Abstract
BackgroundA pair of dizygotic twins discordantly affected by heavy prenatal alcohol exposure (PAE) was reported previously by Riikonen, suggesting the role of genetic risk or protective factors in the etiology of alcohol‐induced developmental disorders. Now, we have re‐examined these 25‐year‐old twins and explored genetic origin of the phenotypic discordancy reminiscent with fetal alcohol syndrome (FAS). Furthermore, we explored alterations in DNA methylation profile of imprinting control region at growth‐related insulin‐like growth factor 2 (IGF2)/H19 locus in twins' white blood cells (WBC), which have been associated earlier with alcohol‐induced genotype‐specific changes in placental tissue.MethodsMicroarray‐based comparative genomic hybridization (aCGH) was used to detect potential submicroscopic chromosomal abnormalities, and developmental as well as phenotypic information about twins were collected. Traditional bisulfite sequencing was used for DNA methylation analysis.ResultsMicroarray‐based comparative genomic hybridization revealed a microdeletion 18q12.3‐q21.1. in affected twin, residing in a known 18q deletion syndrome region. This syndrome has been associated with growth restriction, developmental delay or intellectual deficiency, and abnormal facial features in previous studies, and thus likely explains the phenotypic discordancy between the twins. We did not observe association between WBCs’ DNA methylation profile and PAE, but interestingly, a trend of decreased DNA methylation at the imprinting control region was seen in the twin with prenatal growth retardation at birth.ConclusionsThe microdeletion emphasizes the importance of adequate chromosomal testing in examining the etiology of complex alcohol‐induced developmental disorders. Furthermore, the genotype‐specific decreased DNA methylation at the IGF2/H19 locus cannot be considered as a biological mark for PAE in adult WBCs.
Highlights
Fetal alcohol spectrum disorders (FASDs) are a consequence of prenatal alcohol exposure (PAE), and an umbrella term for all alcohol-related neurodevelopmental disorders and birth defects
We observed a single-nucleotide polymorphism (SNP) rs10732516 (NC_000011.10:g.1999976G > A) at the regulation region of insulin-like growth factor 2 (IGF2) (OMIM *147,470)/H19 imprinted maternally expressed transcript (H19) (OMIM *103,280) locus which associates in parent-of-origin manner with altered placental DNA methylation and phenotype of alcohol-exposed newborns (Marjonen, Kahila, & Kaminen-Ahola, 2017)
We explored the effects of PAE on imprinted IGF2/H19 locus on chromosome 11p15.5 (Figure 1a)
Summary
Fetal alcohol spectrum disorders (FASDs) are a consequence of prenatal alcohol exposure (PAE), and an umbrella term for all alcohol-related neurodevelopmental disorders and birth defects. We observed a single-nucleotide polymorphism (SNP) rs10732516 (NC_000011.10:g.1999976G > A) at the regulation region of insulin-like growth factor 2 (IGF2) (OMIM *147,470)/H19 imprinted maternally expressed transcript (H19) (OMIM *103,280) locus which associates in parent-of-origin manner with altered placental DNA methylation and phenotype of alcohol-exposed newborns (Marjonen, Kahila, & Kaminen-Ahola, 2017). We saw an association between the genotype and head circumference (HC) of newborns, which is extremely interesting since the HC has been used in the diagnosis of FASD Both of the twins have this particular rs10732516 patA/matG genotype and we studied whether alcohol-induced genotype-specific decreased methylation level at IGF2/H19 locus could be detected in their white blood cells (WBCs). 3 months phenotype, we explored if similar decreased methylation level could be seen in addition to alcohol-exposed placentas (Marjonen et al, 2017) in twin B who had growth-restricted phenotype at birth
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