Shafique Sobia, Siddiqi Saima, Schraders Margit, Oostrik Jaap, Ayub Humaira, Bilal Ammad, Ajmal Muhammad, Seco Celia Zazo, Strom Tim M, Mansoor Atika, Mazhar Kehkashan, Shah Syed Tahir A, Hussain Alamdar, Azam Maleeha, Kremer Hannie, Qamar Raheel
COMSATS Institute of Information Technology, Park Road, Islamabad, Pakistan.
Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan.
PLoS One. 2014 Jun 20;9(6):e100146. doi: 10.1371/journal.pone.0100146. eCollection 2014.
The frequency of inherited bilateral autosomal recessive non-syndromic hearing loss (ARNSHL) in Pakistan is 1.6/1000 individuals. More than 50% of the families carry mutations in GJB2 while mutations in MYO15A account for about 5% of recessive deafness. In the present study a cohort of 30 ARNSHL families was initially screened for mutations in GJB2 and MYO15A. Homozygosity mapping was performed by employing whole genome single nucleotide polymorphism (SNP) genotyping in the families that did not carry mutations in GJB2 or MYO15A. Mutation analysis was performed for the known ARNSHL genes present in the homozygous regions to determine the causative mutations. This allowed the identification of a causative mutation in all the 30 families including 9 novel mutations, which were identified in 9 different families (GJB2 (c.598G>A, p.Gly200Arg); MYO15A (c.9948G>A, p.Gln3316Gln; c.3866+1G>A; c.8767C>T, p.Arg2923* and c.8222T>C, p.Phe2741Ser), TMC1 (c.362+18A>G), BSND (c.97G>C, p.Val33Leu), TMPRSS3 (c.726C>G, p.Cys242Trp) and MSRB3 (c.20T>G, p.Leu7Arg)). Furthermore, 12 recurrent mutations were detected in 21 other families. The 21 identified mutations included 10 (48%) missense changes, 4 (19%) nonsense mutations, 3 (14%) intronic mutations, 2 (9%) splice site mutations and 2 (9%) frameshift mutations. GJB2 accounted for 53% of the families, while mutations in MYO15A were the second most frequent (13%) cause of ARNSHL in these 30 families. The identification of novel as well as recurrent mutations in the present study increases the spectrum of mutations in known deafness genes which could lead to the identification of novel founder mutations and population specific mutated deafness genes causative of ARNSHL. These results provide detailed genetic information that has potential diagnostic implication in the establishment of cost-efficient allele-specific analysis of frequently occurring variants in combination with other reported mutations in Pakistani populations.
巴基斯坦遗传性双侧常染色体隐性非综合征性听力损失（ARNSHL）的发病率为1.6/1000。超过50%的家庭携带GJB2基因突变，而MYO15A基因突变约占隐性耳聋的5%。在本研究中，对30个ARNSHL家庭进行了队列研究，最初筛查了GJB2和MYO15A基因的突变。对于未携带GJB2或MYO15A基因突变的家庭，通过全基因组单核苷酸多态性（SNP）基因分型进行纯合性定位。对纯合区域中存在的已知ARNSHL基因进行突变分析，以确定致病突变。这使得在所有30个家庭中都鉴定出了致病突变，包括9个新突变，分别在9个不同家庭中鉴定出来（GJB2（c.598G>A，p.Gly200Arg）；MYO15A（c.9948G>A，p.Gln3316Gln；c.3866+1G>A；c.8767C>T，p.Arg2923*和c.8222T>C，p.Phe2741Ser），TMC1（c.362+18A>G），BSND（c.97G>C，p.Val33Leu），TMPRSS3（c.726C>G，p.Cys242Trp）和MSRB3（c.20T>G，p.Leu7Arg））。此外，在其他21个家庭中检测到12个复发性突变。所鉴定的21个突变包括10个（48%）错义变化、4个（19%）无义突变、3个（14%）内含子突变、2个（9%）剪接位点突变和2个（9%）移码突变。GJB2基因突变的家庭占53%，而MYO15A基因突变是这30个家庭中ARNSHL的第二大常见病因（13%）。本研究中鉴定出的新突变和复发性突变增加了已知耳聋基因的突变谱，这可能有助于鉴定新的奠基者突变和导致ARNSHL的特定人群突变耳聋基因。这些结果提供了详细的遗传信息，对于在巴基斯坦人群中结合其他报道的突变建立常见变异的高效等位基因特异性分析具有潜在的诊断意义。
