Clinical Deep Whole Exome Sequencing of a Syndromic Orofacial Clefts Cohort from Ghana (DECIDE)

Background: the most common congenital malformation of the head and neck region is orofacial clefts (OFCs). OFCs have a birth incidence of 1 per 700 live births; however, there are significant variations in incidence based on ancestry and geographical location. The condition largely presents clinically as cleft lip only (CL), cleft palate only (CL), and cleft lip and palate (CLP). CL and CLP have a 30% chance of being syndromic whereas CP has a 50% chance of being syndromic. According to the online inheritance in man (OMIM) database, there are over 300 genetic syndromes that may present with OFCs. Syndromic OFCs present with additional congenital malformations that may complicate treatment regimens. Genetic testing helps in the accurate and definitive diagnosis of genetic syndromes, including those that present with OFCs. Unfortunately, genetic testing and genetic counseling are not an integral part of the health system in Ghana, and obviously most parts of Africa. This makes syndrome diagnosis a herculean task. The specific aims of the study are twofold: (a) decipher low-frequency genetic and genomic variants that may contribute to the etiology of the syndromic OFCs in affected individuals through clinical deep whole exome sequencing, and (b) Ascertain secondary genetic and genomic findings that may impact the health of patients and family members through further bioinformatics analysis of the whole exome data. The Principal Investigator (PI) has access to 125 families with a history of syndromic OFCs.
Methods: A case-parent trio approach will be adopted for this study. A total of 40 families with a history of OFCs will be recruited. There will be a review of medical records to ascertain additional phenotypes that were missed at the initial recruitment. Probands will be recalled to the Cleft-Craniofacial Clinic at Komfo Anokye Teaching Hospital (KATH), Kumasi, for further clinical review to ascertain additional phenotypic presentations. Saliva and cheek swab samples will be collected from the 40 case-parent trios (120 individuals) for DNA extraction. DNA samples will undergo whole exome sequencing employing the Illumina platform. Variants will be called from the WES data employing the industry-standard GATK4 workflow. Missense, nonsense, indels, and other variants that may impact the etiology of syndromic OFCs will be ascertained. In addition, the study will search for secondary findings based on the guidelines of the American College of Medical Genetics (ACMG).
Expected outcomes: genetic and genomic variants observed, together with the phenotypic data, will enable the accurate diagnosis of genetic syndromes associated with OFCs among Ghanaians. Some of the expected variants may be population-specific and novel. In addition, we are likely to observe secondary findings from the WES data that may positively impact the personalized healthcare of the affected families.