Update of the GJB2/DFNB1 mutation spectrum in Russia: a founder Ingush mutation del(GJB2-D13S175) is the most frequent among other large deletions

Abstract

Although mutations in the GJB2 gene sequence make up the majority of variants causing autosomal-recessive non-syndromic hearing loss, few large deletions have been shown to contribute to DFNB1 deafness. Currently, genetic testing for DFNB1 hearing loss includes GJB2 sequencing and DFNB1 deletion analysis for two common large deletions, del(GJB6-D13S1830) and del(GJB6-D13S1854). Here, we report frequency in Russia, clinical significance and evolutionary origins of a 101 kb deletion, del(GJB2-D13S175), recently identified by us. In multiethnic cohort of 1104 unrelated hearing loss patients with biallelic mutations at the DFNB1 locus, the del(GJB2-D13S175) allele frequency of up to 0.5% (11/2208) was determined and this allele was shown to be predominantly associated with profound sensorineural hearing loss. Additionally, eight previously unpublished GJB2 mutations were described in this study. All patients carrying del(GJB2-D13S175) were of the Ingush ancestry. Among normal hearing individuals, del(GJB2-D13S175) was observed in Russian Republic of Ingushetia with a carrier rate of ~1% (2/241). Analysis of haplotypes associated with the deletion revealed a common founder in the Ingushes, with age of the deletion being ~3000 years old. Since del(GJB2-D13S175) was missed by standard methods of GJB2 analysis, del(GJB2-D13S175) detection has been added to our routine testing strategy for DFNB1 hearing loss.

DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes

“…About 200 GJB2 mutations have been reported to cause DFNB1 HI 2 (Stenson et al, 2017 ). They can be classified into many different types: large deletions that remove the whole GJB2 gene (Feldmann et al, 2009 ; Bliznetz et al, 2014 , 2017 ), large deletions that remove regulatory sequences that are needed for the expression of GJB2 but keep the gene intact (del Castillo et al, 2002 , 2005 ; Wilch et al, 2010 ; Tayoun et al, 2016 ; Table 1 ), and a plethora of small-scale alterations, including nonsense, missense and splice-site point mutations, as well as frameshifting small insertions and deletions (del Castillo and del Castillo, 2011 ). The frequencies of these mutations are diverse, with different mutant alleles overrepresented in different populations.…”

Updated carrier rates for c.35delG (GJB2) associated with hearing loss in Russia and common c.35delG haplotypes in Siberia

“…The c.35delG predominance in deaf patients was reported in several studies conducted in the European part of Russia [ 30 – 38 ]. In the ethnically heterogeneous population of Siberia, epidemiological and molecular genetic studies of hereditary deafness are currently limited to regions of the Altai Republic, the Tuva Republic (Southern Siberia), and the Sakha Republic (Yakutia, Eastern Siberia) [ 39 – 41 ].…”

Obesity predisposition associated with FTO gene polymorphism among different ethnic groups of Russia and Mongolia

“…Ñðåäè âñåõ îáñëåäîâàííûõ ìî-íîýòíè÷íûõ ãðóïï ìîíãîëû îêàçàëèñü â íàèìåíüøåé ñòåïåíè ñêëîííû ê îaeèðåíèþ, äåòåðìèíèðîâàííîìó FTO, ÷òî õîðîøî ñîãëàñóåòñÿ ñ äàííûìè ïîëó÷åííûìè â ìàñøòàáíîì èññëåäîâàíèè Ìàî ñ êîëëåãàìè, ïîêàçàâøèìè, ÷òî ãåíîôîíäû ïîïóëÿöèè Âîñòî÷íîé Àçèè (Êèòàé, Ìîíãîëèÿ, Êîðåÿ è ßïîíèÿ) îáåäíåíû àëëåëÿìè ðèñêà îaeèðåíèÿ è íàñûùåííû ïðîòåêöèîííûìè àëëåëÿìè [Mao et al, 2017]. Ðóññêèå, îáñëåäîâàííûå â ðàìêàõ äàííîé ðàáîòû, ïðîaeèâàþò ïîñòîÿííî èëè íà ïðîòÿaeåíèè äëèòåëüíîãî âðåìåíè â Ìîñêâå, ÷òî, â èçâåñòíîé ñòåïåíè, îãðàíè÷èâàåò ðåïðåçåíòàòèâíîñòü äàííîé ãðóïïû [Bliznetz et al, 2017]. Ðàíåå, â ðàìêàõ èçó÷åíèÿ àññîöèàöèé Ò/À-ïîëèìîðôèçìà ñî ñêëîííîñòüþ ê íàáîðó âåñà, íàìè áûëè îáñëåäîâàíû ýòíè÷åñêèå Òàáëèöà 3.…”