Genetic factors influencing risk to orofacial clefts: today's challenges and tomorrow's opportunities.
Genetic factors influencing risk to orofacial clefts: today's challenges and tomorrow's opportunities.
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DOI：
10.12688/f1000research.9503.1
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Leslie EJ
中科院分区：
文献类型：
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作者：
Beaty TH;Marazita ML;Leslie EJ
口面裂包括唇裂（CL）、腭裂（CP）和唇腭裂（CLP），它们共同代表了人类最大的颅面畸形组，总体患病率为每1,000例活产1例。这些出生缺陷中的每一种都显示出强烈的家族聚集性，表明其病因学的主要遗传成分。口面裂的遗传学研究可以追溯到几个世纪前，但事实证明很难确定任何单一的病因机制，因为许多基因似乎会影响风险。连锁和关联研究已经确定了几个影响风险的基因，但这些基因在家庭和人群中存在差异。全基因组关联研究已经确定了近24种不同的基因，实现了全基因组的意义，并且有广泛的“因果基因”用于口面裂：一些基因与风险密切相关，并可能直接导致孟德尔综合征，其中包括口面裂作为综合征的关键表型特征，以及对风险具有适度个体影响但在适当情况下（可能包括暴露于环境风险因素）能够破坏正常颅面发育的多个基因。基因组测序研究正在进行中，这无疑将揭示更多的基因/区域，其中变体（序列和结构）可以在控制口面裂风险方面发挥作用。对医学和公共卫生的真实的挑战是双重的：在有受影响成员的家庭中确定特定的基因和其他病因因素，然后针对这些不同的生物机制设计有效的干预措施，控制复杂和异质性出生缺陷（如口面裂）的风险。
Orofacial clefts include cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP), which combined represent the largest group of craniofacial malformations in humans with an overall prevalence of one per 1,000 live births. Each of these birth defects shows strong familial aggregation, suggesting a major genetic component to their etiology. Genetic studies of orofacial clefts extend back centuries, but it has proven difficult to define any single etiologic mechanism because many genes appear to influence risk. Both linkage and association studies have identified several genes influencing risk, but these differ across families and across populations. Genome-wide association studies have identified almost two dozen different genes achieving genome-wide significance, and there are broad classes of ‘causal genes’ for orofacial clefts: a few genes strongly associated with risk and possibly directly responsible for Mendelian syndromes which include orofacial clefts as a key phenotypic feature of the syndrome, and multiple genes with modest individual effects on risk but capable of disrupting normal craniofacial development under the right circumstances (which may include exposure to environmental risk factors). Genomic sequencing studies are now underway which will no doubt reveal additional genes/regions where variants (sequence and structural) can play a role in controlling risk to orofacial clefts. The real challenge to medicine and public health is twofold: to identify specific genes and other etiologic factors in families with affected members and then to devise effective interventions for these different biological mechanisms controlling risk to complex and heterogeneous birth defects such as orofacial clefts.