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Genetic Elucidation of Ultrasonography Fetal Anomalies in Children with Autism Spectrum Disorder
- O. Regev, A. Shil, T. Bronshtein, A. Hadar, G. Meiri, H. Flusser, A. Michaelovski, I. Dinshtein, R. Hershkovitz, I. Menashe
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- Journal:
- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, pp. S98-S99
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Introduction
Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder affecting 1-2% of the population worldwide. Recent large-scale whole-exome sequencing (WES) studies identified hundreds of rare, highly penetrant genetic variations associated with ASD. Many of these genetic variations underlie particular genetic syndromes characterized by a variety of congenital anomalies in addition to the core ASD symptoms. Recently, we reported about certain ultrasonography fetal anomalies (UFAs) associated with later development of ASD (Regev et al. Brain 2022).
ObjectivesTo identify genetic mutations associated with UFAs in children with ASD.
MethodsWe conducted a cross-sectional study of all children diagnosed with ASD registered at the Azrieli National Centre for Autism and Neurodevelopment (ANCAN) who have both fetal ultrasound and WES data. We used an integrative in-house bioinformatics pipeline specifically designated to identify gene-disrupting variants (GDVs) in a panel of >1200 genes associated with ASD according to SFARI gene database. Then, we compared the prevalence of GDVs in these genes between children with and without UFAs. Finally, we applied the Gene Analytics tool to disrupted genes in children with specific fetal anomalies to identify biological pathways associated with both ASD and these fetal anomalies.
ResultsOverall, 115 ASD children were included in this study, of which 49 (42.6%) of them had UFAs in their ultrasound scans (Figure 1). Children with and without UFAs did not differ in their sociodemographic and clinical characteristics except for a significantly lower proportion of males in the UFA group (63.4% vs. 84.8%, respectively; p=0.011). Notably, children with UFAs were more likely to carry GDVs in ASD genes than their counterparts even after adjustment to the sex differences between the groups (aOR=2.27, 95%CI: 1.05-4.93), and this association was the most prominent with GDVs in the most notable ASD genes (i.e., those with SFARI gene score=1). Also, the study shows higher prevalence of children with GDVs in most anatomical systems, with UFAs in fetal size (14.8% vs. 1.6%, p=0.012, cases vs. controls) and the head&brain (16.7% vs. 4.9%, p=0.040, cases vs. controls) being the most prominent (Figure 2). In addition, children with UFAs had significantly more co-occurring mutations, and the number of mutations in a single fetus was significantly correlated with the number of UFAs (r=0.20, p=0.035).
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ConclusionsOur findings suggest distinct genetic mechanisms for ASD subtypes that are characterized by unique UFAs. These findings may form a basis for future prenatal screening approaches for ASD using both ultrasound and genetic testing. Our findings suggest distinct genetic mechanisms for ASD subtypes that arecharacterized by unique UFAs. These findings may form a basis for future prenatal screening approaches for ASD using both ultrasound and genetic testing.
Disclosure of InterestNone Declared
Association between abnormal fetal head growth and autism spectrum disorder
- O. Regev, G. Cohen, A. Hadar, G. Meiri, H. Flusser, A. Michaelovski, I. Dinstein, R. Hershkovitz, I. Menashe
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- Journal:
- European Psychiatry / Volume 64 / Issue S1 / April 2021
- Published online by Cambridge University Press:
- 13 August 2021, pp. S130-S131
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Introduction
Despite evidence for the prenatal onset of abnormal head growth in ASD children, studies on fetal ultrasound data in ASD are limited and controversial.
ObjectivesTo understand whether people with ASD have abnormal head growth during gestation
MethodsA longitudinal matched case-sibling-control study on prenatal ultrasound biometric measures of ASD children was conducted. Children with ASD were matched to two control groups: (1) typically developed sibling (TDS) and (2) typically developed population (TDP). The cohort comprised 528 children (72.7% males): 174 ASD, 178 TDS, and 176 TDP.
ResultsSecond-trimester ASD and TDS fetuses had significantly smaller biparietal diameter (BPD) than TDP fetuses (aORzBPD=0.685, 95%CI=0.527-0.890 and aORzBPD=0.587, 95%CI=0.459-0.751, respectively). However, these differences became statistically indistinguishable in the third trimester. Head biometric measures were associated with the sex of the fetus, with males having larger heads than females within and across groups. A linear mixed-effect model assessing the effects of sex and group assignment on fetal longitudinal head growth indicated faster BPD growth in TDS vs both ASD and TDP in males (β=0.084 and β=0.100 respectively; p<0.001) but not in females, suggesting an ASD–sex interaction in head growth during gestation. Fetal head shape showed sex-specific characteristics, and head growth was inversely correlated with ASD severity in males and females, thus further supporting the sex effect on the association between fetal head growth and ASD.
ConclusionsOur findings suggest that abnormal fetal head growth is a familial trait of ASD, which is modulated by sex and is associated with the severity of the disorder.
DisclosureNo significant relationships.