an!overview!of!35delg!muta5on!! distribu5on!across!europe! · no. thecarrierfrequencyof35delg...

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


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.


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)


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)


The carrier frequency of 35delG is different among European popula?ons.


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;

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 -‐

25422 healthy persons 517 carriers


-‐ Results -‐

COLLECTED DATA 29 EUROPEAN COUNTRIES

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 -‐


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%).

35de

lG M

uta5

on A

cross

Europe

-‐ R

esults -‐


-‐ 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...”


-‐ 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


-‐ 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

•  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).


These studies have reported a considerable higher 35delG carrier frequency for eastern Europe:

•  Ukraine 3.3%

•  Romania 3.38%

•  Belarus 5.73%

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.


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;


-‐ 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;


-‐ 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.”

an!overview!of!35delg!muta5on!! distribu5on!across!europe! · no. thecarrierfrequencyof35delg...

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