학술논문

Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism
Document Type
article
Source
Human Genomics. 15(1)
Subject
Biological Sciences
Genetics
Mental Health
Human Genome
Intellectual and Developmental Disabilities (IDD)
Autism
Pediatric
Neurosciences
Clinical Research
Brain Disorders
1.1 Normal biological development and functioning
Underpinning research
Aetiology
2.1 Biological and endogenous factors
Mental health
Neurological
Autistic Disorder
Enhancer Elements
Genetic
Exome
Female
Gene Regulatory Networks
Genetic Predisposition to Disease
Humans
Male
Muscle Hypotonia
Mutation
Neurodevelopmental Disorders
Neurons
Transcription Factors
Neurodevelopmental disorder
Enhancer
Gene regulatory network
EBF3
hs737
Genome
Variant
De novo
Genetics & Heredity
Biochemistry and cell biology
Language
Abstract
BackgroundPrevious research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of protein-coding (coding) de novo variants (DNVs) within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2671 families with autism (discovery cohort of 516 families, replication cohort of 2155 families). We focused on DNVs in enhancers with characterized in vivo activity in the brain and identified an excess of DNVs in an enhancer named hs737.ResultsWe adapted the fitDNM statistical model to work in noncoding regions and tested enhancers for excess of DNVs in families with autism. We found only one enhancer (hs737) with nominal significance in the discovery (p = 0.0172), replication (p = 2.5 × 10-3), and combined dataset (p = 1.1 × 10-4). Each individual with a DNV in hs737 had shared phenotypes including being male, intact cognitive function, and hypotonia or motor delay. Our in vitro assessment of the DNVs showed they all reduce enhancer activity in a neuronal cell line. By epigenomic analyses, we found that hs737 is brain-specific and targets the transcription factor gene EBF3 in human fetal brain. EBF3 is genome-wide significant for coding DNVs in NDDs (missense p = 8.12 × 10-35, loss-of-function p = 2.26 × 10-13) and is widely expressed in the body. Through characterization of promoters bound by EBF3 in neuronal cells, we saw enrichment for binding to NDD genes (p = 7.43 × 10-6, OR = 1.87) involved in gene regulation. Individuals with coding DNVs have greater phenotypic severity (hypotonia, ataxia, and delayed development syndrome [HADDS]) in comparison to individuals with noncoding DNVs that have autism and hypotonia.ConclusionsIn this study, we identify DNVs in the hs737 enhancer in individuals with autism. Through multiple approaches, we find hs737 targets the gene EBF3 that is genome-wide significant in NDDs. By assessment of noncoding variation and the genes they affect, we are beginning to understand their impact on gene regulatory networks in NDDs.