AJMB  Vol.3 No.4 , October 2013
Confirmation of diagnosis in Romanian children with DFNB1 related hearing loss
Abstract
DFNB1 locus has been linked to a nonsyndromic “invisible disability” called congenital sensorineural hearing loss and deafness. Mutations of GJB2 and GJB6 genes are associated with deafness at the DFNB1 locus. The diagnosis of DFNB1 is made with molecular genetic testing. DNA-based testing can be used both prenatally and postnatally. Purpose: to get evidence for implementation of newborn hearing screening programs at national level; to use the molecular testing of children at risk for confirmation of diagnosis and early intervention. OAEs and ABR were performed for 4303 newborns. Audiologic evaluation of 38 children suspected of having hearing loss was performed too. Physical examinations and family history were used to get information about congenital deafness. DNA from blood samples was isolated, and two PCR multiplex assays were developed to detect DFNB1 mutations. Only 23 newborns were screened positive. Newborns were referred to audiologic evaluation, genetic counseling and testing for the etiologic diagnosis. Physical examination revealed no other abnormal findings. GJB2 mutations were detected in 36.03% of patients, and all of them have 35delG mutation. None of them was found to have GJB6 mutations. Our results suggested that molecular testing was an accurate method of early determining cause of congenital hearing loss and helped us to exclude GJB6 gene from the routine hearing screening protocol.

Cite this paper
Dragomir, C. , Stan, A. , Stefanescu, D. , Savu, L. , Sarafoleanu, C. , Toma, A. and Severin, E. (2013) Confirmation of diagnosis in Romanian children with DFNB1 related hearing loss. American Journal of Molecular Biology, 3, 229-234. doi: 10.4236/ajmb.2013.34029.
References

[1]   ASHA Web Site (2005) Audiology information series: Effects of hearing loss on development.
http://www.asha.org/uploadedFiles/aud/InfoSeriesHearingLossEffects.pdf

[2]   ACMG (2002) Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic Evaluation of Congenital Hearing Loss Expert Panel: ACMG statement. Genetics in Medicine, 4, 162-171.
http://dx.doi.org/10.1097/00125817-200205000-00011

[3]   Morton, N.E. (1991) Genetic epidemiology of hearing impairment. Annals of the New York Academy of Sciences, 630, 16-31.
http://dx.doi.org/10.1111/j.1749-6632.1991.tb19572.x

[4]   Van Camp, G., Willems, P.J. and Smith, R.J. (1997) Nonsyndromic hearing impairment: Unparalleled heterogeneity. The American Journal of Human Genetics, 60, 758-764.

[5]   Zelante, L., Gasparini, P., Estivill, X., Melchionda, S., D’Agruma, L., Govea, N., Mila, M., Monica, M.D., Lutfi, J., Shohat, M., Manfield, E., Delgroso, K., Rappaport, E., Surrey, S. and Fortina, P. (1997) Connexin 26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. Human Molecular Genetics, 6, 1605-1609.
http://dx.doi.org/10.1111/j.1749-6632.1991.tb19572.x

[6]   Morell, R.J., Kim, H.J., Hood, L.J., Goforth, L., Friderici, K., Fisher, R., Van Camp, G., Berlin, C.I., Oddoux, C., Ostrer, H., Keats, B., Friedman, T.B. (1998) Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness. The New England Journal of Medicine, 339, 1500-1505.
http://dx.doi.org/10.1056/NEJM199811193392103

[7]   Scott, D.A., Kraft, M.L., Carmi, R., Ramesh, A., Elbedour, K., Yairi, Y., Srikumari Srisailapathy, C.R., Rosengren, S.S., Markham, A.F., Mueller, R.F., Lench, N.J., Van Camp, G., Smith, R.J.H. and Sheffield, V.C. (1998) Identification of mutation in the connexin 26 gene that cause autosomal recessive nonsyndromic hearing loss. Human Mutation, 11, 387-394.
http://dx.doi.org/10.1002/(SICI)1098-1004(1998)11:5<387::AID-HUMU6>3.0.CO;2-8

[8]   Del Castillo, I., Villamar, M., Moreno-Pelayo, M.A., Del Castillo, F.J., Alvarez, A., Telleria, D. and Menendez, I., Moreno, F. (2002) A deletion involving the connexin 30 gene in nonsyndromic hearing impairment. The New England Journal of Medicine, 346, 243-249.
http://dx.doi.org/10.1056/NEJMoa012052

