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

Abstract

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 casecontrol 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.

Genetic factors influencing risk to orofacial clefts: today’s challenges and tomorrow’s opportunities

“…This inconsistency could merely be because of limited sample sizes of individual studies, subtle biases in study design, or could reflect genetic differences across populations. Interestingly, sequencing the candidate genes themselves (and the regions immediately surrounding the gene) has identified some rare mutations that would impair the function of the corresponding gene product and could be directly causal 31, 32 . While such rare variants are potentially biologically relevant and certainly justify further study of that candidate gene, their very low frequency in the population makes them difficult to incorporate either into standard statistical tests or for use in predicting risk to individuals (which is notoriously difficult for heterogeneous disorders).…”

Precision Dentistry in Early Childhood

“…The environmental and genetic underpinning of orofacial clefts has been the focus of major collaborative research efforts. 42 Although a comprehensive characterization of the genetic basis of various subtypes of orofacial clefts has yet to be accomplished, substantial progress has been made in the discovery of implicated genetic loci in diverse ancestral populations, as recently reviewed and reported by Dixon and colleagues. 43 Other conditions include ectodermal dysplasias, 44,45 and other issues related to histodifferentiation, apposition, and mineralization including amelogenesis imperfecta, dentinogenesis imperfecta, and dentin dysplasia—all of these conditions have profound impacts on the oral health functioning and related quality of life of affected individuals and require specialized, precise oral health care.…”

PAX7nucleotide variants and the risk of non‐syndromic orofacial clefts in the Polish population

“…In addition, common nucleotide variants of this gene have been shown to correlate with the risk of non‐syndromic cleft lip with or without cleft palate (nsCL/P, OMIM %119530) (Lee, Park, Kim, & Baek, ). The increased risk of nsCL/P, as well as craniofacial skeletal variation among patients with malocclusion, has also been found to be associated with common variants of PAX5 and PAX7 (Beaty et al, , ; Böhmer et al, ; Butali et al, ; da Fontoura et al, ; Gowans et al, ; Leslie et al, ; Ludwig et al, ; Sull et al, ). In the meta‐analyses of genome‐wide association studies (GWASs) for nsCL/P, the results for the PAX7 variants reached the genome‐wide significance (Leslie et al, ; Ludwig et al, ).…”

“…In the meta‐analyses of genome‐wide association studies (GWASs) for nsCL/P, the results for the PAX7 variants reached the genome‐wide significance (Leslie et al, ; Ludwig et al, ). Moreover, several rare and potentially pathogenic variants located in or near the PAX7 gene have recently been detected in patients with orofacial clefts (Butali et al, ; Gowans et al, ; Leslie et al, ).…”