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

仅使用全外显子组测序鉴定非综合征性腭裂的致病基因

• 批准号: 418073540
• 负责人: Privatdozentin Dr. Elisabeth Mangold
• 金额: --
• 依托单位: Institut für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/418073540?language=en
• 关键词: Identification; causal; genes; nonsyndromic; cleft

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.

“单纯腭裂”（CPO）是第二种最常见的口颌裂形式。目前已知有超过 500 种 CPO 发生的综合征，这些综合征在遗传上是异质的，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，称为“非综合征性腭裂”(nsCPO)。对于 nsCPO，正式的遗传学和流行病学研究表明，其病因有多种因素。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中的复发风险较高，并且研究对 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类型的非综合征性口颌裂的遗传病因学方面取得了重大突破。 伴有或不伴有腭裂 (nsCL/P) 的非综合征性唇裂，已鉴定出 37 个 nsCL/P 易感位点。相比之下，尽管 nsCPO 的 GWAS 样本量与 nsCL/P 早期 GWAS 中使用的样本量相当，但通过 GWAS 生成的有关 nsCPO 分子基础的知识仍然有限。到目前为止，仅发现了一种致病变异，即 GRHL3 基因的错义突变。 可能的情况是，其他 nsCPO 风险位点的个体效应大小太小，无法在之前的样本量中进行检测。然而，也可以想象，效应量较大的罕见变异在 nsCPO 病因学中比在 nsCL/P 中发挥更显着的作用。报道称，尽管婴儿死亡率较高，但 nsCPO 发生在多个受影响的家庭中，且发病率稳定，这表明存在以显性遗传方式遗传的高外显性遗传风险因素。近亲父母的后代发生 nsCPO 的风险几乎增加两倍，也表明存在常染色体隐性突变。明显非综合征型 CPO 的致病突变可能位于综合征型口面裂的基因中，正如申请人和她的团队先前针对 GRHL3 基因和 Van-der-Woude 综合征所证明的那样。拟议项目的目的是在 nsCPO 三人组中进行全外显子组测序。显性从头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 低效综合征形式以及 nsCPO 的新功能途径。了解遗传病因学将有助于了解胚胎学过程中的扰动如何导致 nsCPO，从长远来看，这可能有助于制定预防措施。