MARVELD2 (DFNB49) Mutations in the Hearing Impaired Central European Roma Population - Prevalence, Clinical Impact and the Common Origin

Abstract

BackgroundIn the present study we aimed: 1) To establish the prevalence and clinical impact of DFNB49 mutations in deaf Roma from 2 Central European countries (Slovakia and Hungary), and 2) to analyze a possible common origin of the c.1331+2T>C mutation among Roma and Pakistani mutation carriers identified in the present and previous studies.MethodsWe sequenced 6 exons of the MARVELD2 gene in a group of 143 unrelated hearing impaired Slovak Roma patients. Simultaneously, we used RFLP to detect the c.1331+2T>C mutation in 85 Hungarian deaf Roma patients, control groups of 702 normal hearing Romanies from both countries and 375 hearing impaired Slovak Caucasians. We analyzed the haplotype using 21 SNPs spanning a 5.34Mb around the mutation c.1331+2T>C.ResultsOne pathogenic mutation (c.1331+2T>C) was identified in 12 homozygous hearing impaired Roma patients. Allele frequency of this mutation was higher in Hungarian (10%) than in Slovak (3.85%) Roma patients. The identified common haplotype in Roma patients was defined by 18 SNP markers (3.89 Mb). Fourteen common SNPs were also shared among Pakistani and Roma homozygotes. Biallelic mutation carriers suffered from prelingual bilateral moderate to profound sensorineural hearing loss.ConclusionsWe demonstrate different frequencies of the c.1331+2T>C mutation in hearing impaired Romanies from 3 Central European countries. In addition, our results provide support for the hypothesis of a possible common ancestor of the Slovak, Hungarian and Czech Roma as well as Pakistani deaf patients. Testing for the c.1331+2T>C mutation may be recommended in GJB2 negative Roma cases with early-onset sensorineural hearing loss.

Excess of rare missense variants in hearing loss genes in sporadic Meniere disease

“…The encoded protein seems to forge barriers between epithelial cells such the ones in the organ of Corti, where, in case of lack of these barriers, normal hearing is affected. Defects in this gene are a cause of deafness autosomal recessive type 49 (DFNB49) [27].…”

Novel Mutations in CLPP, LARS2, CDH23, and COL4A5 Identified in Familial Cases of Prelingual Hearing Loss

“…It is estimated that up to 1% of human genes are essential for hearing function [4], and at least 1000 genes are associated with inherited HL, based upon studies on HL-associated diseases, unique inner-ear transcripts [5][6][7][8][9], and model organisms [10][11][12][13][14][15]. Intriguingly, of the 72 known nonsyndromic HL genes, 34 were initially identified in Pakistani families [3], and eventually, the variants in these genes were identified in populations around the world [16][17][18][19][20][21]. The Pakistani population is ideal for genetic studies because of its rich anthropogeneological background, via successive waves of invasions due to its pivotal location at crossroads of South Asia, the Middle East, and Central Asia, as well as its high consanguinity.…”

New SNP variants of MARVELD2 (DFNB49) associated with non-syndromic hearing loss in Chinese population

“…Up to now, more than 50 genes with autosomal recessive inheritance and 30 genes with autosomal dominant inheritance have been reported to be associated with NSHL Avraham, 2009, 2010;Schraders et al, 2012). MARVELD2, which encodes tricellulin, is located on chromosome 5q13.2 and linked to the DFNB49 locus (Ramzan et al, 2005;Riazuddin et al, 2006;Mašindová et al, 2015). In the human inner ear, there are many fluid-filled compartments of different ionic compositions.…”

“…Thus, it is easy to understand that variants in MARVELD2 may cause hearing loss to varying degrees (Chishti et al, 2008). Up to now, seven single nucleotide polymorphism (SNP) variants of MARVELD2 have been reported to cause human NSHL, including c. 1183-1G>A, c.1331+1G>A, c.1331+2T>C, c.1331+2deITGAG, c.1498C>T, c.1543delA, and p.C395-Q501del (Riazuddin et al, 2006Chishti et al, 2008;Babanejad et al, 2012;Šafka Brožková et al, 2012;Mašindová et al, 2015;Nayak et al, 2015). However, the mutational spectrum and frequency of MARVELD2 in the Chinese NSHL population are still poorly understood.…”

“…Up to now, seven SNP variants of MARVELD2 causing NSHL have been reported in families of Pakistan, Slovak, Hungarian, and Czech Roma origins (Riazuddin et al, 2006;Chishti et al, 2008;Babanejad et al, 2012;Šafka Brožková et al, 2012;Mašindová et al, 2015;Nayak et al, 2015), as shown in Table 2. However, the MARVELD2 variants identified in this study were not found in any of the previously reported studies.…”