Challenges in whole exome sequencing: an example from hereditary deafness.
Challenges in whole exome sequencing: an example from hereditary deafness.
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DOI：
10.1371/journal.pone.0032000
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Tekin M
中科院分区：
文献类型：
--
作者：
Sirmaci A;Edwards YJ;Akay H;Tekin M
全外显子组测序提供了前所未有的机会，以确定罕见的孟德尔疾病的致病DNA变异。由于高度的遗传异质性，通过传统方法在听力损失家族中找到负责突变是困难的。在这项研究中，我们结合了同源性定位和全外显子组测序在一个家庭与3个受影响的儿童有非综合征性听力损失所生的近亲父母。两个新的错义纯合突变体，在GIPC 3中的c.508C>A（p.H170N）和在ZNF 57中的c.1328C>T（p.T443M），在该家族的受影响成员的19号染色体上的相同的136Mb纯合区域中被鉴定。这两种变异与表型共分离，在335个种族匹配的对照中不存在。双等位基因GIPC 3突变最近被报道可导致常染色体隐性遗传性非综合征型感音神经性听力损失。因此，我们得出结论，在本报告中描述的家庭听力损失是由一个新的GIPC 3错义突变。GIPC 3中鉴定的变体具有低读取深度，其在分析期间最初被过滤掉，留下ZNF 57作为唯一的潜在致病基因。这项研究强调了在整个外显子组数据分析中的一些挑战，以建立孟德尔疾病的真正致病变异。
Whole exome sequencing provides unprecedented opportunities to identify causative DNA variants in rare Mendelian disorders. Finding the responsible mutation via traditional methods in families with hearing loss is difficult due to a high degree of genetic heterogeneity. In this study we combined autozygosity mapping and whole exome sequencing in a family with 3 affected children having nonsyndromic hearing loss born to consanguineous parents. Two novel missense homozygous variants, c.508C>A (p.H170N) in GIPC3 and c.1328C>T (p.T443M) in ZNF57, were identified in the same ∼6 Mb autozygous region on chromosome 19 in affected members of the family. Both variants co-segregated with the phenotype and were absent in 335 ethnicity-matched controls. Biallelic GIPC3 mutations have recently been reported to cause autosomal recessive nonsyndromic sensorineural hearing loss. Thus we conclude that the hearing loss in the family described in this report is caused by a novel missense mutation in GIPC3. Identified variant in GIPC3 had a low read depth, which was initially filtered out during the analysis leaving ZNF57 as the only potential causative gene. This study highlights some of the challenges in the analyses of whole exome data in the bid to establish the true causative variant in Mendelian disease.
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DOI：
10.1073/pnas.0402191101
发表时间：
2004-05-18
影响因子：
11.1
作者：
Jantz, D;Berg, JM
通讯作者：
Berg, JM
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
9.8
作者：
Ahmed, ZM;Morell, RJ;Wilcox, ER
通讯作者：
Wilcox, ER
影响因子：
7
作者：
Li, Heng;Ruan, Jue;Durbin, Richard
通讯作者：
Durbin, Richard
影响因子：
3.3
作者：
Reed, BC;Cefalu, C;Bunn, RC
通讯作者：
Bunn, RC