The role of gene-environment interactions on the development of non-syndromic cleft lip with or without cleft palate

: a systematic review

Abstract

Introduction: Cleft lip with or without cleft palate affects thousands of children globally and represents a major functional, psychological, and economic burden. Most clefts are non-syndromic, which means they occur spontaneously in a non-Mendelian pattern. Their etiology is complex and multifactorial and involves both genetic and environmental factors and their possible interactions. Objective: To identify all previously associated gene-environment interactions with the development of non-syndromic cleft lip with or without cleft palate in the scientific literature. Materials and Methods: This systematic review was conducted according to PRISMA methodology and PICO criteria. PubMed, Scopus, and Web of Science were searched using a query that combined keywords and MeSH terms related to broad domains such as gene-environment interaction, genetic predisposition to disease, orofacial cleft, and single nucleotide polymorphism. This review’s protocol was registered on the PROSPERO platform (CRD42024498960). Results: From 23 included studies, we identified 99 significant gene-environment interactions linked to one of five different maternal environmental exposures: smoking, environmental tobacco smoke, vitamin use, alcohol, and agrotoxins. Maternal smoking and environmental tobacco smoke were studied factors in 65.7% of these interactions. In our study, the genes ELAVL2, FGFR2, RUNX2, GRID2, and TP63 were notable for being involved in the highest number of significant interactions. The analysis of the biological functions of these genes highlighted their roles in signaling, development of anatomical structures, and regulation of DNA-templated transcription. Conclusion: Interventions based solely on isolated environmental risk factors may not adequately protect individuals who are genetically more susceptible to NSCL/P. From a public health perspective, the identification of a greater number of gene-environment interactions relevant to the etiology of these defects is highly desirable.

Date of Award	31 Jul 2024
Original language	English
Awarding Institution	Universidade Católica Portuguesa
Supervisor	Luís Santos (Supervisor), Raquel Silva (Co-Supervisor) & Patrícia Nunes Correia (Co-Supervisor)