Association Studies and Direct DNA Sequencing Implicate Genetic Susceptibility Loci in the Etiology of Nonsyndromic Orofacial Clefts in Sub-Saharan African Populations.

Orofacial clefts (OFCs) are congenital dysmorphologies of the human face and oral cavity, with a global incidence of 1 per 700 live births. These anomalies exhibit a multifactorial pattern of inheritance, with genetic and environmental factors both playing crucial roles. Many loci have been implicated in the etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in populations of Asian and European ancestries, through genome-wide association studies and candidate gene studies. However, few populations of African descent have been studied to date. Here, the authors show evidence of an association of some loci with NSCL/P and nonsyndromic cleft palate only (NSCPO) in cohorts from Africa (Ghana, Ethiopia, and Nigeria). The authors genotyped 48 single-nucleotide polymorphisms that were selected from previous genome-wide association studies and candidate gene studies. These markers were successfully genotyped on 701 NSCL/P and 163 NSCPO cases, 1,070 unaffected relatives, and 1,078 unrelated controls. The authors also directly sequenced 7 genes in 184 nonsyndromic OFC (NSOFC) cases and 96 controls from Ghana. Population-specific associations were observed in the case-control analyses of the subpopulations, with West African subpopulations (Ghana and Nigeria) showing a similar pattern of associations. In meta-analyses of the case-control cohort, PAX7 (rs742071, P = 5.10 × 10(-3)), 8q24 (rs987525, P = 1.22 × 10(-3)), and VAX1 (rs7078160, P = 0.04) were nominally associated with NSCL/P, and MSX1 (rs115200552, P = 0.01), TULP4 (rs651333, P = 0.04), CRISPLD2 (rs4783099, P = 0.02), and NOG1 (rs17760296, P = 0.04) were nominally associated with NSCPO. Moreover, 7 loci exhibited evidence of threshold overtransmission in NSOFC cases through the transmission disequilibrium test and through analyses of the family-based association for disease traits. Through DNA sequencing, the authors also identified 2 novel, rare, potentially pathogenic variants (p.Asn323Asp and p.Lys426IlefsTer6) in ARHGAP29 In conclusion, the authors have shown evidence for the association of many loci with NSCL/P and NSCPO. To the best of this knowledge, this study is the first to demonstrate any of these association signals in any African population.

Aesthetic outcome and the need for revision of unilateral cleft lip repair at Komfo Anokye Teaching Hospital.

BACKGROUND: The Millard method of unilateral cleft lip repair has been associated with a short lip and a flattened nose on the cleft side. The aim of this study was to determine the need for revision surgery following repair of unilateral cleft lip repair at the Komfo Anokye Teaching Hospital. METHOD: Satisfaction with facial appearance (upper lip, nose and general facial appearance) was assessed quantitatively by means of a Visual Analogue Scale (VAS), where 0 cm indicates totally unsatisfied or "highly unattractive" and 10 cm indicates totally satisfied or "highly attractive". Three assessors--parents, surgeon and lay-person--were purposively selected to score their level of satisfaction with repair of complete and incomplete unilateral cleft lip. The assessors also indicated the need for any revision. RESULTS: The total sample size was 120, of which 40.0% were male and 60.0% were female. There were 79 cases of repaired complete unilateral cleft lip and 41 incomplete unilateral cleft lip. Average scores of satisfaction of parents were 6.6, 6.8 and 7.2 for nose, lip and general facial appearance (GFA) respectively. Satisfaction scores for surgeon were 6.1(nose), 6.0 (lip) and 6.5 (GFA), while those of the lay-assessor were 5.2(nose), 5.4 (lip) and 6.0(GFA). Concerning the need for revision, parents indicated 30.2% as needing revision, surgeon 33%; and lay-assessor 40%. Of the cases that needed revision, 33.3% were complete cleft lip and 0.1% were incomplete cleft lip. CONCLUSION: Parents were more satisfied with unilateral cleft lip repair using the Millard procedure than either the surgeon or lay assessor. Those who needed revision were mostly children who presented with complete unilateral cleft lip.