Identification of causal genes for nonsyndromic cleft palate only using whole exome sequencing

“单纯腭裂”（CPO）是第二常见的唇腭裂。目前已知发生CPO的综合征超过500种，这些综合征具有遗传异质性，通常遵循单基因遗传模式。只有大约一半的CPO患者没有其他异常，被称为“非综合征性腭裂”（nsCPO）。对于非scpo，正式的遗传和流行病学研究表明它们具有多因素病因。基于人群的研究发现，与一般人群的发病率相比，受影响个体的一级亲属有较高的复发风险，研究得出了nsCPO的遗传率估计约为90%。全基因组关联研究（GWAS）和随后的荟萃分析在破译更常见的非综合征性口面部裂的遗传病因方面取得了重大突破，即非综合征性唇裂伴或不伴腭裂（nsCL/P），已确定了37个nsCL/P的易感位点。相比之下，尽管nsCPO GWAS的样本量与早期nsCL/P GWAS的样本量相当，但通过GWAS产生的关于nsCPO分子基础的知识仍然有限。到目前为止，只发现了一种致病变异，即GRHL3基因的错义突变。这可能是由于在以前的样本量中，进一步的非scpo风险基因座的个体效应量太小而无法检测。然而，与nsCL/P相比，具有较大效应量的罕见变异在nsCPO病因学中发挥的作用更为明显。有报道称，在多个受影响家庭中，非scpo连续几代发生，尽管婴儿死亡率很高，但发病率稳定，这表明涉及以显性方式遗传的高渗透遗传风险因素。近亲父母的后代患非scpo的风险几乎增加了两倍，这也表明常染色体隐性突变。正如申请人和她的研究小组先前对GRHL3基因和Van-der-Woude综合征所证明的那样，表面上非综合征型CPO的致病突变可能位于口面部裂综合征型的基因中。该计划的目的是在nsCPO三重奏中进行全外显子组测序。显性新生突变和常染色体隐性突变的鉴定将导致鉴定新的nsCPO风险基因，可能的CPO亚型综合征形式和nsCPO的新功能途径。遗传病因学的知识将有助于了解胚胎学期间的扰动如何导致nsCPO，从长远来看，这可能有助于建立预防措施。

The “cleft palate only” (CPO) is the second most common form of orofacial clefting. Over 500 syndromes in which CPO occur are presently known, which are genetically heterogenous and typically follow a monogenic mode of inheritance. Only about half of those affected with CPO have no other abnormalities, referred to as "non-syndromic cleft palate only" (nsCPO). For nsCPO, formal genetic and epidemiological studies have shown that they have a multifactorial aetiology. Population-based studies have found high recurrence risks among the first-degree relatives of affected individuals compared to the incidence in the general population, and research has generated heritability estimates of approximately 90% for nsCPO.Genome-wide association studies (GWAS) and subsequent meta-analyses have led to major breakthroughs in deciphering the genetic aetiology of the more common type of nonsyndromic orofacial cleft, the nonsyndromic cleft lip with or without cleft palate (nsCL/P), with 37 susceptibility loci for nsCL/P being identified. In contrast the knowledge generated via GWAS concerning the molecular basis of nsCPO remains limited, despite the fact that samples sizes for GWAS of nsCPO have been comparable to those used in the early GWAS of nsCL/P. So far, only one causal variant, a missense mutation in the GRHL3 gene, has been identified. It may have been the case that the individual effect sizes of further nsCPO risk loci were too small for detection in previous sample sizes. However, it is also conceivable that rare variants with a larger effect size play a more pronounced role in the aetiology of nsCPO than in nsCL/P. Reports of multiply affected families in which nsCPO occurs across several successive generations and a stable incidence despite a high infant mortality rate suggest the involvement of high penetrant genetic risk factors that are inherited in a dominant manner. An almost two-fold increased risk for nsCPO in offspring of consanguineous parents also suggests autosomal-recessive mutations. Causative mutations for apparently nonsyndromic CPO may be located in genes underlying syndromic forms of orofacial clefting, as demonstrated previously by the applicant and her group for the GRHL3 gene and the Van-der-Woude syndrome. The aim of the proposed project is to perform whole exome sequencing in nsCPO trios. Identification of dominant de novo and autosomal-recessive mutations will lead to identification of novel nsCPO risk genes, possible hypomorphic syndromic forms of CPO and novel functional pathways for nsCPO. Knowledge of the genetic aetiology will help to understand how perturbations during embryology result in nsCPO, which could in the long run help establishing preventative measures.