Candidate Genes for Nonsyndromic Cleft Palate Detected by Exome Sequencing
Candidate Genes for Nonsyndromic Cleft Palate Detected by Exome Sequencing
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DOI：
10.1177/0022034517722761
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发表时间：
2017-10-01
影响因子：
7.6
通讯作者：
Ludwig, K. U.
中科院分区：
文献类型：
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作者：
Hoebel, A. K.;Drichel, D.;Ludwig, K. U.
非综合征性腭裂（nsCPO）是一种面部畸形，活产患病率为1/2500。研究表明，nsCPO的病因是多因素的，具有明确的遗传成分。迄今为止，全基因组关联研究仅确定了nsCPO的1个决定性常见变体，即基因grainyhead-like-3（GRHL 3）中的错义变体。因此，nsCPO的潜在遗传原因在很大程度上仍然未知。本研究的目的是通过全外显子组测序（WES），在多受影响的中欧nsCPO家系中鉴定可能导致nsCPO风险的罕见变异。在每个家庭的2名受影响的一级亲属中进行WES。分析了两个个体之间共有的变异体的潜在有害性质和在一般人群中的低频率。携带有希望的变体的基因被注释为1）与面部发育的报道关联，2）变体的多次出现，和3）在小鼠胚胎腭架中的表达。该策略导致使用分子倒置探针在132个独立nsCPO病例和2个不同种族的623个独立对照中鉴定了一组26个候选基因，并对其进行了重新测序。在WES或重测序步骤中均未发现罕见的功能丧失突变。然而，我们确定了2个或更多的错义变异预测是有害的3个基因（ACACB，PTPRS，MIB 1）在独立的家庭的个人。此外，这些分析在1名患者中发现了GRHL 3的新变体，在2名同胞中发现了CREBBP的变体。这两种基因都是CPO不同综合征形式的基础。一个合理的假设是，这3例患者的明显非综合征性裂可能代表各自综合征的亚型形式。总之，本研究确定了可能导致nsCPO风险的罕见变异，并提出了进一步研究的候选基因。
Nonsyndromic cleft palate only (nsCPO) is a facial malformation that has a livebirth prevalence of 1 in 2,500. Research suggests that the etiology of nsCPO is multifactorial, with a clear genetic component. To date, genome-wide association studies have identified only 1 conclusive common variant for nsCPO, that is, a missense variant in the gene grainyhead-like-3 (GRHL3). Thus, the underlying genetic causes of nsCPO remain largely unknown. The present study aimed at identifying rare variants that might contribute to nsCPO risk, via whole-exome sequencing (WES), in multiply affected Central European nsCPO pedigrees. WES was performed in 2 affected first-degree relatives from each family. Variants shared between both individuals were analyzed for their potential deleterious nature and a low frequency in the general population. Genes carrying promising variants were annotated for 1) reported associations with facial development, 2) multiple occurrence of variants, and 3) expression in mouse embryonic palatal shelves. This strategy resulted in the identification of a set of 26 candidate genes that were resequenced in 132 independent nsCPO cases and 623 independent controls of 2 different ethnicities, using molecular inversion probes. No rare loss-of-function mutation was identified in either WES or resequencing step. However, we identified 2 or more missense variants predicted to be deleterious in each of 3 genes (ACACB, PTPRS, MIB1) in individuals from independent families. In addition, the analyses identified a novel variant in GRHL3 in 1 patient and a variant in CREBBP in 2 siblings. Both genes underlie different syndromic forms of CPO. A plausible hypothesis is that the apparently nonsyndromic clefts in these 3 patients might represent hypomorphic forms of the respective syndromes. In summary, the present study identified rare variants that might contribute to nsCPO risk and suggests candidate genes for further investigation.