BCL3 gene role in facial morphology.

BACKGROUND: Cleft lip (CL) with or without palate (CLP) and isolated cleft palate (CP) are etiologically complex diseases with interactions among various environmental and genetic factors. The aim of the current study was to identify association with genetic markers and phenotypic craniofacial data in patients with CL/CLP/CP parents. METHODS: Posteroanterior and lateral digital radiographs of the cranium were obtained from 74 parents of patients with CL/CLP/CP. One hundred seventy-three patients with CL/CLP/CP and 190 controls were enrolled in the study for the association test. Five genetic markers of the IRF6 gene and 14 markers of the 19q13 locus were genotyped. Linear regression analysis was performed for the relationship of cephalometric measurements with genotype data adjusted for age, gender, and cleft type. Chi-square and transmission disequilibrium tests were performed to evaluate differences in alleles of the BCL3 gene. Positive findings were replicated in an independent sample (n = 95) of patients with CL/CLP/CP parents. RESULTS: Genetic markers of the BCL3 gene at 19q13, rs7257231, and rs1979377 in the familial association test and rs10401176 in the case-control association test, were associated with craniofacial phenotype. Carriers of BCL3 allele rs7257231T had longer posterior cranial bases than noncarriers (p(adjusted) = 0.0028), and in the familial-based association test showed the statistically strongest relationship (p(adjusted) = 0.05) to phenotype. Relation of rs7257231 to facial formation was confirmed in the replication group (p = 0.0024). CONCLUSIONS: The results indicate that BCL3, which has functions related to cell adhesion and whose downregulation can cause disruption of ectodermal development, is likely to be important in facial formation. Birth Defects Research (Part A), 2012.

Monogenic Versus Multifactorial Inheritance in the Development of Isolated Cleft Palate: A Whole Genome Sequencing Study.

Craniofacial morphogenesis is highly complex, as is the anatomical region involved. Errors during this process, resulting in orofacial clefts, occur in more than 400 genetic syndromes. Some cases of cleft lip and/or palate (CLP) are caused by mutations in single genes; however, complex interactions between genetic and environmental factors are considered to be responsible for the majority of non-syndromic CLP development. The aim of the current study was to identify genetic risk factors in patients with isolated cleft palate (CP) by whole genome sequencing. Patients with isolated CP (n = 30) recruited from the Riga Cleft Lip and Palate Centre, Institute of Stomatology, Riga, were analyzed by whole genome sequencing. Pathogenic or likely pathogenic variants were discovered in genes associated with CP (TBX22, COL2A1, FBN1, PCGF2, and KMT2D) in five patients; hence, rare disease variants were identified in 17% of patients with non-syndromic isolated CP. Our results were relevant to routine genetic counselling practice and genetic testing recommendations. Based on our data, we propose that all newborns with orofacial clefts should be offered genetic testing, at least for a panel of known CLP genes. Only if the results are negative and there is no suggestive family history or additional clinical symptoms (which would support additional exome or genome-wide investigation), should multifactorial empiric recurrence risk prediction tools be applied for families.

Variation in FGF1, FOXE1, and TIMP2 genes is associated with nonsyndromic cleft lip with or without cleft palate.

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common complex birth defect caused by the interaction between multiple genes and environmental factors. METHODS: Five hundred and eighty-seven single nucleotide polymorphisms in 40 candidate genes related to orofacial clefting were tested for association with CL/P in a clefting sample composed of 300 patients and 606 controls from Estonian, Latvian, and Lithuanian populations. RESULTS: In case-control comparisons, the minor alleles of FGF1 rs34010 (p = 4.56 × 10(-4) ), WNT9B rs4968282 (p = 0.0013), and FOXE1 rs7860144 (p = 0.0021) were associated with a decreased risk of CL/P. Multiple haplotypes in FGF1, FOXE1, and TIMP2 and haplotypes in WNT9B, PVRL2, and LHX8 were associated with CL/P. The strongest association was found for protective haplotype rs250092/rs34010 GT in the FGF1 gene (p = 5.01 × 10(-4) ). The strongest epistatic interaction was observed between the COL2A1 and WNT3 genes. CONCLUSIONS: Our results provide for the first time evidence implicating FGF1 in the occurrence of CL/P, and support TIMP2 and WNT9B as novel loci predisposing to CL/P. We have also replicated recently reported significant associations between variants in or near FOXE1 and CL/P. It is likely that variation in FOXE1, TIMP2, and the FGF and Wnt signaling pathway genes confers susceptibility to nonsyndromic CL/P in Northeastern European populations.

Genetic variants in COL2A1, COL11A2, and IRF6 contribute risk to nonsyndromic cleft palate.

