Maternal transmission effects of the PAX genes among cleft case–parent trios from four populations

Abstract

Isolated cleft lip with or without cleft palate (CL/P) is among the most common human birth defects, with a prevalence of 1 in 700 live births. The paired box (PAX) genes have been suggested as candidate genes for CL/P based largely on mouse models; however, few human studies have focused on this gene family. This study tests for association between markers in four PAX genes and CL/P using a case-parent trio design considering parent-of-origin effects. Trios from four populations (76 from Maryland, 146 from Taiwan, 35 from Singapore, and 40 from Korea) were genotyped for 34 single nucleotide polymorphisms (SNPs) in the PAX3, PAX6, PAX7, and PAX9 genes. We performed the transmission disequilibrium test (TDT) on individual SNPs. Parent-of-origin effects were assessed using the transmission asymmetry test (TAT) and the parent-of- origin likelihood ratio test (PO-LRT). TDT analysis showed one SNP (rs766325) in PAX7 yielding evidence of linkage and association when parent-of-origin was not considered, with an OR(transmission) = 1.62 (P = 0.003), and five SNPs in PAX6 (including two pairs in near perfect linkage disequilibrium). TAT analysis of all trios revealed two SNPs in PAX7 and four SNPs in PAX3 showing significant excess maternal transmission. For these six SNPs, the maternal OR(transmission) ranged between 1.74 and 2.40, and PO-LRT was also significant (P-values = 0.035–0.012). When this analysis was limited to trios with male cases, SNPs in PAX7 showed higher maternal OR(transmission) and greater significance. PAX genes may influence the risk of CL/P through maternal effects, possibly imprinting, which seems to be stronger among male cases.

Analysis of early human neural crest development

“…7E–F), it is possible that Pax7 may be involved in the development of human orofacial clefts or additional craniofacial disturbances. In agreement with this view, a recent study suggests a strong correlation of maternally transmitted single nucleotide polymorphisms of Pax7 and Pax3 with cleft lip with or without cleft palate (Sull et al 2009). Furthermore, from CS12–18, we have shown the expression of p75 NTR within the early migratory neural crest, cranial or dorsal root ganglia, sympathetic tissue, and gut wall (Fig.…”

Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts

“…In this regard, it is interesting to note effects of maternal genotype and maternalspecific environmental modifiers such as smoking, drinking and vitamin intake during pregnancy on oral cleft susceptibility have been previously reported in various studies. 2,[10][11][12][13][14][15][16][17][18][19] However, it should be noted that the parental asymmetry tests we applied here do not specifically test for maternal effects which would be expected to occur via alterations of the in utero environment. Calculation of genomic inflation factors for the MAT and PAT tests showed a small increase for the MAT compared with the PAT in all categories, this increased inflation factor in the MAT does not discern the underlying cause, being consistent with either a true excess of biological associations with the maternally inherited alleles, or alternatively differing population structure between the two parental populations.…”

“…Previous candidate gene studies have suggested evidence for PofO effects in CL/P providing a strong rationale for performing comprehensive analysis to identify unconventional modes of inheritance. [16][17][18][19] However, non-Mendelian inheritance patterns such as imprinting are generally ignored in conventional GWAS, as these tests ignore the differential effects of maternally and paternally inherited alleles on phenotype. Indeed, simple case-control GWAS are unable to address this question.…”

Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease

“…Considering cleft lip with or without cleft palate, the sex ratio is biased with more affected males than females and an excess of maternal transmission in sporadic cases has been reported for several disease-causing genes. [23][24][25][26] As cleft lip may harbor a social disadvantage and more males than females are affected, reduced fertility of affected individuals could lead to the observation of an excess of maternal transmission. Another example is hereditary cystatin C amyloid angiopathy (HCCAA), which is an autosomal dominant disease with high penetrance, responsible for brain hemorrhages in young normotensive adults.…”