Dataset Information

Likely Pathogenic Variants in One Third of Non-Syndromic Discontinuous Cleft Lip and Palate Patients.

ABSTRACT: Oral clefts are composed of cleft of the lip, cleft of the lip and palate, or cleft of the palate, and they are associated with a wide range of expression and severity. When cleft of the palate is associated with cleft of the lip with preservation of the primary palate, it defines an atypical phenotype called discontinuous cleft. Although this phenotype may represent 5% of clefts of the lip and/or palate (CLP), it is rarely specifically referred to and its pathophysiology is unknown. We conducted whole exome sequencing (WES) and apply a candidate gene approach to non-syndromic discontinuous CLP individuals in order to identify genes and deleterious variants that could underlie this phenotype. We discovered loss-of-function variants in two out of the seven individuals, implicating FGFR1 and DLG1 genes, which represents almost one third of this cohort. Whole exome sequencing of clinically well-defined subgroups of CLP, such as discontinuous cleft, is a relevant approach to study CLP etiopathogenesis. It could facilitate more accurate clinical, epidemiological and fundamental research, ultimately resulting in better diagnosis and care of CLP patients. Non-syndromic discontinuous cleft lip and palate seems to have a strong genetic basis.

SUBMITTER: Demeer B

PROVIDER: S-EPMC6826364 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

Likely Pathogenic Variants in One Third of Non-Syndromic Discontinuous Cleft Lip and Palate Patients.

Demeer Bénédicte B Revencu Nicole N Helaers Raphael R Gbaguidi Cica C Dakpe Stéphanie S François Geneviève G Devauchelle Bernard B Bayet Bénédicte B Vikkula Miikka M

Genes 20191022 10

Oral clefts are composed of cleft of the lip, cleft of the lip and palate, or cleft of the palate, and they are associated with a wide range of expression and severity. When cleft of the palate is associated with cleft of the lip with preservation of the primary palate, it defines an atypical phenotype called discontinuous cleft. Although this phenotype may represent 5% of clefts of the lip and/or palate (CLP), it is rarely specifically referred to and its pathophysiology is unknown. We conducte ...[more]

PMID: 31652620

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Project description:The etiology and pathogenesis of non-syndromic cleft lip and palate (NSCL/P) are largely unknown. Long non-coding RNAs (lncRNA) are thought to play important roles in NSCL/P, but reports on the underlying processes are currently unavailable. Our study focused on children diagnosed with NSCL/P alone. Based on the morphology, patients were categorized as either cleft lip with or without cleft palate (CL/P) or cleft palate-only (CPO). When patients received surgery for NSCL/P, tissue excised from the trimmed wound edge was reserved to serve as experimental samples; adjacent normal tissue was used as a positive control. Target lncRNAs in the collected tissues were identified using microarray and quantitative reverse transcription PCR (RT-qPCR). Immunohistochemical (IHC) staining and RT-qPCR were used to verify the target mRNAs. Pathway, gene ontology (GO) enrichment, and TargetScan prediction were employed to construct endogenous RNA networks (ceRNA networks) and explore their potential functions. RNA-Seq analysis revealed 24 upregulated and 43 downregulated lncRNAs in the CL/P and CPO groups compared with those in the control group; of these, MALAT1and NEAT1 were screened and validated using RT-qPCR. Common NSCL/P risk factors positively correlated with MALAT1 and NEAT1 expression (ORMALAT1 = 28.111, 95% CI: 4.054-194.923; ORNEAT1 = 30.556, 95% CI: 4.422-211.142; P < 0.05). Bioinformatics predicted four ceRNA networks: MALAT1-hsa-miR-1224-3p-SP1, MALAT1-hsa-miR-6734-5p/hsa-miR-1224-3p-WNT10A, NEAT1-hsa-miR-140-3p.1-CXCR4, and NEAT1-hsa-miR-3129-5p/hsa-miR-199a-3p/hsa-miR-199b-3p-ZEB1. GO enrichment focused on the potential functions of ceRNA networks, including biosynthesis of organic cyclic compounds, formation of membrane-enclosed and organelle lumens, and Wnt-protein binding. The results of RT-qPCR were consistent with those of IHC staining with regard to expression of related mRNAs. MALAT1 and NEAT1, which are upregulated in NSCL/P, are associated with the severity of NSCL/P. This study provides a new insight into NSCL/P pathogenesis and suggests that MALAT1 and NEAT1 act as potential therapeutic targets and prognostic biomarkers for NSCL/P.

Dataset Information

Likely Pathogenic Variants in One Third of Non-Syndromic Discontinuous Cleft Lip and Palate Patients.

Publications

Likely Pathogenic Variants in One Third of Non-Syndromic Discontinuous Cleft Lip and Palate Patients.

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