Fetal alcohol spectrum disorder (FASD) is one of the most disabling potential outcomes of prenatal alcohol exposure. The population-based prevalence of FASD among the general population of Canada was unknown. The objective of this study was to determine the population-based prevalence of FASD among elementary school students, aged 7 to 9 years, in the Greater Toronto Area (GTA) in Ontario, Canada. This screening study used a cross-sectional, observational design utilizing active case ascertainment, along with retrospective collection of prenatal alcohol exposure information. Data collection involved two phases. Phase I consisted of taking growth measurements, a dysmorphology examination, and obtaining a history of behavioral and/or learning problems. Phase II consisted of a neurodevelopmental assessment, maternal interview, and behavioral observations/ratings by parents/guardians. Final diagnostic screening conclusions were made by consensus by a team of experienced multidisciplinary experts during case conferences, using the 2005 Canadian guidelines for FASD diagnosis. The prevalence of FASD was estimated, taking into consideration the selection rate, which was used to account for students who dropped out or were lost to follow-up during each phase. Monte Carlo simulations were employed to derive the confidence interval (CI) for the point estimates. A total of 2555 students participated. A total of 21 cases of suspected FASD were identified. The prevalence of FASD was estimated to be 18.1 per 1000, or about 1.8%. Using a less conservative approach (sensitivity analysis), the prevalence of FASD was estimated to be 29.3 per 1000, or about 2.9%. Therefore, the population-based prevalence of FASD is likely to range between 2 and 3% among elementary school students in the GTA in Ontario, Canada. This study provides the first population-based estimate of the prevalence of FASD in Canada. The estimate is approximately double or possibly even triple previous crude estimates. FASD prevalence exceeds that of other common birth defects such as Down’s syndrome, spina bifida, trisomy 18, as well as autism spectrum disorder in Canada. More effective prevention strategies targeting alcohol use during pregnancy, surveillance of FASD, and timely interventions and support to individuals with FASD and their families are urgently needed.

Fetal alcohol spectrum disorder (FASD) is a developmental disorder that manifests through a range of cognitive, adaptive, physiological, and neurobiological deficits resulting from prenatal alcohol exposure. Although the North American prevalence is currently estimated at 2–5%, FASD has proven difficult to identify in the absence of the overt physical features characteristic of fetal alcohol syndrome. As interventions may have the greatest impact at an early age, accurate biomarkers are needed to identify children at risk for FASD. Building on our previous work identifying distinct DNA methylation patterns in children and adolescents with FASD, we have attempted to validate these associations in a different clinical cohort and to use our DNA methylation signature to develop a possible epigenetic predictor of FASD. Genome-wide DNA methylation patterns were analyzed using the Illumina HumanMethylation450 array in the buccal epithelial cells of a cohort of 48 individuals aged 3.5–18 (24 FASD cases, 24 controls). The DNA methylation predictor of FASD was built using a stochastic gradient boosting model on our previously published dataset FASD cases and controls (GSE80261). The predictor was tested on the current dataset and an independent dataset of 48 autism spectrum disorder cases and 48 controls (GSE50759). We validated findings from our previous study that identified a DNA methylation signature of FASD, replicating the altered DNA methylation levels of 161/648 CpGs in this independent cohort, which may represent a robust signature of FASD in the epigenome. We also generated a predictive model of FASD using machine learning in a subset of our previously published cohort of 179 samples (83 FASD cases, 96 controls), which was tested in this novel cohort of 48 samples and resulted in a moderately accurate predictor of FASD status. Upon testing the algorithm in an independent cohort of individuals with autism spectrum disorder, we did not detect any bias towards autism, sex, age, or ethnicity. These findings further support the association of FASD with distinct DNA methylation patterns, while providing a possible entry point towards the development of epigenetic biomarkers of FASD.

Objective: To compare the characteristics of mothers of children with Fetal Alcohol Spectrum Disorder (FASD) with mothers of typically developing control children. Methods: The study utilized a cross-sectional, observational design, using active case ascertainment. Biological mothers were interviewed using a standardized retrospective questionnaire to collect data on demographics, living environment, pregnancy history, nutrition, alcohol and other drug use prior to and following pregnancy recognition. Results: A total of 173 mothers were interviewed. Of these, 19 had a child who was diagnosed with FASD, five had a child who had received a deferred FASD diagnosis, and 37 had children who were selected into the control group as typically developing children. The remaining 112 mothers had children who did not meet diagnostic criteria for FASD. The mothers of children with FASD did not differ significantly from mothers of the control group children with respect to age, ethnicity, marital status, and employment status at the time of pregnancy. However, mothers of children with FASD had lower levels of education (p < 0.01) and were more likely to have received financial support (p < 0.05) at the time of pregnancy, to have smoked tobacco (p < 0.001), and to have used marijuana or hashish (p < 0.01) prior to pregnancy recognition, compared with mothers of control children. All mothers of children with FASD reported alcohol consumption prior to pregnancy recognition; however, only 10.5% reported alcohol consumption following pregnancy recognition. None of the mothers interviewed reported any drug use following pregnancy recognition. Conclusions: Population-based preventive interventions, including repeated screening, monitoring, and education regarding the effects of alcohol use, as well as other substances, before and during pregnancy, are needed to eliminate risk for FASD and other negative consequences on child and maternal health.

Fetal alcohol spectrum disorder (FASD) is characterized by a combination of neurological, developmental, and congenital defects that may occur as a consequence of prenatal alcohol exposure. Earlier reports showed that large chromosomal anomalies may link to FASD. Here, we examined the prevalence and types of copy number variations (CNVs) in FASD cases previously diagnosed by a multidisciplinary FASD team in sites across Canada. We genotyped 95 children with FASD and 87 age-matched, typically developing controls on the Illumina Human Omni2.5 SNP (single nucleotide polymorphisms) array platform. We compared their CNVs with those of 10 851 population controls to identify rare CNVs (<0.1% frequency), which may include large unbalanced chromosomal abnormalities, that might be relevant to FASD. In 12/95 (13%) of the FASD cases, rare CNVs were found that impact potentially clinically relevant developmental genes, including the CACNA1H involved in epilepsy and autism, the 3q29 deletion disorder, and others. Our results show that a subset of children diagnosed with FASD have chromosomal deletions and duplications that may co-occur or explain the neurodevelopmental impairments in a diagnosed cohort of FASD individuals. Children suspected to have FASD with or without sentinel facial features of fetal alcohol syndrome and neurodevelopmental delays should potentially be evaluated by a clinical geneticist and possibly have genetic investigations as appropriate to exclude other etiologies.

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.