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A de novo TOP2B variant associated with global developmental delay and autism spectrum disorder.

ABSTRACT: BACKGROUND:TOP2B encodes type II topoisomerase beta, which controls topological changes during DNA transcription. TOP2B is expressed in the developing nervous system and is involved in brain development and neural differentiation. Recently, a de novo missense TOP2B variant (c.187C>T) has been identified in an individual with neurodevelopmental disorder (NDD). However, the association between TOP2B variants and NDDs remains uncertain. METHODS:Trio-based whole-exome sequencing was performed on a 7-year-old girl, presenting muscle hypotonia, stereotypic hand movements, epilepsy, global developmental delay, and autism spectrum disorder. Brain magnetic resonance images were normal. She was unable to walk independently and spoke no meaningful words. RESULTS:We found a de novo variant in TOP2B (NM_001330700.1:c.187C>T, p.(His63Tyr)), which is identical to the previous case. The clinical features of the two individuals with the c.187C>T variant overlapped. CONCLUSION:Our study supports the finding that TOP2B variants may cause NDDs.

SUBMITTER: Hiraide T

PROVIDER: S-EPMC7057084 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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A de novo TOP2B variant associated with global developmental delay and autism spectrum disorder.

Hiraide Takuya T Watanabe Seiji S Matsubayashi Tomoko T Yanagi Kumiko K Nakashima Mitsuko M Ogata Tsutomu T Saitsu Hirotomo H

Molecular genetics & genomic medicine 20200117 3

<h4>Background</h4>TOP2B encodes type II topoisomerase beta, which controls topological changes during DNA transcription. TOP2B is expressed in the developing nervous system and is involved in brain development and neural differentiation. Recently, a de novo missense TOP2B variant (c.187C>T) has been identified in an individual with neurodevelopmental disorder (NDD). However, the association between TOP2B variants and NDDs remains uncertain.<h4>Methods</h4>Trio-based whole-exome sequencing was p ...[more]

PMID: 31953910

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Project description:Increasing evidence suggests that autism spectrum disorder (ASD) and many forms of developmental delay (DD) originate during fetal development. Preeclampsia may trigger aberrant neurodevelopment through placental, maternal, and fetal physiologic mechanisms.To determine whether preeclampsia is associated with ASD and/or DD.The Childhood Autism Risks from Genetics and the Environment (CHARGE) study is a population-based, case-control investigation of ASD and/or DD origins. Children from 20 California counties aged 24 to 60 months at the time of recruitment and living in catchment areas with a biological parent fluent in English or Spanish were enrolled from January 29, 2003, through April 7, 2011. Children with ASD (n?=?517) and DD (n?=?194) were recruited through the California Department of Developmental Services, the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, and referrals. Controls with typical development (TD) (n?=?350) were randomly selected from birth records and frequency matched on age, sex, and broad geographic region. Physicians diagnosing preeclampsia were masked to neurodevelopmental outcome, and those assessing neurodevelopmental function were masked to preeclampsia status.Preeclampsia and placental insufficiency were self-reported and abstracted from medical records.The Autism Diagnostic Observation Schedule and Autism Diagnostic Interview-Revised were used to confirm ASD, whereas children with DD and TD were confirmed by Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales and were free of autistic symptoms. Hypotheses were formulated before data collection.Children with ASD were twice as likely to have been exposed in utero to preeclampsia as controls with TD after adjustment for maternal educational level, parity, and prepregnancy obesity (adjusted odds ratio, 2.36; 95% CI, 1.18-4.68); risk increased with greater preeclampsia severity (test for trend, P?=?.02). Placental insufficiency appeared responsible for the increase in DD risk associated with severe preeclampsia (adjusted odds ratio, 5.49; 95% CI, 2.06-14.64).Preeclampsia, particularly severe disease, is associated with ASD and DD. Faulty placentation manifests in the mother as preeclampsia with vascular damage, enhanced systemic inflammation, and insulin resistance; in the placenta as oxygen and nutrient transfer restriction and oxidative stress; and in the fetus as growth restriction and progressive hypoxemia. All are potential mechanisms for neurodevelopmental compromise.

Dataset Information

A de novo TOP2B variant associated with global developmental delay and autism spectrum disorder.

Publications

A de novo TOP2B variant associated with global developmental delay and autism spectrum disorder.

Similar Datasets

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