High throughput SNP and expression analyses of candidate genes for non-syndromic oral clefts

Abstract

Background: Recent work suggests that multiple genes and several environmental risk factors influence risk for non-syndromic oral clefts, one of the most common birth defects in humans. Advances in highthroughput genotyping technology now make it possible to test multiple markers in many candidate genes simultaneously. Methods: We present findings from family based association tests of single nucleotide polymorphism (SNP) markers in 64 candidate genes genotyped using the BeadArray approach in 58 case-parent trios from Maryland (USA) to illustrate how multiple markers in multiple genes can be analysed. To assess whether these genes were expressed in human craniofacial structures relevant to palate and lip development, we also analysed data from the Craniofacial and Oral Gene Expression Network (COGENE) consortium, and searched public databases for expression profiles of these genes. Results: Thirteen candidate genes showed significant evidence of linkage in the presence of disequilibrium, and ten of these were found to be expressed in relevant embryonic tissues: SP100, MLPH, HDAC4, LEF1, C6orf105, CD44, ALX4, ZNF202, CRHR1, and MAPT. Three other genes showing statistical evidence (ADH1C, SCN3B, and IMP5) were not expressed in the embryonic tissues examined here. Conclusions: This approach demonstrates how statistical evidence on large numbers of SNP markers typed in case-parent trios can be combined with expression data to identify candidate genes for complex disorders. Many of the genes reported here have not been previously studied as candidates for oral clefts and warrant further investigation.

Heterozygous nonsense mutationSATB2 associated with cleft palate, osteoporosis, and cognitive defects

“…Cleft palate has various known and suspected genetic etiologies in humans [Stanier and Moore, 2004;Park et al, 2006]. One possibly causative gene is SATB2, encoding a cell type-specific transcription factor that functions as a regulator of the transcription of large chromatin domains.…”

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

“…5,10,11 Previous studies showed that complete functional loss of Satb2 leads to increased apoptosis in the developing jaw primordia and subsequent down-regulation of the expression of genes (Pax9, Alx4 and Msx1) involved in craniofacial development in humans and mice. 12,13 Although initial cytogenetic studies showed two translocation break breakpoints on 2q32, which harbours SATB2 gene, 2 a meta-analysis of genome scans of cleft lip and palate indicated 2q32-q35 region as a clefting susceptibility locus. 14 Sequencing of 184 cleft lip and palate cases revealed T190A mutation in a single Philippine case, which was not found in CEPH controls.…”

An Analysis of the Association between Epilepsy-Related Genes and Vertigo in the Polish Population

“…Conversely, rs1939012:T-rs1783901:A haplotype was suggestive of a protective value against the condition (Table 6). MMP8 rs1939012 was recently found to be associated with genetic generalized epilepsy on a genomewide level [International League against Epilepsy Consortium on Complex Epilepsies, 2014], while rs1783901 in SCN3B was also implicated in association with nonsyndromic oral clefts [Park et al, 2006]. Considering that the lack of association of these SNPs individually could be due the small number of individuals in our study, we compared the SNP minor allele frequencies of patients in the Polish groups to the Eu-ropean population included in the gnomAD and 1000 Genomes Project databases; likewise, no significant differences were found (p = 0.5421 and p = 0.5317 for rs1939012; p = 0.8883 and p = 0.4396 for rs1783901, respectively).…”