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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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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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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.

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| S-EPMC5992119 | biostudies-literature

FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate.

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