Genetics of FASD: Confounding Rare Craniofacial and Neurodevelopmental Disorders May Identify Ethanol-Sensitizing Genetic Variants of FASD

Abstract

AbstractFetal alcohol spectrum disorder (FASD) is a clinically diverse teratogenic disorder with many underlying contributing risk factors including other environmental influences and temporal, epigenetic, and genetic factors. Twin studies of children with FASD have established a genetic component to the disorder; however, identifying which genes and their variants contribute to the pathogenesis of this complex and common disorder remains elusive. In this chapter, we highlight the genetic determinants of rare neurodevelopmental disorders that share overlapping clinical phenotypes to FASD, including CHARGE, Aarskog, Smith-Lemli-Optiz, Opitz-Kaveggia, Campomelic dysplasia, Noonan, Cornelia de Lange, and 22q11.2 deletion syndrome (DS). We hypothesize that by examining the genetic determinants of these rare developmental disorders, we can identify potential prenatal alcohol exposure susceptibility genes of FASD. Indeed, our investigation identified many specific candidate genes in neurodevelopmental signaling pathways that are well established in animal models of FASD-like outcomes following prenatal alcohol exposure, including those in the RAS/MAPK, Wnt/Ca2+, SHH, cholesterol, and retinoic acid pathways. Our findings support the notion that causative alleles of these rare developmental disorders may be sensitizing to prenatal alcohol exposure outcomes as seen in FASD. Sensitization by prenatal alcohol exposure could result in a direct functional modulation of protein activity or induction of an epigenetic modulation of candidate gene expression and define new underlying etiologies of FASD. Moreover, the frequency of PAE-sensitizing variants should be enriched in children with FASD and may provide new FASD diagnostic biomarkers.Key wordsFASFASDPrenatal alcohol exposure22q11.2 deletion syndromeCHARGE syndromeAarskog syndromeSmith-Lemli-Optiz syndromeOpitz-Kaveggia syndromeCampomelic dysplasiaNoonan syndromeCornelia de Lange syndromeRare genetic disordersCraniofacial disordersNeurodevelopmental disorders