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Integrative approaches generate insights into the architecture of non-syndromic cleft lip with or without cleft palate.

ABSTRACT: Non-syndromic cleft lip with or without cleft palate (nsCL/P) is a common congenital facial malformation with a multifactorial etiology. Genome-wide association studies (GWASs) have identified multiple genetic risk loci. However, functional interpretation of these loci is hampered by the underrepresentation in public resources of systematic functional maps representative of human embryonic facial development. To generate novel insights into the etiology of nsCL/P, we leveraged published GWAS data on nsCL/P as well as available chromatin modification and expression data on mid-facial development. Our analyses identified five novel risk loci, prioritized candidate target genes within associated regions, and highlighted distinct pathways. Furthermore, the results suggest the presence of distinct regulatory effects of nsCL/P risk variants throughout mid-facial development and shed light on its regulatory architecture. Our integrated data provide a platform to advance hypothesis-driven molecular investigations of nsCL/P and other human facial defects.

SUBMITTER: Welzenbach J

PROVIDER: S-EPMC8756534 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Identification of novel susceptibility loci for non-syndromic cleft lip with or without cleft palate.

Project description:Although several genome-wide association studies (GWAS) of non-syndromic cleft lip with or without cleft palate (NSCL/P) have been reported, more novel association signals are remained to be exploited. Here, we performed an in-depth analysis of our previously published Chinese GWAS cohort study with replication in an extra dbGaP case-parent trios and another in-house Nanjing cohort, and finally identified five novel significant association signals (rs11119445: 3' of SERTAD4, P = 6.44 × 10-14 ; rs227227 and rs12561877: intron of SYT14, P = 5.02 × 10-13 and 2.80 × 10-11 , respectively; rs643118: intron of TRAF3IP3, P = 4.45 × 10-6 ; rs2095293: intron of NR6A1, P = 2.98 × 10-5 ). The mean (standard deviation) of the weighted genetic risk score (wGRS) from these SNPs was 1.83 (0.65) for NSCL/P cases and 1.58 (0.68) for controls, respectively (P = 2.67 × 10-16 ). Rs643118 was identified as a shared susceptible factor of NSCL/P among Asians and Europeans, while rs227227 may contribute to the risk of NSCL/P as well as NSCPO. In addition, sertad4 knockdown zebrafish models resulted in down-regulation of sox2 and caused oedema around the heart and mandibular deficiency, compared with control embryos. Taken together, this study has improved our understanding of the genetic susceptibility to NSCL/P and provided further clues to its aetiology in the Chinese population.

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LAMA5: A new pathogenic gene for non-syndromic cleft lip with or without cleft palate.

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SATB2 gene variants in non-syndromic cleft lip with or without cleft palate in Indian population.

Project description:OBJECTIVES:Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common craniofacial birth defects and little is known about its aetiology. Initial studies of cytogenetic analysis provided the clues for possible genes involved in the pathogenesis of NSCL/P. This approach led to the identification of SATB2 gene on 2q32-q33. The aim of this study was to determine the association between SATB2 mutations and NSCL/P. MATERIALS AND METHODS:The rs137853127, rs200074373 and rs1992950 mutations of the SATB2 gene were investigated in 173 patients with NSCL/P and 176 normal controls using Kbioscience KASPar chemistry, which is a competitive allele-specific PCR SNP genotyping system. RESULTS:The mutations in exon 6 (rs137853127 and rs200074373) were monomorphic, the intronic variant (rs1992950) was polymorphic and genotype distribution was in agreement with Hardy-Weinberg equilibrium. The rs1992950 genotype distribution is not statistically significant between NSCL/P and controls. CONCLUSION:Our findings suggest that the SATB2 gene variations do not contribute to the development of NSCL/P in the south Indian population.

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Variation in WNT genes is associated with non-syndromic cleft lip with or without cleft palate.

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Expression Quantitative Trait Locus Study of Non-Syndromic Cleft Lip with or without Cleft Palate GWAS Variants in Lip Tissues.

Project description:Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a complex disease with a strong genetic component. More than 40 loci have been identified to be associated with the risk of NSCL/P by genome-wide association studies (GWASs), but the majority of these variants are mapped to non-coding regions of the genome. Expression quantitative trait locus (eQTL) studies have increasingly been integrated with GWASs to identify target genes for these non-coding variants. In this study, we generated a unique, lip-specific eQTL dataset from 40 NSCL/P patients. A total of 5158 eQTL SNPs (eSNPs) -689 eQTL genes were identified after multiple corrections. Then, we integrated nominal eQTL SNPs with NSCL/P risk SNPs and identified 243 variants associated with the expression of 18 genes in lip tissues. Functional annotation analysis indicated that these risk eSNPs were significantly enriched in transcription regulation and chromatin open regions on the genome. These susceptible genes were enriched in cell fate determination, the pluripotency of stem cells, and Wnt signaling pathways. Finally, 8 of the 18 susceptible genes were differentially expressed in NSCL/P case-control studies. In summary, we have generated a unique lip-specific eQTL resource and identified multiple associations for NSCL/P risk loci, which should inform functional studies of NSCL/P biology.

| S-EPMC9600070 | biostudies-literature

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| S-EPMC6207999 | biostudies-literature

Identification of susceptibility genes in non-syndromic cleft lip with or without cleft palate using whole-exome sequencing.

