Whole-genome sequencing analyses of Africans with clefts 2.0-insights gained

Orofacial clefts (OFCs), including cleft lip and cleft palate, are the most common birth defects affecting the head and neck. While certain harmful genetic mutations are known to increase the risk of these conditions, their effects can vary widely. Even within the same family, some individuals with these mutations may have no cleft at all, while others may have different types and severities of clefts.

To better understand the genetic causes of OFCs, we conducted a large whole-genome study involving 148 African families with a child affected by nonsyndromic cleft lip with or without cleft palate. Africa is the most genetically diverse population in the world, making it a vital region for genetic discovery. We searched for mutations in genes known to affect facial development and analyzed how these might relate to cleft formation.

Our analyses revealed novel pathogenic protein-altering mutations in several key genes regulating lip and palate development including: KIF1B, QSOX1, MEGF6, FAP, SLC8A1, LRP2, TTN, FLNB, COL6A6, COL7A1, and CPO. Notably, mutations in LRP2 and TTN were previously reported in Africans with cleft following the first WGS analysis. Interestingly, some of these mutations were found in parents without clefts, suggesting that other factors—genetic or environmental—may influence whether clefts develop.

These discoveries deepen our understanding of the complex genetic foundations of orofacial clefts and highlight the importance of studying diverse populations. Our findings could help improve early diagnosis, inform genetic counseling, and ultimately support better outcomes for families affected by these conditions.