Increased Prevalence of Rare Copy Number Variants in Australian Children With Fetal Alcohol Spectrum Disorder: Experience in a State‐Wide Diagnostic Service
TL;DR
Evaluating the prevalence and types of DNA copy number variants in children diagnosed with FASD and to identify genes known to be associated with neurodevelopmental disorders suggests that approximately one in four children diagnosed with FASD may harbor a rare CNV.
Abstract
ABSTRACT Background Prenatal alcohol exposure (PAE) can result in fetal alcohol spectrum disorder (FASD), a permanent, heterogeneous condition characterized by severe neurodevelopmental impairments with or without microcephaly, characteristic facial dysmorphology, and congenital anomalies. Clinical and pre‐clinical studies suggest that genetic factors, in the mother or fetus, influence the phenotypic outcomes following PAE. The objectives of this study were to evaluate the prevalence and types of DNA copy number variants (CNVs) in children (0–18 years) diagnosed with FASD and to identify genes known to be associated with neurodevelopmental disorders. Methods Chromosomal microarray (CMA) was performed in children diagnosed with FASD in the NSW CICADA FASD Service—a state‐wide multidisciplinary diagnostic clinic in Australia. We performed a retrospective chart review of 175 patients diagnosed with FASD between 2015 and 2022 to obtain data on medical and family history, phenotype, and genotype. All CMA results were reviewed by a clinical geneticist. Results A rare CNV was identified in 38 of 157 (24.2%) patients who had CMA testing and 40 unique CNVs were identified. In four patients, a neurodevelopmental susceptibility syndrome was identified including Xq28 microduplication syndrome, 16p12.2 microdeletion syndrome, 17q11.2 microduplication syndrome, and an atypical variant of 22q11.2 deletion syndrome. Two children had incidental pathogenic variants. In 32 of 38 (84.2%) cases with a rare CNV, 34 variants of unknown significance (VOUS) were identified, of which 13 encoded a total of 14 genes associated with common neurodevelopmental disorders. Three variants of uncertain significance (VOUS) encoded different subunits of the voltage‐dependent calcium channel complex protein (CACNB2, CACNA1A, CACNA2D3). Conclusion These novel results suggest that approximately one in four children diagnosed with FASD may harbor a rare CNV, of which 85.0% are currently of uncertain clinical significance. Genetic testing can support the FASD diagnostic process and may reveal additional diagnoses or sources of genetic vulnerability to FASD.