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

Publication ,  Journal Article
Padhi, EM; Hayeck, TJ; Cheng, Z; Chatterjee, S; Mannion, BJ; Byrska-Bishop, M; Willems, M; Pinson, L; Redon, S; Benech, C; Uguen, K; Férec, C ...
Published in: Hum Genomics
July 13, 2021

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.

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Published In

Hum Genomics

DOI

EISSN

1479-7364

Publication Date

July 13, 2021

Volume

15

Issue

1

Start / End Page

44

Location

England

Related Subject Headings

  • Transcription Factors
  • Neurons
  • Neurodevelopmental Disorders
  • Mutation
  • Muscle Hypotonia
  • Male
  • Humans
  • Genetics & Heredity
  • Genetic Predisposition to Disease
  • Gene Regulatory Networks
 

Citation

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Padhi, E. M., Hayeck, T. J., Cheng, Z., Chatterjee, S., Mannion, B. J., Byrska-Bishop, M., … Turner, T. N. (2021). Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism. Hum Genomics, 15(1), 44. https://doi.org/10.1186/s40246-021-00342-3
Padhi, Evin M., Tristan J. Hayeck, Zhang Cheng, Sumantra Chatterjee, Brandon J. Mannion, Marta Byrska-Bishop, Marjolaine Willems, et al. “Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism.Hum Genomics 15, no. 1 (July 13, 2021): 44. https://doi.org/10.1186/s40246-021-00342-3.
Padhi EM, Hayeck TJ, Cheng Z, Chatterjee S, Mannion BJ, Byrska-Bishop M, et al. Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism. Hum Genomics. 2021 Jul 13;15(1):44.
Padhi, Evin M., et al. “Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism.Hum Genomics, vol. 15, no. 1, July 2021, p. 44. Pubmed, doi:10.1186/s40246-021-00342-3.
Padhi EM, Hayeck TJ, Cheng Z, Chatterjee S, Mannion BJ, Byrska-Bishop M, Willems M, Pinson L, Redon S, Benech C, Uguen K, Audebert-Bellanger S, Le Marechal C, Férec C, Efthymiou S, Rahman F, Maqbool S, Maroofian R, Houlden H, Musunuri R, Narzisi G, Abhyankar A, Hunter RD, Akiyama J, Fries LE, Ng JK, Mehinovic E, Stong N, Allen AS, Dickel DE, Bernier RA, Gorkin DU, Pennacchio LA, Zody MC, Turner TN. Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism. Hum Genomics. 2021 Jul 13;15(1):44.
Journal cover image

Published In

Hum Genomics

DOI

EISSN

1479-7364

Publication Date

July 13, 2021

Volume

15

Issue

1

Start / End Page

44

Location

England

Related Subject Headings

  • Transcription Factors
  • Neurons
  • Neurodevelopmental Disorders
  • Mutation
  • Muscle Hypotonia
  • Male
  • Humans
  • Genetics & Heredity
  • Genetic Predisposition to Disease
  • Gene Regulatory Networks