Mutations in EBF3 disturb transcriptional profiles and underlie a novel syndrome of intellectual disability, ataxia and facial dysmorphism

Frederike Leonie Harms; Katta Mohan Girisha; Andrew Alexander Hardigan; Fanny Kortum; Anju Shukla; Malik Alawi; Ashwin Dalal; Lauren Brady; Mark Tarnopolsky; Lynne M. Bird; Sophia Ceulemans; Martina Bebin; Kevin M. Bowling; Susan M. Hiatt; Edward J. Lose; Michelle Primiano; Wendy K. Chung; Jane Juusola; Zeynep C. Akdemir; Matthew Bainbridge; Wu-Lin Charng; Margaret Drummond-Borg; Mohammad K. Eldomery; Ayman W. El-Hattab; Mohammed A.M. Saleh; Stephane Bezieau; Benjamin Cogne; Bertrand Isidor; Sebastien Kury; James R. Lupski; Richard M. Myers; Gregory M. Cooper; Kerstin Kutsche

doi:10.1101/067454

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bioRxiv · 10.1101/067454

Mutations in EBF3 disturb transcriptional profiles and underlie a novel syndrome of intellectual disability, ataxia and facial dysmorphism

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Abstract

From a GeneMatcher-enabled international collaboration, we identified ten individuals with intellectual disability, speech delay, ataxia and facial dysmorphism and a mutation in EBF3, encoding a transcription factor required for neuronal differentiation. Structural assessments, transactivation assays, in situ fractionation, RNA-seq and ChlP-seq experiments collectively show that the mutations are deleterious and impair EBF3 transcriptional regulation. These findings demonstrate that EBF3-mediated dysregulation of gene expression has profound effects on neuronal development in humans.

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Frederike Leonie Harms, Katta Mohan Girisha, Andrew Alexander Hardigan, Fanny Kortum, Anju Shukla, Malik Alawi, Ashwin Dalal, Lauren Brady, Mark Tarnopolsky, Lynne M. Bird, Sophia Ceulemans, Martina Bebin, Kevin M. Bowling, Susan M. Hiatt, Edward J. Lose, Michelle Primiano, Wendy K. Chung, Jane Juusola, Zeynep C. Akdemir, Matthew Bainbridge, Wu-Lin Charng, Margaret Drummond-Borg, Mohammad K. Eldomery, Ayman W. El-Hattab, Mohammed A.M. Saleh, Stephane Bezieau, Benjamin Cogne, Bertrand Isidor, Sebastien Kury, James R. Lupski, Richard M. Myers, Gregory M. Cooper, Kerstin Kutsche. 2016-08-03. Mutations in EBF3 disturb transcriptional profiles and underlie a novel syndrome of intellectual disability, ataxia and facial dysmorphism. https://doi.org/10.1101/067454

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