An Overview of 35delG Muta5on Distribu5on Across Europe
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1 Luminița Rădulescu, Cris'an Mârțu, Dan Mârțu, Gabriela Damean, Sebas'an Cozma University of Medicine and Pharmacy Gr.T.Popa Iași ENT Clinic, Rehabilita'on Hospital Iași / ROMANIA
2 Hearing loss is the most frequent congenital sensory impairment affecting 1 in 650 newborns. Mehl and Thomson 2002 The cause of deafness is gene?c in 60% of congenital sensorineural hearing loss.
3 Autosomal recessive non- syndromic hearing loss (ARNSHL) accounts for the majority (70-80%) of the gene?c forms of deafness. Although near 70 loci were described for ARNSHL, a single locus DFNB1 (GJB2) is responsible for the most of the autosomal recessive forms of deafness. There were described more than 100 pathogenic muta?ons in GJB2 gene. (del Cas?llo, 2012)
4 The freguency of a certain type of muta5on in GJB2 gene appear to be associated with the ethnicity. THE MOST FREQUENT MUTATIONS IN THE GJB2 GENE RELATED TO THE ETHNICITY ARE: 35delG - in the Caucasian popula?on (Denoyelle, 1997; Kelley, 1998) c.235delc - in East Asia ( Abe,2000; Yan, 2003) c.71g >A - in India (RamShankar,2003) c.167delt in Jews (Morell,1998)
5 The carrier frequency of 35delG is different among European popula?ons.
6 PubMed search for papers from 1998 un5l regarding 35delG carriers. - Methods - SELECTION CRITERIA 1. English papers; 2. The gene?c tests were performed on healthy individuals from European countries; FORTY SIX ARTICLES WERE SELECTED
7 35delG Muta5on Across Europe - Results - Bibliography The carrier frequency of 35delG muta5on Number of tested subjects Number of carriers Country Gasparini, UK Hall A, , UK 1, UK Dragomir C 3, RO Farcas M 3, RO 3, ROMANIA Gasparini, 2000/Teek, , ESTONIA Kokotas H, ,5 Grecia Antoniadi, , Grecia Gasparini, Grecia 3, GRECIA Neocleous V, , Cipru/greci Sansović I, ,5 342 Croa5a Gasparini, , Franta Denoyelle, Franta Mercier, , Franta Marseilles Gasparini, , Franta Briaany Mercier G, , Franta 2, FRANTA Lucoae G, ,9 Europa Bors, , Ungaria Bors A, , Ungaria Toth, , Ungaria 3, UNGARIA Gasparini, , Belgia Storm K, , Belgia 1, BELGIA Gasparini, , Bulgaria Gasparini, , Cehia Gasparini, , Danemarca Kupka, , Germania Gasparini, Germania 1, GERMANIA Gasparini, , Italia Sardinia Estvill, , Italia Denoyelle, Italia Lucoae G, , Italia Sicilia Gasparini, , Italia 3, ITALIA Janecke et al., , Austria Frei, , Austria E 1, AUSTRIA Lopponen, , Finlanda Gasparini, , Malta Heders5erna, , Suedia Heders5erna, , Suedia N 1, SUEDIA Gasparini, , Norvegia Gasparini, , Olanda Wiszniewski, Polonia Gasparini, , Portugalia Anichkina, , Rusia Gasparini, , Slovenia Gasparini, , Spania Gasparini, , Spania 2, SPANIA Gurtler, Elve5a Uyguner, , Turcia Tekin, , Turcia Gasparini, , Turcia Uyguner, , Turcia 1, TURCIA Danilenko, , Belarus Dzhemileva, , Belarus 5, BELARUS
8 - Results - COLLECTED DATA 29 EUROPEAN COUNTRIES healthy persons 517 carriers
9 35delG Muta5on Across Europe - Results - No. The carrier frequency of 35delG muta5on Number of tested subjects Number of carriers Country 1 1, AUSTRIA 2 5, BELARUS 3 1, BELGIUM 4 0, BULGARIA 5 2, CZECH REPUBLIC 6 2, CYPRUS/GRECI 7 1,5 342 CROATIA 8 2, DENMARK SWITZERLAND 10 4, ESTONIA 11 1, FINLANDA 12 2, FRANCE 13 1, GERMANY 14 3, GREECE 15 3, ITALY 16 2, MALTA 17 0, NORWAY 18 2, OLANDA POLONIA 20 2, PORTUGALIA 21 3, ROMANIA 22 2, RUSIA 23 0, SLOVENIA 24 2, SPANIA 25 1, SUEDIA 26 1, TURCIA 27 3, UCRAINA 28 1, UK 29 3, UNGARIA TOTAL
10 Like previous authors (papers published un?l 2009) we found: The highest carrier frequency was found in Greece (3.27%) and Italy (3.5%), and even much higher than in southern Europe in Estonia (4.5). Lower carrier rates were located in northern Europe (Norway 0.52%), but also in Slovenia (0.55%) and Bulgaria (0.64%).
