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, the incidence varies significantly by ancestry and geographic location. The condition essentially 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 Mendelian 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 were twofold: (a) decipher rare genetic and genomic variants that may contribute to the etiology of the syndromic OFCs in affected individuals through 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.

## Methods:
A case-parent trio approach was adopted for this study. However, for some families, we could not obtain paternal samples due to the unavailability of fathers. A total of 47 families with a history of syndromic OFCs were recruited. These comprised 26 case parent trios and 21 case mother dyads, yielding a total of 120 individuals. Participants were recruited from the National Cleft Care Centre (NCCC) at Komfo Anokye Teaching Hospital (KATH), Kumasi, Ghana. Saliva and cheek swab samples were collected from the 120 individuals for DNA extraction. Whole exome sequencing was carried out on the DNA samples employing the Illumina HiSeq platform at a read depth of 100X. Variants calling employed the Sentieon 202112.01 (DNAscope algorithm) workflow. Missense, nonsense, indels, and other variants that may impact the etiology of syndromic OFCs were curated. In addition, the study searched for secondary findings based on the guidelines of the American College of Medical Genetics (ACMG). In essence, the genomic data to be shared is available in both FastQ files and variant calling files (VCFs)