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

• Applicant: Privatdozentin Dr. Elisabeth Mangold
• Subject Area: Human Genetics
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 418073540

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.

• DFG Programme: Research Grants