Abstract
The objective of this study was to investigate the relevance of routine assessment of c.−259C>T in the Austrian newborn screening program. Homozygous and compound heterozygous mutations in the coding region of the human gene encoding gap junction protein GJB2 (Connexin 26) cause up to 50 % of neonatal autosomal recessive non-syndromic hearing impairment identified in Caucasian newborn screening programs. More recently, a null mutation in the GC box of the GJB2 basal promoter c.−259C>T has been described which causes hearing impairment by completely suppressing GJB2 promoter activity. We determined the occurrence of c.−259C>T in cases of non-syndromic hearing impairment lacking known pathogenic alterations in GJB2 (n = 43), a non-syndromic hearing impaired patient group (n = 15) bearing the heterozygous GJB2 mutations c.35delG, c.[79G>A];[341A>G] (p. [V27I];[E114G]), c.109G>A (p.V37I), c.154G>C (p.V52L), c.262G>T (p.A88S), c.269T>C (p.L90P) and c.551G>C (p.R184P) and in a normal hearing group lacking alterations in GJB2 (n = 50). In the analyzed groups, no occurrence of c.−259C>T was found. The c.−259C>T mutation, previously described as −3438C>T, is not a common cause of non-syndromic hearing impairment alone or together with heterozygous pathogenic GJB2 mutations that are statistically overrepresented in non-syndromic hearing impaired patient groups. Screening of newborns for c.−259C>T is therefore unlikely to be commonly found in Austrian NSHI patients but could make a significant contribution to non-syndromic hearing impairment in other populations.
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References
Fortnum H, Davis A (1997) Epidemiology of permanent childhood hearing impairment in Trent Region, 1985–1993. Br J Audiol 31:409–446
Morton NE (1991) Genetic epidemiology of hearing impairment. Ann N Y Acad Sci 630:16–31
Estivill X, Fortina P, Surrey S et al (1998) Connexin-26 mutations in sporadic and inherited sensorineural deafness. Lancet 351:394–398
Denoyelle F, Weil D, Maw MA et al (1997) Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene. Hum Mol Genet 6:2173–2177
Ramsebner R, Volker R, Lucas T et al (2007) High incidence of GJB2 mutations during screening of newborns for hearing loss in Austria. Ear Hear 28:298–301
Zelante L, Gasparini P, Estivill X et al (1997) Connexin26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. Hum Mol Genet 6:1605–1609
Frei K, Ramsebner R, Lucas T et al (2005) GJB2 mutations in hearing impairment: identification of a broad clinical spectrum for improved genetic counseling. Laryngoscope 115:461–465
Denoyelle F, Marlin S, Weil D et al (1999) Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling. Lancet 353:1298–1303
Seeman P, Sakmaryová I (2006) High prevalence of the IVS 1 + 1 G to A/GJB2 mutation among Czech hearing impaired patients with monoallelic mutation in the coding region of GJB2. Clin Genet 69:410–413
Tu ZJ, Kiang DT (1998) Mapping and characterization of the basal promoter of the human connexin26 gene. Biochim Biophys Acta 1443:169–181
Houseman MJ, Ellis LA, Pagnamenta A et al (2001) Genetic analysis of the connexin-26 M34T variant: identification of genotype M34T/M34T segregating with mild-moderate non-syndromic sensorineural hearing loss. J Med Genet 38:20–25
Matos TD, Caria H, Simões-Teixeira H et al (2007) A novel hearing-loss-related mutation occurring in the GJB2 basal promoter. J Med Genet 44:721–725
Frei K, Szuhai K, Lucas T et al (2002) Connexin 26 mutations in cases of sensorineural deafness in eastern Austria. Eur J Hum Genet 10:427–432
Altschul SF, Gish W, Miller W et al (1990) Basic local alignment search tool. J Mol Biol 215:403–410
Frei K, Lucas T, Ramsebner R et al (2004) A novel connexin 26 mutation associated with autosomal recessive sensorineural deafness. Audiol Neurootol 9:47–50
Tekin M, Duman T, Boğoçlu G et al (2003) Spectrum of GJB2 mutations in Turkey comprises both Caucasian and Oriental variants: roles of parental consanguinity and assortative mating. Hum Mutat 21:552–553
Kelley PM, Harris DJ, Comer BC et al (1998) Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. Am J Hum Genet 62:792–799
Murgia A, Orzan E, Polli R et al (1999) Cx26 deafness: mutation analysis and clinical variability. J Med Genet 36:829–832
Van Camp G, Smith RJH (1999) Hereditary Hearing Loss Homepage. http://hereditaryhearingloss.org. Accessed 10 July 2013
Hilgert N, Huentelman MJ, Thorburn AQ et al (2009) Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene. Eur J Hum Genet 17:517–524
Rothrock CR, Murgia A, Sartorato EL et al (2003) Connexin 26 35delG does not represent a mutational hotspot. Hum Genet 113:18–23
Pollak A, Mueller-Malesinska M, Skórka A et al (2008) GJB2 and hearing impairment: promoter defects do not explain the excess of monoallelic mutations. J Med Genet 45:607–608
Acknowledgments
The authors wish to thank the patients and their families for cooperation and Marlene Almeder for technical assistance. This project was supported by funds of the Oesterreichische National bank (Anniversary Fund, project number AP14058ONB).
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The authors declare that they have no conflict of interest.
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Koenighofer, M., Lucas, T., Parzefall, T. et al. The promoter mutation c.−259C>T (−3438C>T) is not a common cause of non-syndromic hearing impairment in Austria. Eur Arch Otorhinolaryngol 272, 229–232 (2015). https://doi.org/10.1007/s00405-014-3223-z
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DOI: https://doi.org/10.1007/s00405-014-3223-z