Diagnostic value of exome and whole genome sequencing in craniosynostosis.
Diagnostic value of exome and whole genome sequencing in craniosynostosis.
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DOI：
10.1136/jmedgenet-2016-104215
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发表时间：
2017-04
影响因子：
4
通讯作者：
Wilkie AO
中科院分区：
文献类型：
--
作者：
Miller KA;Twigg SR;McGowan SJ;Phipps JM;Fenwick AL;Johnson D;Wall SA;Noons P;Rees KE;Tidey EA;Craft J;Taylor J;Taylor JC;Goos JA;Swagemakers SM;Mathijssen IM;van der Spek PJ;Lord H;Lester T;Abid N;Cilliers D;Hurst JA;Morton JE;Sweeney E;Weber A;Wilson LC;Wilkie AO
颅缝早闭，一个或多个颅缝过早融合，发生在2250例新生儿中的101例，无论是孤立的还是作为综合征的一部分。至少有57个基因的突变与颅缝早闭症有关，但其中只有少数被纳入常规实验室基因检测。我们使用外显子组或全基因组测序在40名患有颅缝早闭的受试者中寻找遗传原因，这些受试者由临床或分子遗传学家选择为高优先级病例，并且先前临床驱动的遗传检测为阴性。我们在15名患者（37.5%）中发现了可能相关的突变，涉及14种不同的基因。除IL 11 RA（两个家族）外，所有基因均在单个家族中突变。我们将其他阳性诊断分类如下：具有非典型表现的常见突变的颅缝早闭基因（EFNB 1，TWIST 1）;其他核心颅缝早闭基因（CDC 45，MSX 2，ZIC 1）;突变仅很少与颅缝早闭相关的基因（FBN 1，HUWE 1，KRAS，STAT 3）;以及与颅缝早闭的因果关系目前未知的已知疾病基因（AHDC 1，NTRK 2）。在另外两个家族中，可能的新疾病基因目前正在进行功能验证。在15例阳性病例中的5例中，（以前未预料到的）分子诊断对遗传或医学管理（EFNB 1，FBN 1，KRAS，NTRK 2，STAT 3突变）产生了直接的，可操作的后果。这种实质性的遗传异质性，以及确定的多个可操作的突变，强调了外显子组/全基因组测序的益处，以确定颅缝早闭病例中的因果突变，其中常规临床测试产生了阴性结果。
Craniosynostosis, the premature fusion of one or more cranial sutures, occurs in ∼1 in 2250 births, either in isolation or as part of a syndrome. Mutations in at least 57 genes have been associated with craniosynostosis, but only a minority of these are included in routine laboratory genetic testing. We used exome or whole genome sequencing to seek a genetic cause in a cohort of 40 subjects with craniosynostosis, selected by clinical or molecular geneticists as being high-priority cases, and in whom prior clinically driven genetic testing had been negative. We identified likely associated mutations in 15 patients (37.5%), involving 14 different genes. All genes were mutated in single families, except for IL11RA (two families). We classified the other positive diagnoses as follows: commonly mutated craniosynostosis genes with atypical presentation (EFNB1, TWIST1); other core craniosynostosis genes (CDC45, MSX2, ZIC1); genes for which mutations are only rarely associated with craniosynostosis (FBN1, HUWE1, KRAS, STAT3); and known disease genes for which a causal relationship with craniosynostosis is currently unknown (AHDC1, NTRK2). In two further families, likely novel disease genes are currently undergoing functional validation. In 5 of the 15 positive cases, the (previously unanticipated) molecular diagnosis had immediate, actionable consequences for either genetic or medical management (mutations in EFNB1, FBN1, KRAS, NTRK2, STAT3). This substantial genetic heterogeneity, and the multiple actionable mutations identified, emphasises the benefits of exome/whole genome sequencing to identify causal mutations in craniosynostosis cases for which routine clinical testing has yielded negative results.