in patients with GJB2 p.V37I variants that exhibited SNHI the of variants in other gap junction genes to the phenotypic variability of GJB2-related SNHI to be in the Taiwanese to pathogenic variants in gap junctions or other deafness genetic may contribute to the phenotypic variability of GJB2-related C. T. T. M. L. B. E. D. Y. M. P. A. M. M. J. Y. A. N. E. E. that genetic to phenotypic variability and Rep. 2015; Full Text Full Text PDF PubMed Scopus Google A. D. D. Y. G. Van S. T. in Res. PubMed Scopus Google Scholar association analyses identified a variant in CRYL1 as a possible of SNHI in GJB2 p.V37I homozygotes. The CRYL1 gene encodes the crystallin lambda which the of in the C. E. S. Petersen K. Van C. D. J. P. K. N. J.C. Van K. association for 2014; PubMed Scopus Google Scholar CRYL1 is highly expressed in and J. Yu L. Li D. Q. Wang J. Huang X. G. Wu H. Zhao S. a in and and in of from Chinese and from other 2003; PubMed Scopus Google Scholar and is in the of A.K. Wong C.K. K.W. M. Wong N. CRYL1 expression in and with 2010; PubMed Scopus Google Scholar and L. G. Y. H. H. of crystallin lambda 1 is a in Med. Google Scholar CRYL1 been linked to C. E. S. Petersen K. Van C. D. J. P. K. N. J.C. Van K. association for 2014; PubMed Scopus Google S. and genes with and in 8: PubMed Scopus Google Scholar The expression of in the mouse is to that of to the in the Analysis with expressed mainly in supporting J. B. J. Y. D. K. E. B. H. B. C. M.W. White A. R. gene expression for PubMed Scopus (77) Google Scholar CRYL1 variants and SNHI CRYL1 have been reported to the of GJB2 and genes in patients with non-syndromic hearing impairment: of mutations and Neurosci. PubMed Scopus Google D. C. L. P. C. R. C. F. S. F. in the nonsyndromic hearing J Genet. 2009; PubMed Scopus Google Scholar association in the Biobank identified that variant CRYL1 and to L. Z. H. Yang J. model association for Genet. PubMed Scopus Google Scholar of have that SNHI is CRYL1 The CRYL1 rs14236 variant as to the of and S. N. S. D. S. J. M. E. E. K. Rehm H.L. and for the of a of the of and and the for Med. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar variants in CRYL1 were as pathogenic or likely pathogenic in Deafness Variation H. B. R.J. D. T. C. T. Smith R.J.H. and of J Hum Genet. Full Text Full Text PDF PubMed Scopus Google Scholar of that the rs14236 variant may as a for SNHI of GJB2 than the CRYL1 gene from that the rs14236 variant GJB2 expression in the and last accessed January 13, 2023). the that the rs14236 variant the of S. A. A. C. C. Characterization of GJB2 in the Genet. PubMed Scopus Google Scholar performed and analyses for in and cells to investigate the of the upstream GJB2 The the >200 upstream of the GJB2 as the GJB2 S. A. A. C. C. Characterization of GJB2 in the Genet. PubMed Scopus Google Scholar The rs14236 variant in CRYL1 is located the and the other of the GJB2 that variant may the the GJB2 and GJB2 the expression of the GJB2 p.V37I to a hearing To the of is the to the genetic to phenotypic variability in GJB2-related SNHI. that were mainly the of patients homozygous for the GJB2 p.V37I variant, which is highly prevalent in the East Asian the GJB2 variants vary populations, be to other ethnic the frequency of the rs14236 variant in the controls significantly than that in the not the of other genomic or are to the mechanisms which the CRYL1 variant GJB2-related we demonstrated that the pathogenic variants in other deafness genes as variants and CRYL1 rs14236 as a genetic may contribute to hearing in GJB2 p.V37I homozygotes. that the phenotypic variability in GJB2-related SNHI is to genetic highlighting the importance of comprehensive genomic surveys of patients with SNHI in

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