11 35delG Muta5on Across Europe - Results -
12 - Results - Meta- analysis of GJB2 muta5on 35delG frequencies in Europe. Lucoae G, Mercier G. Genet Test Summer;5(2): The 35delG muta5on in the connexin 26 gene (GJB2) associated with congenital deafness: European carrier frequencies and evidence for its origin in ancient Greece. Lucoae G, Diéterlen F. Genet Test Spring; 9(1):20-5. Sta5s5cal study of 35delG muta5on of GJB2 gene: a meta- analysis of carrier frequency. Mahdieh N, Rabbani B.Int J Audiol. 2009;48(6): Review...the average 35delG carrier frequency is highest in southern Europe... The south- to- north European gradient in the carrier frequency of 35delG was confirmed...
13 - Results - Sta5s5cal study of 35delG muta5on of GJB2 gene: a meta- analysis of carrier frequency. Mahdieh N, Rabbani B. Int J Audiol. 2009;48(6): Review!ESTONIA was a small country and consanguine marriage was prevalent
14 - Results - Meta- analysis of GJB2 muta5on 35delG frequencies in Europe. Lucoae G, Mercier G. Genet Test Summer;5(2):149-52!ESTONIA When Estonia is removed from the analysis, and so the sta5s5cal difference in carrier frequency between south and north of Europe appears significant.
15 Prenatal screening for the 35delG GJB2, del (GJB6- D13S1830), and del (GJB6- D13S1854) muta'ons in the Romanian popula'on. Dragomir C and colab. Genet Test Mol Biomarkers Nov;15(11): Carrier frequency of GJB2 gene muta'ons c.35delg, c.235delc and c. 167delT among the popula'ons of Eurasia. Dzhemileva LU and colab. J Hum Genet Nov;55(11): Spectrum of gene'c changes in pa'ents with non- syndromic hearing impairment and extremely high carrier frequency of 35delG GJB2 muta'on in Belarus. Danilenko N and colab. PLoS One. 2012;7(5).
16 These studies have reported a considerable higher 35delG carrier frequency for eastern Europe: Ukraine 3.3% Romania 3.38% Belarus 5.73%
17
18 When Ukraine (3.3%), Romania (3.38%) and Belarus (5.73%) join Estonia (4.5%) and compare with Germany, Austria, Belgium, UK etc (1.73%) (1.3%) (1.82) (1.34) the est to west gradient of 35delG muta?on becomes obvious.
19 There are two main theories that try to explain the high frequence of 35delG muta?on in some areas: 1. the presence of a muta?onal hot spot within GJB2; 2. the common founder theory;
20 - Conclusion - OUR STUDY: confirms once more the South-to-North gradient in the carrier frequency of 35delG in Europe; brings in the attention the East part of the Europe where was found a rate of mutation at least similar with that found in the South; suggests also an East-to-West European gradient;
21 - Conclusion - A common founder for the 35delG GJB2 gene muta5on in connexin 26 hearing impairment L Van Laer and colab. J Med Genet August; 38(8): The reason for the high frequency of 35delG remains to be elucidated.
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