Speaker
Description
ABSTRACT
Background:
Orofacial clefts (OFCs) are common congenital malformations often complicated by adverse drug reactions (ADRs), highlighting the importance of pharmacogenomic insights. Genetic variation in drug-metabolising and transporting enzymes may underlie variable drug responses in affected populations. This study investigated rare pathogenic variants in pharmacogenes among OFC case-parent trios from sub-Saharan Africa.
Methods:
A total of 130 families with OFCs from Ghana and Nigeria were recruited. DNA was extracted from saliva and cheek swab samples and quantified using a Qubit fluorometer. Whole genome sequencing (WGS) produced 390 datasets from 130 case-parent trios. Variant calling was performed using the GATK workflow, with annotation and prioritisation via multiple bioinformatics tools. Structural impacts of variants were assessed using HOPE in-silico modelling, and drug-binding effects were evaluated with PyRx molecular docking.
Results:
Pathogenic variants were detected in CYP1A2, CYP2C18, CYP27A1, CYP2B6, SLC6A2, and ABCC3. HOPE analysis showed that mutations disrupted conserved domains, altering protein properties and function. PyRx docking revealed changes in drug-binding affinity, with some mutations enhancing and others reducing interactions. These variants were linked to metabolism of widely used drugs, including ketoconazole, carbamazepine, efavirenz, nevirapine, artemether, acetaminophen, and chloramphenicol. The results suggest a genetic basis for ADRs in African OFC populations and underscore the clinical importance of pharmacogenetic variation.
Conclusion:
We identified novel and known pathogenic variants in pharmacogenes from OFC case-parent trios in sub-Saharan Africa. These findings provide new pharmacogenomic insights into ADRs, support the need for genetic screening, and lay a foundation for implementing precision medicine in African clinical practice.