Molecular outcomes, clinical consequences, and genetic diagnosis of Oculocutaneous Albinism in Pakistani population.
Molecular outcomes, clinical consequences, and genetic diagnosis of Oculocutaneous Albinism in Pakistani population.
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DOI：
10.1038/srep44185
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发表时间：
2017-03-07
影响因子：
4.6
通讯作者：
University of Washington Center for Mendelian Genomics (UW CMG) Consortium
中科院分区：
文献类型：
--
作者：
Shahzad M;Yousaf S;Waryah YM;Gul H;Kausar T;Tariq N;Mahmood U;Ali M;Khan MA;Waryah AM;Shaikh RS;Riazuddin S;Ahmed ZM;University of Washington Center for Mendelian Genomics (UW CMG) Consortium
非综合征性眼皮肤白化病(NsOCA)的临床特征是皮肤、头发和虹膜的色素沉着消失。OCA是导致儿童视力障碍的最常见原因之一。到目前为止，已经在nsOCA患者中发现了六个基因的致病变异。在这里，我们确定了94个以前未报道的巴基斯坦家庭中OCA等位基因的身份、频率和临床后果。Sanger和Exome联合测序发现38个等位基因，其中包括22个新变异体，与80个家系的nsOCA表型分离。TYR和OCA2基因变异是nsOCA最常见的原因，分别发生在43个和30个家系中。22个新的变异体包括9个错义、4个剪接点、2个无义、1个插入和6个粗略缺失。体外研究表明，携带新的错义等位基因的OCA蛋白保留在转基因细胞的内质网(ER)中。外显子捕获分析显示，含有剪接位点等位基因的构建体在剪接中存在错误。由于8个等位基因约占nsOCA病例的56%(95%可信区间：46.52-65.24%)，主要来自巴基斯坦旁遮普省，因此在相似来源的家族中进行OCA基因检测的分层策略将是可行的和成本高效的。因此，我们开发了四引物臂分析方法，用于快速、可靠、可重复性和经济地筛选大多数常见的等位基因。
Nonsyndromic oculocutaneous Albinism (nsOCA) is clinically characterized by the loss of pigmentation in the skin, hair, and iris. OCA is amongst the most common causes of vision impairment in children. To date, pathogenic variants in six genes have been identified in individuals with nsOCA. Here, we determined the identities, frequencies, and clinical consequences of OCA alleles in 94 previously unreported Pakistani families. Combination of Sanger and Exome sequencing revealed 38 alleles, including 22 novel variants, segregating with nsOCA phenotype in 80 families. Variants of TYR and OCA2 genes were the most common cause of nsOCA, occurring in 43 and 30 families, respectively. Twenty-two novel variants include nine missense, four splice site, two non-sense, one insertion and six gross deletions. In vitro studies revealed retention of OCA proteins harboring novel missense alleles in the endoplasmic reticulum (ER) of transfected cells. Exon-trapping assays with constructs containing splice site alleles revealed errors in splicing. As eight alleles account for approximately 56% (95% CI: 46.52–65.24%) of nsOCA cases, primarily enrolled from Punjab province of Pakistan, hierarchical strategies for variant detection would be feasible and cost-efficient genetic tests for OCA in families with similar origin. Thus, we developed Tetra-primer ARMS assays for rapid, reliable, reproducible and economical screening of most of these common alleles.