Risk and Resilience Variants in the Retinoic Acid Metabolic and Developmental Pathways Associated with Risk of FASD Outcomes
Leo McKay,
Berardino Petrelli,
Molly Pind,
James N. Reynolds,
Richard F. Wintle,
Albert E. Chudley,
Britt Drögemöller,
Abraham Fainsod,
Stephen W. Scherer,
Ana Hanlon-Dearman,
Geoffrey G. Hicks
Affiliations
Leo McKay
Department of Biochemistry & Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
Berardino Petrelli
Department of Biochemistry & Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
Molly Pind
Department of Biochemistry & Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
James N. Reynolds
Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 2V7, Canada
Richard F. Wintle
The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
Albert E. Chudley
Department of Biochemistry & Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
Britt Drögemöller
Department of Biochemistry & Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
Abraham Fainsod
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, P.O. Box 12271, Jerusalem 9112102, Israel
Stephen W. Scherer
The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
Ana Hanlon-Dearman
Department of Pediatrics and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3A 1S1, Canada
Geoffrey G. Hicks
Department of Biochemistry & Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
Fetal Alcohol Spectrum Disorder (FASD) is a common neurodevelopmental disorder that affects an estimated 2–5% of North Americans. FASD is induced by prenatal alcohol exposure (PAE) during pregnancy and while there is a clear genetic contribution, few genetic factors are currently identified or understood. In this study, using a candidate gene approach, we performed a genetic variant analysis of retinoic acid (RA) metabolic and developmental signaling pathway genes on whole exome sequencing data of 23 FASD-diagnosed individuals. We found risk and resilience alleles in ADH and ALDH genes known to normally be involved in alcohol detoxification at the expense of RA production, causing RA deficiency, following PAE. Risk and resilience variants were also identified in RA-regulated developmental pathway genes, especially in SHH and WNT pathways. Notably, we also identified significant variants in the causative genes of rare neurodevelopmental disorders sharing comorbidities with FASD, including STRA6 (Matthew–Wood), SOX9 (Campomelic Dysplasia), FDG1 (Aarskog), and 22q11.2 deletion syndrome (TBX1). Although this is a small exploratory study, the findings support PAE-induced RA deficiency as a major etiology underlying FASD and suggest risk and resilience variants may be suitable biomarkers to determine the risk of FASD outcomes following PAE.