BACKGROUND: Orofacial clefts are among the most common birth defects with a strong genetic component. Nonsyndromic cleft palate (NSCP) is a complex malformation determined by the interaction between multiple genes and environmental risk factors. METHODS: We conducted a case-control association study to investigate the role of 40 candidate genes in predisposition to orofacial clefting. Five hundred ninety-one haplotype tagging single nucleotide polymorphism (tagSNPs) were genotyped in a clefting sample from the Baltic region, composed of 104 patients with nonsyndromic cleft palate and 606 controls from an Estonian, Latvian, and Lithuanian population. RESULTS: In case-control comparisons, the minor alleles of IRF6 rs17389541 (p = 5.45 × 10(-4)) and COL2A1 rs1793949 (p = 7.26 × 10(-4)) were associated with increased risk of NSCP. Multiple haplotypes in COL2A1 and COL11A2 and haplotypes in WNT3, FGFR1, and CLPTM1were associated with NSCP. The strongest associations were found for IRF6 haplotype rs17389541/rs9430018 GT (p = 2.23 × 10(-4)) and COL2A1 haplotype rs12822608/rs6823 GC (p = 3.68 × 10(-4)). The strongest epistatic interactions were observed between MSX1 and BMP2, FGF1 and PVRL2, and COL2A1 and FGF2 genes. CONCLUSIONS: This study provides for the first time evidence of the implication of IRF6, COL2A1, and WNT3 in the occurrence of NSCP. It is likely that variation in cartilage collagen II and XI genes, IRF6, and the Wnt and FGF signaling pathway genes contributes susceptibility to nonsyndromic cleft palate in Northeastern European populations.

The most common genetic syndromes and associated anomalies in Latvian patients with cleft lip with or without palate.

UNLABELLED: 1 over 700 newborns every year is born with cleft lip with/or without palate, in 30% of cases there is a certain genetic mechanism underlying development of disease: chromosomal anomalies, monogenic diseases, exposure to teratogens or in utero disruptive mechanisms. The objective of our study is to describe the most common genetic syndromes and associated anomalies in patients with CL/CP in Latvia. MATERIALS AND METHODS: Study material was medical records obtained from Riga Cleft Lip and Palate Centre Registry in a time period of 1980 till 2005. There was analyzed information about patients with identified genetic syndromes and associated anomalies. RESULTS: In a time period from 1980 till 2005, the following genetic syndromes were identified: Van der Woude, Fetal alcohol syndrome, Holzgreve syndrome, Marfan syndrome, Myotonic dystrophy, Klippel-Feil syndrome, Patau syndrome, Potter sequence and Pierre Robin sequence. 16% of CL/CP patients have recognized genetic syndromes or associated anomalies, including profound, severe and moderate mental retardation. Number is lower than expected, but still correlates with date presented in other populations. CONCLUSIONS: Long term follow-up of multidisciplinary specialists which includes cardiologists, clinical-geneticists and paediatricians, is needed for CL/CP patients with associated anomalies in order to identify timely side diseases and complications. Grant: Baltic-Taiwan joint research project "Identification of genes involved in craniofacial morphogenesis and susceptibility to orofacial clefting in a human genome scan 2004-2006".

Mutation analysis of the MSX1 gene exons and intron in patients with nonsyndromic cleft lip and palate.

UNLABELLED: Cleft lip with or without cleft palate and cleft palate (CL/CLP/CP) is one of the most common malformations among newborns. The estimated prevalence in Latvia is 1/700. Nonsyndromic CL/CLP/CP is a complex trait determined by multiple, interacting genetic and environmental factors. MSX1 gene is one of the most important candidate-genes, which had been analyzed in relation with nonsyndromic CL/CLP/CP. The objective of our study was to examine the etiologic role of MSX1 gene mutations in the development of nonsyndromic CL/CLP/CP in Latvian population. MATERIALS AND METHODS: DNA was extracted from venous blood of 53 patients with cleft lip with or without palate. Polymerase chain reaction (PCR) was performed of selected segments of MSX1 gene. These were sequenced and analysed by comparison with reference sequence, accession Nr. AF426432 (NCBI). RESULTS: 16 DNA sequence variations were identified in 53 patient samples; 6 of them have not been previously described. Identified sequence variations localized in coding regions do not cause amino acid substitutions, therefore they are not considered as mutations with an etiological role in CL/CLP/CP development. Baltic-Taiwan joint research project "Identification of genes involved in craniofacial morphogenesis and susceptibility to orofacial clefting in a human genome scan 2004-2006".

Association of BMP4 polymorphisms with non-syndromic cleft lip with or without cleft palate and isolated cleft palate in Latvian and Lithuanian populations.

Cleft lip with or without cleft palate (CLP and CL, respectively) and isolated cleft palate (CP) represent one of the most common human birth defects, with a prevalence of approximately 1 in 300-2500 depending on the population. Formation of non-syndromic CL/CLP and CP arises from the interaction of environmental and genetic factors. The objective of this study was to investigate the association between the BMP4 gene (encoding bone morphogenetic protein 4) and non-syndromic CL/CLP and CP in order to clarify the role of this gene in the aetiology of the malformation in Latvian and Lithuanian populations. We genotyped three markers of the BMP4 gene (rs17563, rs2071047 and rs1957860) in order to perform single marker and haplotype association analyses for Latvian and Lithuanian non-syndromic CL/CLP and CP patients and controls. Transmission disequilibrium test was also conducted for Latvian and Lithuanian proband-parent trios. The case-control analysis revealed that SNP rs2071047 allele A was associated with a decreased risk of CL/CLP in the Latvian population, which was confirmed by the haplotype analysis. A modest association was detected between SNP rs1957860 and CP in the Lithuanian population, where allele C was associated with a decreased risk of this cleft phenotype, corroborating haplotype analysis data. Our findings support a role of the BMP4 gene in the aetiology of non-syndromic CL/CLP and CP in the studied populations.