Associations Between Alcohol Dehydrogenase Mutations and Cleft Lip/Palate: A Scoping Review

BackgroundThe incidence of cleft lip with or without cleft palate (CL ± P) varies significantly according to genetic ancestry. The alcohol dehydrogenase (ADH) family comprises several enzymes with polymorphisms that are also highly disparate between genetic backgrounds. A small number of heterogeneous studies have linked ADH variants with risk of CL ± P. Therefore, the authors conducted a scoping review to better understand these potential associations.MethodsThis review was conducted following PRISMA 2020 guidelines, screening for studies published in PubMed and Medline databases. Case-control, cohort, case-series, and cross-sectional studies published in English between 1966 and 2024 that reported associations between ADH polymorphisms and CL ± P were included.ResultsFive studies met inclusion criteria, accounting for 1630 cases of CL ± P. Despite significant variation in study design and results, four studies linked polymorphisms in the maternal and/or fetal genotype ADH1C to CL ± P risk. Two also examined whether ADH1C genotype modifies the risk that prenatal alcohol exposure imparts for fetal CL ± P; one found that high-activity ADH1C polymorphisms in mother and child together reduced this alcohol-attributable CL ± P risk, while the other found no effect of ADH1C genotype on this risk. The fifth study reported a novel duplication in ADH7 in a family with CL ± P cases.ConclusionsCurrent evidence, though limited, suggests that certain maternal and fetal ADH polymorphisms may influence risk of fetal CL ± P. Existing data have been primarily limited to demographically homogenous cohorts, and ancestry was not analyzed in concert with ADH polymorphisms. The interaction of ancestry, ADH mutations, and CL ± P remains an important, open question.