The role of Interferon regulatory factor 6 and Grainyhead-like 3 gene variants in South African patients with orofacial clefts

Orofacial clefts (OFC) are one of the most common birth defects worldwide. The malformation is caused by disturbances in the developmental processes of the facial region from the fourth to tenth week of embryonic development. Varying disturbances in the fusion of the different facial regions result in different phenotypes of orofacial clefts. The global prevalence of orofacial clefts is 15.4 per 10,000 births. In a recent study of South African patients presenting at specialized academic treatment centres, the estimated prevalence of OFCs was 3 per 10,000 live-births. Deleterious variants in the IRF6- and GRHL3-genes have been identified as the cause of the two most common OFC-syndromes, Van der Woude (VWS) and Popliteal pterygium syndrome (PPS). In addition, both of the genes have been shown to cause non-syndromic/isolated cases of clefts. The only clinical difference between VWS and non-syndromic clefting is the presence of lip pits. In this retrospective study, patients with non-syndromic/isolated cleft lip and/or palate, who attended the University of Pretoria Facial Cleft Deformity Clinic, were investigated. A total of 91 patients (68 of African- and 23 of European ancestry) with isolated OFCs and no family history were screened for sequence variants in the IRF6 and GRHL3 genes, using Sanger sequencing. While no pathogenic IRF6 variants were found in non-syndromic CL/P cases of European ancestry, ~1.5% of non-syndromic CL/P cases of African ancestry were found to carry a pathogenic IRF6 variant. Two novel GRHL3 pathogenic variants, p.Asn336Ilefster1 and p.Tyr445Ter, were identified in non-syndromic cleft cases of African ancestry. Proven pathogenic GRHL3 variants, that include the previously mentioned two novel variants, account for 1.47% of cleft lip and palate and 2.94% of cleft palate only cases of African ancestry. These results are comparable to previously reported studies, further demonstrating the association between deleterious GRHL3 variants and cleft palate only cases. For patients of European ancestry, there were an equal number of cleft lip and palate and cleft palate only cases (4.35% each). In conclusion, this study represents the first investigation of both the IRF6 and GRHL3 genes in South African patients with isolated/non-syndromic orofacial clefts. To our knowledge, it is the first study to identify pathogenic variants in the IRF6 gene and the second study to identify pathogenic variants in the GRHL3 gene in South Africans of African or European ancestry, who have non-syndromic/isolated orofacial clefts. Of note, deleterious variants in III GRHL3 were five-fold more common than IRF6 deleterious variants in our cohort. Appropriate genetic counselling of the families with pathogenic variants will be carried out by Dr EM Honey. These results contribute further information on the role of these genes in isolated cases of orofacial clefts, especially in African populations.Dissertation (MSc (Human Genetics))--University of Pretoria, 2021.GeneticsMSc (Human Genetics)Unrestricte