Craniofacial Microsomia and Variants in Genes Related to Retinoic Acid, Endothelin, and Phenotypically Overlapping Syndromes

Abstract

Background: Craniofacial microsomia (CFM) is the second most common facial congenital anomaly. It involves asymmetric underdevelopment of facial skeletal bones and soft tissues, mostly the lower face and ear. Aberration of vascular development and cranial neural crest cell (NCC) migration are believed to be two underlying mechanisms. Etiological factors are heterogeneous and may involve the interplay of environmental and genetic factors. In complex disorders, in addition to an affected child’s own genotypes, maternal genotypes can also increase the risk of offspring disease by influencing the in utero milieu. Here we studied three groups of candidate genes those relating to retinoic acid, endothelin, and syndromes with phenotypic characteristics overlapping those of CFM. Most of these genes are involved in the development of cranial NCCs or in vasculogenesis, Methods: We applied tagSNPs (tagged single nucleotide polymorphisms) method to identify 336 SNPs from 14 candidate genes in the retinoic acid pathway, 8 candidate genes in the endothelin pathway, and 8 candidate genes from syndromes with overlapping phenotypes in 98 case-parent sets (83 case-parent trios, 15 case-mother dyads). We used a log-linear approach applied in the software Estimation of Maternal, Imprinting and interaction effects using Multinomial modelling (EMIM) to estimate the relative risk of CFM associated with offspring and maternal genotypes. Results: After accounting for multiple comparisons, we identified 5 associated child variants and 3 associated maternal variants with the top SNP, rs429738, from TBX1 [heterozygous and homozygous relative risks (95% CI): 0.4 (0.2, 0.6) and 0.7 (0.3, 1.6) respectively]. The top 5 loci from child genotype effects, harbored by candidate genes of HOXA1, RXRB, and TBX1, are found to be part of transcriptional regulators involved in NCCs development. For maternal genotype effects, the top 3 loci are harbored by candidate genes of ALDH1A2 and CRABP1, both of which are known to regulate cellular retinoic acid level. Conclusions: In one of the first studies of genetic risk factors in association to CFM, results provide evidence for the role of genetics as part of CFM pathogenesis. We observed association between genetic variants known to involve in NCC development in both offspring and mothers and the risk of CFM. Follow-up studies with greater power are necessary to validate these results.