[9]   Dragomir C., Stan A., Stefanescu T.D., Savu L. and Severin E. (2011) Prenatal Screening for the 35delG GJB2, Del (GJB6-D13S1830), and Del (GJB6-D13S1854) Mutations in Romanian Population. Genetic Testing and Molecular Biomarkers, 15, 749-753.
http://dx.doi.org/10.1089/gtmb.2011.0048

[10]   Wang, X.W., Rinehart, T.A., Wadl, P.A., Spiers, J.M., Hadziabdic, D., Windham1 M.T. and Robert Trigiano N. (2009) A new electrophoresis technique to separate microsatellite alleles, African Journal of Biotechnology, 8, 2432-2436.

[11]   Denoyelle, F., Weil, D., Maw, M.A., Wilcox, S.A., Lench, N.J., Allen-Powell, D.R., Osborn, A.H., Dahl, H.H., Middleton, A., Houseman, M.J., Dode, C., Marlin, S., Boulila-ElGaied, A., Grati, M., Ayadi, H., BenArab, S., Bitoun, P., Lina-Granade, G., Godet, J., Mustapha, M., Loiselet, J., El-Zir, E., Aubois, A., Joannard, A., Petit, C., et al. (1997) Prelingual deafness: High prevalence of a 30delG mutation in the connexin 26 gene. Human Molecular Genetics, 6, 2173-2177.
http://dx.doi.org/10.1093/hmg/6.12.2173

[12]   Estivill, X., Fortina, P., Surrey, S., Rabionet, R., Melchionda, S., D’Agruma, L., Mansfield, E., Rappaport, E., Govea, N., Mila, M., Zelante, L. and Gasparini, P. (1998) Connexin-26 mutations in sporadic and inherited sensorineural deafness. Lancet, 351, 394-398.
http://dx.doi.org/10.1016/S0140-6736(97)11124-2

[13]   Green, G.E., Scott, D.A., McDonald, J.M., Woodworth, G.G., Sheffield, V.C. and Smith, R.J.H. (1999) Carrier rates in the mid-western United States for GJB2 mutations causing inherited deafness. JAMA, 281, 2211-2116.
http://dx.doi.org/10.1001/jama.281.23.2211

[14]   Kudo, T., Ikeda, K., Kure, S., Matsubara, Y., Oshima, T., Watanabe, K., Kawase, T., Narisawa, K. and Takasaka, T. (2000) Novel mutations in the connexin 26 gene (GJB2) responsible for childhood deafness in the Japanese population. American Journal of Medical Genetics, 90, 141-145.
http://dx.doi.org/10.1002/(SICI)1096-8628(20000117)90:2<141::AID-AJMG10>3.0.CO;2-G

[15]   Anichkina, A., Kulenich, T., Zinchenko, S., Shagina, I., Polyakov, A., Ginter, E., Evgrafov, O., Viktorova, T. and Khusnitdonova, E. (2001) On the origin and frequency of the 35delG allele in GJB2-linked deafness in Europe. European Journal of Human Genetics, 9, 151.
http://dx.doi.org/10.1038/sj.ejhg.5200596

[16]   Lucotte, G. and Mercier, G. (2001) Meta-analysis of GJB2 mutation 35delG frequencies in Europe. Genet Test, 5, 149-152.
http://dx.doi.org/10.1089/109065701753145646

[17]   Hwa, H.L., Ko, T.M., Hsu, C.J., Huang, C.H., Chiang, Y.L., Oong, J.L., Chen, C.C. and Hsu, C.K. (2003) Mutation spectrum of the connexin 26 (GJB2) gene in Taiwanese patients with prelingual deafness. Genetics in Medicine, 5, 161-165.
http://dx.doi.org/10.1097/01.GIM.0000066796.11916.94

[18]   Rothrock, C.R., Murgia, A., Sartorato, E.L., Leonardi, E., Wei, S., Lebeis, S.L., Yu, L.E., Elfenbein, J.L., Fisher, R.A. and Friderici, K.H. (2003) Connexin 26 35delG does not represent a mutational hotspot. Human Genetics, 113, 18-23.

