an!overview!of!35delg!muta5on!! distribu5on!across!europe! · no. thecarrierfrequencyof35delg...
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![Page 1: An!Overview!of!35delG!Muta5on!! Distribu5on!Across!Europe! · No. Thecarrierfrequencyof35delG mutaon! Numberoftestedsubjects Numberofcarriers Country! 1 1,3 230 3 AUSTRIA 2 5,73 854](https://reader033.vdocument.in/reader033/viewer/2022041702/5e41ebdca439713f6532c8f4/html5/thumbnails/1.jpg)
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
An Overview of 35delG Muta5on Distribu5on Across Europe
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An Overview of 35delG Muta5on Distribu5on Across Europe
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.
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An Overview of 35delG Muta5on Distribu5on Across Europe
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)
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An Overview of 35delG Muta5on Distribu5on Across Europe
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)
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An Overview of 35delG Muta5on Distribu5on Across Europe
The carrier frequency of 35delG is different among European popula?ons.
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An Overview of 35delG Muta5on Distribu5on Across Europe
PubMed search for papers from 1998 un5l 2012 -‐ regarding 35delG carriers.
-‐ Methods -‐
SELECTION CRITERIA
FORTY SIX ARTICLES WERE SELECTED
1. English papers;
2. The gene?c tests were performed on healthy individuals from European countries;
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Bibliography The carrier frequency of 35delG muta5on Number of tested subjects Number of carriers Country Gasparini, 2000 0 119 0 UK Hall A, 2012 1,36 9202 125 UK
1,34 9321 125 UK Dragomir C 3,14 350 11 RO Farcas M 3,66 300 11 RO
3,38 650 22 ROMANIA Gasparini, 2000/Teek, 2010 4,5 1111 50 ESTONIA
Kokotas H, 2008 3,5 Grecia Antoniadi, 1999 3,54 395 14 Grecia Gasparini, 2000 3 400 12 Grecia
3,27 795 26 GRECIA Neocleous V, 2006 2,5 405 10 Cipru/greci Sansović I, 2005 1,5 342 Croa5a Gasparini, 2000 0,5 200 1 Franta Denoyelle, 1999 0 68 0 Franta Mercier, 2005 3,26 644 21 Franta Marseilles Gasparini, 2000 1,04 96 1 Franta Briaany Mercier G, 2005 1,88 1584 30 Franta
2,04 2592 53 FRANTA Lucoae G, 2005 1,9 Europa Bors , 2001 1,16 173 2 Ungaria Bors A, 2004 0,6 163 1 Ungaria Toth, 2004 4,8 500 24 Ungaria
3,22 836 27 UNGARIA Gasparini, 2000 0,52 190 1 Belgia Storm K, 1999 2,5 360 9 Belgia
1,82 550 10 BELGIA Gasparini, 2000 0,64 157 1 Bulgaria Gasparini, 2000 2,1 195 4 Cehia Gasparini, 2000 2,1 95 2 Danemarca Kupka, 2002 1,6 376 6 Germania
Gasparini, 2000 2 200 4 Germania 1,73 576 10 GERMANIA
Gasparini, 2000 3,45 116 4 Italia Sardinia Estvill, 1998 3,92 150 6 Italia
Denoyelle, 1999 4 150 6 Italia Lucoae G, 2005 2,96 101 3 Italia Sicilia Gasparini, 2000 3,14 255 8 Italia
3,5 772 27 ITALIA Janecke et al., 2002 0,91 110 1 Austria
Frei, 2000 1,7 120 2 Austria E 1,3 230 3 AUSTRIA
Lopponen, 2003 1,28 313 4 Finlanda Gasparini, 2000 2,78 144 4 Malta
Heders5erna, 2005 1,67 1501 25 Suedia Heders5erna, 2005 1,09 551 6 Suedia N
1,51 2052 31 SUEDIA Gasparini, 2000 0,52 190 1 Norvegia Gasparini, 2000 2,2 89 2 Olanda
Wiszniewski, 2001 2 150 3 Polonia Gasparini, 2000 2,23 179 4 Portugalia Anichkina, 2001 2,14 560 12 Rusia Gasparini, 2000 0,55 182 1 Slovenia Gasparini, 2000 2,5 200 5 Spania Gasparini, 2000 2,31 130 3 Spania
2,42 330 8 SPANIA Gurtler, 2003 2 50 1 Elve5a Uyguner, 2001 0,84 359 3 Turcia Tekin, 2001 1,78 674 12 Turcia
Gasparini, 2000 2,7 150 4 Turcia Uyguner, 2001 1,17 429 5 Turcia
1,49 1612 24 TURCIA Danilenko, 2012 5,7 757 43 Belarus Dzhemileva, 2011 6,2 97 6 Belarus
5,73 854 49 BELARUS Dzhemileva, 2011 3,3 90 3 Ucraina
35de
lG M
uta5
on Across
Europe
-‐ Results -‐
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25422 healthy persons 517 carriers
