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A mutation of the p63 gene in non-syndromic cleft lip.

ABSTRACT: Mutations in the p63 gene (TP63) underlie several monogenic malformation syndromes manifesting cleft lip with or without cleft palate (CL/P). We investigated whether p63 mutations also result in non-syndromic CL/P. Specifically, we performed mutation analysis of the 16 exons of the p63 gene for 100 Thai patients with non-syndromic CL/P. In total, 21 variant sites were identified. All were single nucleotide changes, with six in coding regions, including three novel non-synonymous changes: S90L, R313G, and D564H. The R313G was concluded to be pathogenic on the basis of its amino acid change, evolutionary conservation, its occurrence in a functionally important domain, its predicted damaging function, its de novo occurrence, and its absence in 500 control individuals. Our data strongly suggest, for the first time, a causative role of a heterozygous mutation in the p63 gene in non-syndromic CL/P, highlighting the wide phenotypic spectrum of p63 gene mutations.

SUBMITTER: Leoyklang P

PROVIDER: S-EPMC2564545 | biostudies-literature | 2006 Jun

REPOSITORIES: biostudies-literature

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A mutation of the p63 gene in non-syndromic cleft lip.

Leoyklang P P Siriwan P P Shotelersuk V V

Journal of medical genetics 20060601 6

Mutations in the p63 gene (TP63) underlie several monogenic malformation syndromes manifesting cleft lip with or without cleft palate (CL/P). We investigated whether p63 mutations also result in non-syndromic CL/P. Specifically, we performed mutation analysis of the 16 exons of the p63 gene for 100 Thai patients with non-syndromic CL/P. In total, 21 variant sites were identified. All were single nucleotide changes, with six in coding regions, including three novel non-synonymous changes: S90L, R ...[more]

PMID: 16740912

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Polygenic risk impacts PDGFRA mutation penetrance in non-syndromic cleft lip and palate.

Project description:Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common, severe craniofacial malformation that imposes significant medical, psychosocial and financial burdens. NSCL/P is a multifactorial disorder with genetic and environmental factors playing etiologic roles. Currently, only 25% of the genetic variation underlying NSCL/P has been identified by linkage, candidate gene and genome-wide association studies. In this study, whole-genome sequencing and genome-wide genotyping followed by polygenic risk score (PRS) and linkage analyses were used to identify the genetic etiology of NSCL/P in a large three-generation family. We identified a rare missense variant in PDGFRA (c.C2740T; p.R914W) as potentially etiologic in a gene-based association test using pVAAST (P = 1.78 × 10-4) and showed decreased penetrance. PRS analysis suggested that variant penetrance was likely modified by common NSCL/P risk variants, with lower scores found among unaffected carriers. Linkage analysis provided additional support for PRS-modified penetrance, with a 7.4-fold increase in likelihood after conditioning on PRS. Functional characterization experiments showed that the putatively causal variant was null for signaling activity in vitro; further, perturbation of pdgfra in zebrafish embryos resulted in unilateral orofacial clefting. Our findings show that a rare PDGFRA variant, modified by additional common NSCL/P risk variants, have a profound effect on NSCL/P risk. These data provide compelling evidence for multifactorial inheritance long postulated to underlie NSCL/P and may explain some unusual familial patterns.

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Non-syndromic Cleft Lip and Palate Polymorphisms Affect Normal Lip Morphology.

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Exon sequencing reveals that missense mutation of PBX1 gene may increase the risk of non-syndromic cleft lip/palate.

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IRF6 polymorphisms in Mexican patients with non-syndromic cleft lip.

Project description:Cleft lip with or without cleft palate (CL/P) is one of the most common birth defects; it is a multifactorial disease affecting > 1/1,000 live births in Europe, and its etiology is largely unknown, although it is very likely genetic and environmental factors contribute to this malformation. Orofacial development is a complex process involving many genes and signaling pathways. Mutations in the gene for the interferon regulatory factor 6 (IRF6) cause a hereditary dominant malformation syndrome including CL/P, and polymorphisms are associated with non-syndromic CL/P (MIM 119530). Five SNPs at the locus with high heterozygosity in Caucasian populations were chosen for the present research due to their very strong association with CL/P. A case-parent trio study was performed using 292 samples from Mexico. Association with the rs1319435-C/C genotype (P = 0.02) was found in patients (73) as compared to pseudocontrols (219), while the genotype rs1319435-T/C was related with protection (P = 0.041) in the triad design. Significant over-transmission of the G allele for marker rs2235375 (P = 0.049) was found. Only the TACGT haplotype was diminished in the affected child, either in single (P = 0.0208) or double (P = 0.0208) dose. The pairwise analysis showed rs2235543 and rs2235371 were in strong linkage disequilibrium. These results point to a substantial contribution of IRF6 in the etiology of non-syndromic CL/P in a sample of the Mexican population.

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Non-syndromic cleft palate: analysis of TBX22 exon 5 gene mutation.

Project description:IntroductionThis study aimed to investigate the mutation of T-box transcription factor TBX22 exon 5 in children with non-syndromic cleft palate. Four mutations in TBX22 exon 5 in X-linked cleft palate with ankyloglossia (CPX) patients had been identified in the previous studies. The study used the syndromic cleft palate susceptibility gene as a candidate gene for more common non-syndromic cleft palate.Material and methodsA family-based study with parents and their children composing parent-child trios was performed in this research. Twenty children with non-syndromic cleft palate and 38 healthy parents were enrolled. TBX22 exon 5 was examined by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and DNA sequencing. The peaks of the sequence diagrams were analyzed using chromas221 and the results of sequencing were proofread using dnastar6.13. The index of the transmission disequilibrium test (TDT) was calculated through McNemar testing.ResultsWe have not found the presence of any mutation of TBX22 exon 5 reported in syndromic cleft palate patients in references. The index of TDT was 0.56 and showed no statistically significant difference (p<0.05). No TBX22 exon 5 mutation was found in the 20 children.ConclusionsMutation of TBX22 exon 5 is not associated with non-syndromic cleft palate in the population of Jiangzhe areas in China.

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Identification of novel susceptibility loci for 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.

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