High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders
High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders
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DOI：
10.1007/s00439-015-1575-0
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发表时间：
2015-09-01
期刊：
影响因子：
5.3
通讯作者：
Ben-Omran, Tawfeg
中科院分区：
文献类型：
--
作者：
Yavarna, Tarunashree;Al-Dewik, Nader;Ben-Omran, Tawfeg
临床外显子组测序（CES）已成为异质性遗传疾病患者，特别是具有神经认知表型的患者中越来越受欢迎的诊断工具。CES在近亲人群中的效用尚未大规模确定。来自卡塔尔的149名疑似孟德尔遗传（主要是神经认知表型）先证者的临床队列于2012年7月至2014年6月接受了CES。智力残疾和整体发育迟缓是最常见的临床表现，但我们的队列显示其他表型，如癫痫，畸形，小头畸形和其他结构性脑异常和自闭症。在89名先证者中鉴定出致病性或可能致病性突变，包括致病性CNVs，诊断率为60%。血缘关系和阳性家族史预测较高的诊断率。在5%（7/149）的病例中，CES涉及新的候选疾病基因（MANF、GJA 9、GLG 1、COL 15 A1、SLC 35 F5、MAGE 4、NEUROG 1）。CES在4%（6/149）的病例中发现了两种共存的遗传性疾病，在2%（3/149）的病例中发现了可采取行动的偶然发现。平均诊断时间从27个月缩短到5个月。CES，它已经有最高的诊断率在所有可用的诊断工具中的孟德尔疾病的设置，似乎是特别有帮助的诊断在高度血亲的中东人口。
Clinical exome sequencing (CES) has become an increasingly popular diagnostic tool in patients with heterogeneous genetic disorders, especially in those with neurocognitive phenotypes. Utility of CES in consanguineous populations has not yet been determined on a large scale. A clinical cohort of 149 probands from Qatar with suspected Mendelian, mainly neurocognitive phenotypes, underwent CES from July 2012 to June 2014. Intellectual disability and global developmental delay were the most common clinical presentations but our cohort displayed other phenotypes, such as epilepsy, dysmorphism, microcephaly and other structural brain anomalies and autism. A pathogenic or likely pathogenic mutation, including pathogenic CNVs, was identified in 89 probands for a diagnostic yield of 60 %. Consanguinity and positive family history predicted a higher diagnostic yield. In 5 % (7/149) of cases, CES implicated novel candidate disease genes (MANF, GJA9, GLG1, COL15A1, SLC35F5, MAGE4, NEUROG1). CES uncovered two coexisting genetic disorders in 4 % (6/149) and actionable incidental findings in 2 % (3/149) of cases. Average time to diagnosis was reduced from 27 to 5 months. CES, which already has the highest diagnostic yield among all available diagnostic tools in the setting of Mendelian disorders, appears to be particularly helpful diagnostically in the highly consanguineous Middle Eastern population.