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In recent decades, many efforts have been made to elucidate the genetic causes of non-syndromic cleft palate (nsCPO), a complex congenital disease caused by the interaction of several genetic and environmental factors. Since genome-wide association studies have evidenced a minor contribution of common polymorphisms in nsCPO inheritance, we used whole exome sequencing data to explore the role of ultra-rare variants in this study. In a cohort of 35 nsCPO cases and 38 controls, we performed a gene set enrichment analysis (GSEA) and a hypergeometric test for assessing significant overlap between genes implicated in nsCPO pathobiology and genes enriched in ultra-rare variants in our cohort. GSEA highlighted an enrichment of ultra-rare variants in genes principally belonging to cytoskeletal protein binding pathway (Probability Density Function corrected p-value = 1.57 × 10−4); protein-containing complex binding pathway (p-value = 1.06 × 10−2); cell adhesion molecule binding pathway (p-value = 1.24 × 10−2); ECM-receptor interaction pathway (p-value = 1.69 × 10−2); and in the Integrin signaling pathway (p-value = 1.28 × 10−2). Two genes implicated in nsCPO pathobiology, namely COL2A1 and GLI3, ranked among the genes (n = 34) with nominal enrichment in the ultra-rare variant collapsing analysis (Fisher's exact test p-value < 0.05). These genes were also part of an independent list of genes highly relevant to nsCPO biology (n = 25). Significant overlap between the two sets of genes (hypergeometric test p-value = 5.86 × 10−3) indicated that enriched genes are likely to be implicated in physiological palate development and/or the pathological processes of oral clefting. In conclusion, ultra-rare variants collectively impinge on biological pathways crucial to nsCPO pathobiology and point to candidate genes that may contribute to the individual risk of disease. Sequencing can be an effective approach to identify candidate genes and pathways for nsCPO. [ABSTRACT FROM AUTHOR]

The epithelial and mesenchymal cells involved in early embryonic facial development are guided by complex regulatory mechanisms. Any factor perturbing the growth, approach and fusion of the frontonasal and maxillary processes could result in orofacial clefts that represent the most common craniofacial malformations in humans. The rarest and, probably for this reason, the least studied form of cleft involves only the secondary palate, which is posterior to the incisive foramen. The etiology of cleft palate only is multifactorial and involves both genetic and environmental risk factors. The intention of this review is to give the reader an overview of the efforts made by researchers to shed light on the underlying causes of this birth defect. Most of the scientific papers suggesting potential environmental and genetic causes of non-syndromic cleft palate are summarized in this review, including genome-wide association and gene–environment interaction studies.

Background Recent genome-wide association studies (GWAS) have reported multiple genetic risk loci for non-syndromic orofacial clefts (NSOFCs) in many populations. However, the contribution of these loci to NSOFC in India, which comprises one-fifth of the global population, is completely lacking. Our aim was to replicate the association of the SNPs located on 1p22 chromosomal loci (rs540026, rs481931) and 20q11.2 (rs13041247, rs11696257) in the aetiology of NSOFCs, in South Indian populations. Methods The SNPs were genotyped by using KBiosciences KASPar SNP genotyping chemistry in 173 cases and 176 controls for NSOFCs in South India. To estimate the association between these SNPs and NSOFCs, chi-square test was adopted. Odds ratios (OR) with 95% confidence intervals (CI) were also calculated in order to assess the risk. Results Single nucleotide polymorphisms located at chromosomal region 1p22 are not found to be associated with cleft lip with or without non-syndromic cleft palate (NSCL/P) and non-syndromic cleft palate only (NSCPO) at either the genotype or allele levels. Further, there is no LD observed between these variants. The polymorphic variants near 20q11.2 (rs13041247, rs11696257) are in complete linkage disequilibrium (LD) and are significantly associated with only NSCL/P in genotypic ( p = 0.013) and allelic models ( p = 0.029). In the genotypic model significance persisted even after Bonferroni correction ( p < 0.016). Conclusion These results suggest that 20q11.2 SNPs could play a contributory role in the pathophysiology and risk of NSCL/P, while the variations in 1p22 do not underlie the pathophysiology of NSOFCs in South Indian populations. [ABSTRACT FROM AUTHOR]