Holzinger Emily R, Li Qing, Parker Margaret M, Hetmanski Jacqueline B, Marazita Mary L, Mangold Elisabeth, Ludwig Kerstin U, Taub Margaret A, Begum Ferdouse, Murray Jeffrey C, Albacha-Hejazi Hasan, Alqosayer Khalid, Al-Souki Giath, Albasha Hejazi Abdullatiff, Scott Alan F, Beaty Terri H, Bailey-Wilson Joan E
Computational and Statistical Genomics BranchNational Human Genome Research InstituteNational Institutes of HealthBaltimoreMaryland.
National Institute of General Medical SciencesNational Institutes of HealthBethesdaMaryland.
Mol Genet Genomic Med. 2017 Aug 9;5(5):570-579. doi: 10.1002/mgg3.320. eCollection 2017 Sep.
Nonsyndromic oral clefts are craniofacial malformations, which include cleft lip with or without cleft palate. The etiology for oral clefts is complex with both genetic and environmental factors contributing to risk. Previous genome-wide association (GWAS) studies have identified multiple loci with small effects; however, many causal variants remain elusive.
In this study, we address this by specifically looking for rare, potentially damaging variants in family-based data. We analyzed both whole exome sequence (WES) data and whole genome sequence (WGS) data in multiplex cleft families to identify variants shared by affected individuals.
Here we present the results from these analyses. Our most interesting finding was from a single Syrian family, which showed enrichment of nonsynonymous and potentially damaging rare variants in two genes: and .
Neither of these candidate genes has previously been associated with oral clefts and, if confirmed as contributing to disease risk, may indicate novel biological pathways in the genetic etiology for oral clefts.
非综合征性口腔颌面部裂隙是一种颅面畸形，包括唇裂伴或不伴腭裂。口腔颌面部裂隙的病因复杂，遗传和环境因素均会增加患病风险。以往的全基因组关联研究（GWAS）已鉴定出多个效应较小的基因座；然而，许多致病变异仍不明确。
在本研究中，我们通过专门在基于家系的数据中寻找罕见的、潜在有害的变异来解决这一问题。我们分析了多个腭裂家系的全外显子组序列（WES）数据和全基因组序列（WGS）数据，以鉴定受影响个体共有的变异。
在此我们展示这些分析的结果。我们最有趣的发现来自一个叙利亚家系，该家系显示两个基因中非同义且潜在有害的罕见变异富集： 和 。
这两个候选基因此前均未与口腔颌面部裂隙相关联，如果被证实与疾病风险相关，可能提示口腔颌面部裂隙遗传病因中的新生物学途径。