An Overview of 35delG Muta5on Distribu5on Across Europe
-‐ Results -‐
COLLECTED DATA 29 EUROPEAN COUNTRIES
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No. The carrier frequency of 35delG
muta5on Number of tested subjects Number of carriers Country
1 1,3 230 3 AUSTRIA 2 5,73 854 49 BELARUS 3 1,82 550 10 BELGIUM 4 0,64 157 1 BULGARIA 5 2,1 195 4 CZECH REPUBLIC 6 2,5 405 10 CYPRUS/GRECI 7 1,5 342 CROATIA 8 2,1 95 2 DENMARK 9 2 50 1 SWITZERLAND 10 4,5 1111 50 ESTONIA 11 1,28 313 4 FINLANDA 12 2,04 2592 53 FRANCE 13 1,73 576 10 GERMANY 14 3,27 795 26 GREECE 15 3,5 772 27 ITALY 16 2,78 144 4 MALTA 17 0,52 190 1 NORWAY 18 2,2 89 2 OLANDA 19 2 150 3 POLONIA 20 2,23 179 4 PORTUGALIA 21 3,38 650 22 ROMANIA 22 2,14 560 12 RUSIA 23 0,55 182 1 SLOVENIA 24 2,42 330 8 SPANIA 25 1,51 2052 31 SUEDIA 26 1,49 1612 24 TURCIA 27 3,3 90 3 UCRAINA 28 1,34 9321 125 UK 29 3,22 836 27 UNGARIA
25422 517 TOTAL
35de
lG M
uta5
on Across
Europ
e -‐ R
esults -‐
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An Overview of 35delG Muta5on Distribu5on Across Europe
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%).
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35de
lG M
uta5
on A
cross
Europe
-‐ R
esults -‐
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An Overview of 35delG Muta5on Distribu5on Across Europe
-‐ Results -‐ Meta-‐analysis of GJB2 muta5on 35delG frequencies in Europe. Lucoae G, Mercier G. Genet Test. 2001 Summer;5(2):149-‐52 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. 2005 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):363-‐70. 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...”
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An Overview of 35delG Muta5on Distribu5on Across Europe
-‐ Results -‐
!ESTONIA
”was a small country and consanguine
marriage was prevalent”
Sta5s5cal study of 35delG muta5on of GJB2 gene: a meta-‐analysis of carrier frequency. Mahdieh N, Rabbani B. Int J Audiol. 2009;48(6):363-‐70. Review
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An Overview of 35delG Muta5on Distribu5on Across Europe
-‐ Results -‐
!ESTONIA
When Estonia is removed from the analysis, and so the
sta5s5cal difference in carrier frequency between south and
north of Europe appears significant.
Meta-‐analysis of GJB2 muta5on 35delG frequencies in Europe. Lucoae G, Mercier G. Genet Test. 2001 Summer;5(2):149-‐52
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• 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. 2011 Nov;15(11):749-‐53.
• 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. 2010 Nov;55(11):749-‐54.
• 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).
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An Overview of 35delG Muta5on Distribu5on Across Europe
These studies have reported a considerable higher 35delG carrier frequency for eastern Europe:
• Ukraine 3.3%
• Romania 3.38%
• Belarus 5.73%
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An Overview of 35delG Muta5on Distribu5on Across Europe
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An Overview of 35delG Muta5on
Distribu5on Across Europe
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.
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An Overview of 35delG Muta5on Distribu5on Across Europe
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;
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An Overview of 35delG Muta5on Distribu5on Across Europe
-‐ 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;
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An Overview of 35delG Muta5on Distribu5on Across Europe
-‐ Conclusion -‐
A common founder for the 35delG GJB2 gene muta5on in connexin 26 hearing impairment L Van Laer and colab. J Med Genet. 2001 August; 38(8): 515–518.
”The reason for the high frequency of 35delG remains to be elucidated.”