[19]   Najmabadi, H., Nishimura, C., Kahrizi, K., Riazalhosseini, Y., Malekpour, M., Daneshi, A., Farhadi, M., Mohseni, M., Mahdieh, N., Ebrahimi, A., Bazazzadegan, N., Naghavi, A., Avenarius, M., Arzhangi, S. and Smith, R.J. (2005) GJB2 mutations: Passage through Iran. American Journal of Medical Genetics Part A, 133, 132-137.
http://dx.doi.org/10.1002/ajmg.a.30576

[20]   Lazar, C., Popp, R., Trifa, A., Mocanu, C., Al-Khzouz, C., Tomescu, E., Figan, I. and Grigorescu-Sido, P. (2010) Prevalence of the c.35delG and p.W24X mutations in the GJB2 gene in patients with nonsyndromic hearing loss from North-West Romania. International Journal of Pediatric Otorhinolaryngology, 74, 351-355.

[21]   Mahdieh N., Rabbani B., Wiley S., Akbari M.T. and Zeinali S. (2010) Genetic causes of nonsyndromic hearing loss in Iran in comparison with other populations. Journal of Human Genetics, 55, 639-648.

[22]   Gasparini, P., Rabionet, R., Barbujani, G., Melchionda, S., Petersen, M. and Brondum-Nielsen, K. (2000) High carrier frequency of the 35delG deafness mutation in European populations. Genetic Analysis Consortium of GJB2 35delG. European Journal of Human Genetics, 8, 19-23.
http://dx.doi.org/10.1038/sj.ejhg.5200406

[23]   Del Castillo, I., Moreno-Pelayo, M.A., Del Castillo, F.J., Brownstein, Z., Marlin, S., Adina, Q., Cockburn, D.J., Pandya, A., Siemering, K.R., Chamberlin, G.P., Balana, E., Wuyts, W., Maciel-Guerra, A.T., Alvarez, A., Villamar, M., Shohat, M., Abelivich, D., Dahl, H.H.M., Estivill, X., Gasparini, P., Hutchin, T., Nance, W.E., Sartorato, E.L., Smith, R.J.H., Van Camp, G., Avraham, K.B., Petit, C. and Moreno, F. (2003) Prevalence and evolutionary origins of the del (GJB6-D13S1830) mutations in the DFNB1 locus in hearing impaired subjects: A multicenter study. The American Journal of Human Genetics, 73, 1452-1458. http://dx.doi.org/10.1086/380205

[24]   Del Castillo, F.J., Rodrigues-Ballesteros, M., Alvarez, A., Hutchin, T., Leonardi, E., De Oliveira, C.A., Azaiez, H., Brownstein, Z., Avenarius, M.R., Marlin, S., Pandya, A., Shahin, H., Siemering, K.R., Weil, D., Wuyts, W., Aguirre, L.A., Martin, Y., Moreno-Pelayo, M.A., Villamar, M., Avraham, K.B., Dahl, H.H.M., Kanaan, M., Nance, W.E., Petit, C., Smith, R.J.H., Van Camp, G., Sartorato, E.L., Murgia, A., Moreno, F. and Del Castillo, I. (2005) A novel deletion involving the connexin-30 gene, del (GJB6-d13s1854), found in trans with mutations in the GJB2 gene (connexin-26) in subjects with DFNB1 nonsyndromic hearing impairment. Journal of Medical Genetics, 42, 588-594.
http://dx.doi.org/10.1136/jmg.2004.028324

[25]   Sirmaci, A., Akcayoz-Duman, D. and Tekin, M. (2006). The c.IVS1+1G>A mutation in the GJB2 gene is prevalent and large deletions involving the GJB6 gene are not present in Turkish population. Journal of Genetics, 85, 213-216.

[26]   Minarik, G., Tretiarova D., Szemes T. and Kadasi L. (2012) Prevalence of DFNB1 mutations in Slovak population with non-syndromic hearing loss. International Journal of Pediatric Otorhinolaryngology, 76, 400-403.
http://dx.doi.org/10.1016/j.ijporl.2011.12.020

[27]   Hilgert, N., Smith, R.J. and Van Camp, G. (2009) Forty-six genes causing nonsyndromic hearing impairment: Which ones should be analyzed in DNA diagnostics. Mutation Research, 681, 189-96.
http://dx.doi.org/10.1016/j.mrrev.2008.08.002

[28]   Morton, C.C. and Nance, W.E. (2006) Newborn hearing screening—A silent revolution. The New England Journal of Medicine, 354, 2151-2164.
http://dx.doi.org/10.1056/NEJMra050700

 
 
Top