Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism

Evin Padhi , Tristan Hayeck , Zhang Cheng (1) , Sumantra Chatterjee , Brandon Mannion , Marta Byrska-Bishop , Marjolaine Willems (2) , Lucile Pinson (3) , Sylvia Redon (4, 5) , Caroline Benech (6) , Kevin Uguen (4, 5) , Séverine Audebert-Bellanger (7) , Cédric Le Marechal (5) , Claude Férec (5) , Stephanie Efthymiou (8) , Fatima Rahman (9, 10) , Shazia Maqbool (9, 10) , Reza Maroofian (8) , Henry Houlden (8) , Rajeeva Musunuri , Giuseppe Narzisi , Avinash Abhyankar (11) , Riana Hunter , Jennifer Akiyama , Lauren Fries , Jeffrey Ng , Elvisa Mehinovic , Nick Stong , Andrew Allen (12, 13) , Diane Dickel , Raphael Bernier (14, 15) , David Gorkin , Len Pennacchio , Michael Zody , Tychele Turner

1 USF - University of South Florida [Tampa]
2 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
3 Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier]
4 CHRU Brest - Centre Hospitalier Régional Universitaire de Brest
5 GGB - Génétique, génomique fonctionnelle et biotechnologies (UMR 1078)
6 EFS
7 Hôpital Morvan [Brest]
8 UCL - University College of London [London]
9 Children's Hospital [Lahore]
10 Institute of Child Health [Lahore]
11 New York Genome Center [New York]
12 SIO - UC San Diego - Scripps Institution of Oceanography
13 J. Craig Venter Institute
14 University of Washington [Seattle]
15 Children's Autism Center [Seattle, WA, USA]

Background: Previous 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. Results; We 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. Conclusions: In 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.

Mots clés: Autism; De novo; EBF3; Enhancer; Gene regulatory network; Genome; Neurodevelopmental disorder; Variant; hs737

Domaines: Sciences du Vivant [q-bio]; Génétique humaine

Evin Padhi, Tristan Hayeck, Zhang Cheng, Sumantra Chatterjee, Brandon Mannion, et al.. Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism. Human Genomics, 2021, 15 (1), pp.44. ⟨10.1186/s40246-021-00342-3⟩. ⟨hal-03617853⟩