Search

Orofacial clefts are the most common malformations of the head and neck. In Africa, orofacial clefts are underascertained, with little or no surveillance system in most parts for clefts and other birth defects. A Nigerian craniofacial anomalies study, NigeriaCRAN, was established in 2006 to support cleft research specifically for epidemiological studies, treatment outcomes, and studies into etiology and prevention. We pooled data from seven of the largest Smile Train treatment centers in the six geopolitical zones in Nigeria. Data from September 2006 to June 2011 were analyzed and clefts compared between sides and genders using the Fisher exact test. A total of 2197 cases were identified during the study period, with an estimated prevalence rate of 0.5 per 1000. Of the total number of orofacial clefts, 54.4% occur in males and 45.6% in females. There was a significant difference ( P=.0001) between unilateral left clefts and unilateral right clefts, and there was a significant difference ( P=.0001) between bilateral clefts and clefts on either the left or right side. A significant gender difference ( P=.03) was also observed for cleft palate, with more females than males. A total of 103 (4.7%) associated anomalies were identified. There were nine syndromic cleft cases, and 10.4% of the total number of individuals with clefts have an affected relative. The significant difference between unilateral clefts and the gender differences in the proportion of cleft palate only are consistent with the literature. The present study emphasizes the need for birth defects registries in developing countries in order to estimate the exact prevalence of birth defects including orofacial clefts.

Orofacial clefts (OFC) are complex genetic traits that are often classified as syndromic or nonsyndromic clefts. Currently, there are over 500 types of syndromic clefts in the Online Mendelian Inheritance in Man (OMIM) database, of which Van der Woude syndrome (VWS) is one of the most common (accounting for 2% of all OFC). Popliteal pterygium syndrome (PPS) is considered to be a more severe form of VWS. Mutations in the IRF6 gene have been reported worldwide to cause VWS and PPS. Here, we report studies of families with VWS and PPS in sub-Saharan Africa. We screened the DNA of eight families with VWS and one family with PPS from Nigeria and Ethiopia by Sanger sequencing of the most commonly affected exons in IRF6 (exons 3, 4, 7, and 9). For the VWS families, we found a novel nonsense variant in exon 4 (p.Lys66X), a novel splice-site variant in exon 4 (p.Pro126Pro), a novel missense variant in exon 4 (p.Phe230Leu), a previously reported splice-site variant in exon 7 that changes the acceptor splice site, and a known missense variant in exon 7 (p.Leu251Pro). A previously known missense variant was found in exon 4 (p.Arg84His) in the PPS family. All the mutations segregate in the families. Our data confirm the presence of IRF6-related VWS and PPS in sub-Saharan Africa and highlights the importance of screening for novel mutations in known genes when studying diverse global populations. This is important for counseling and prenatal diagnosis for high-risk families.

Nonsyndromic clefts of the lip and palate (NSCLP) are complex genetic traits. Together, they are classified as one of the most common birth defects with a prevalence of 1/700 live births. Genome-wide association studies (GWAS) for nonsyndromic cleft lip with or without cleft palate (NSCL[P]) revealed significant association for common single nucleotide polymorphisms near genes involved in craniofacial development i.e., MAFB, PAX7, VAX1, ARHGAP29 (ABCA4 locus), and IRF6. Sequencing of protein coding regions of the NSCL(P) GWAS candidate genes or adjacent genes suggest a role for rare functional variants. Replication studies in the African population did not observe any significant association with the GWAS candidate genes. On the other hand, the role of rare functional variants in GWAS candidate genes has not been evaluated in the African population. We obtained saliva samples from case triads in Nigeria and Ethiopia for Sanger sequencing of the GWAS candidate genes (MAFB, PAX7, VAX1, ARHGAP29, and IRF6) in order to identify rare functional variants. A total of 220 African samples (140 Nigerians and 80 Ethiopians) were sequenced and we found the following new rare variants— p.His165Asn in the MAFB gene, p.Asp428Asn in the PAX7, a splice-site variant that creates a new donor splice-site in PAX7. We also found three previously reported missense variants p.Gly466Ser in PAX7; p.Leu913Ser and Arg955His in ARHGAP29. No de novo mutations were found. Future genome-wide association and sequencing studies should be conducted using samples from Africa in order to identify new molecular genetic factors that contribute to the etiology of NSCLP. © 2014 Wiley Periodicals, Inc.