Project description:Non-syndromic cleft lip with or without cleft palate (NSCL/P) is among the most common congenital malformations. The etiology of NSCL/P remains poorly characterized owing to its complex genetic heterogeneity. The objective of this study was to identify genetic variants that increase susceptibility to NSCL/P.Whole-exome sequencing (WES) was performed in 8 fetuses with NSCL/P in China. Bioinformatics analysis was performed using commercially available software. Variants detected by WES were validated by Sanger sequencing.By filtering out synonymous variants in exons, we identified average 8575 nonsynonymous single nucleotide variants (SNVs). We subsequently compared the SNVs against public databases including NCBI dbSNP build 135 and 1000 Genomes Project and obtained an average of 203 SNVs. Total 12 reported candidate genes were verified by Sanger sequencing. Sanger sequencing also confirmed 16 novel SNVs shared by two or more samples.We have found and confirmed 16 susceptibility genes responsible for NSCL/P, which may play important role in the etiology of NSCL/P. The susceptibility genes identified in this study will not only be useful in revealing the etiology of NSCL/P but also in diagnosis and treatment of the patients with NSCL/P.

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Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate.

Project description:Non-syndromic cleft lip with or without cleft palate (NS-CL/P) is one of the most common human birth defects and is generally considered a complex trait. Despite numerous loci identified by genome-wide association studies, the effect sizes of common variants are relatively small, with much of the presumed genetic contribution remaining elusive. We report exome-sequencing results in 209 people from 72 multi-affected families with pedigree structures consistent with autosomal-dominant inheritance and variable penetrance. Herein, pathogenic variants are described in four genes encoding components of the p120-catenin complex (CTNND1, PLEKHA7, PLEKHA5) and an epithelial splicing regulator (ESRP2), in addition to the known CL/P-associated gene, CDH1, which encodes E-cadherin. The findings were also validated in a second cohort of 497 people with NS-CL/P, comprising small families and singletons with pathogenic variants in these genes identified in 14% of multi-affected families and 2% of the replication cohort of smaller families. Enriched expression of each gene/protein in human and mouse embryonic oro-palatal epithelia, demonstration of functional impact of CTNND1 and ESRP2 variants, and recapitulation of the CL/P spectrum in Ctnnd1 knockout mice support a causative role in CL/P pathogenesis. These data show that primary defects in regulators of epithelial cell adhesion are the most significant contributors to NS-CL/P identified to date and that inherited and de novo single gene variants explain a substantial proportion of NS-CL/P.

| S-EPMC5992119 | biostudies-literature

Three GLI2 mutations combined potentially underlie non-syndromic cleft lip with or without cleft palate in a Chinese pedigree.

Project description:BackgroundNonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect. Its etiology is complex and it has a lifelong influence on affected individuals. Despite many studies, the pathogenic gene alleles are not completely clear. Here, we recruited a Chinese NSCL/P family and explored the candidate causative variants in this pedigree.MethodsWe performed whole-exome sequencing on two patients and two unaffected subjects of this family. Variants were screened based on bioinformatics analysis to identify the potential etiological alleles. Species conservation analysis, mutation function prediction, and homology protein modeling were also performed to preliminarily evaluate the influence of the mutations.ResultsWe identified three rare mutations that are located on a single chromatid (c.2684C > T_p.Ala895Val, c.4350G > T_p.Gln1450His, and c.4622C > A_p.Ser1541Tyr) in GLI2 as candidate causative variants. All of these three mutations were predicted to be deleterious, and they affect amino acids that are conserved in many species. The mutation c.2684C > T was predicted to affect the structure of the GLI2 protein.ConclusionOur results further demonstrate that GLI2 variants play a role in the pathogenesis of NSCL/P, and the three rare missense mutations combined are probably the potential disease-causing variants in this family.

| S-EPMC6732289 | biostudies-literature

Identification of New miRNA-mRNA Networks in the Development of Non-syndromic Cleft Lip With or Without Cleft Palate.

Project description:Objective: To identify new microRNA (miRNA)-mRNA networks in non-syndromic cleft lip with or without cleft palate (NSCL/P). Materials and Methods: Overlapping differentially expressed miRNAs (DEMs) were selected from cleft palate patients (GSE47939) and murine embryonic orofacial tissues (GSE20880). Next, the target genes of DEMs were predicted by Targetscan, miRDB, and FUNRICH, and further filtered through differentially expressed genes (DEGs) from NSCL/P patients and controls (GSE42589), MGI, MalaCards, and DECIPHER databases. The results were then confirmed by in vitro experiments. NSCL/P lip tissues were obtained to explore the expression of miRNAs and their target genes. Results: Let-7c-5p and miR-193a-3p were identified as DEMs, and their overexpression inhibited cell proliferation and promoted cell apoptosis. PIGA and TGFB2 were confirmed as targets of let-7c-5p and miR-193a-3p, respectively, and were involved in craniofacial development in mice. Negative correlation between miRNA and mRNA expression was detected in the NSCL/P lip tissues. They were also associated with the occurrence of NSCL/P based on the MGI, MalaCards, and DECIPHER databases. Conclusions: Let-7c-5p-PIGA and miR-193a-3p-TGFB2 networks may be involved in the development of NSCL/P.

| S-EPMC7957012 | biostudies-literature

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