Rare predicted deleterious FEZF2 variants are associated with a neurodevelopmental phenotype

Author:

Garber Alison1ORCID,Weingarten Lisa S.1ORCID,Abreu Nicolas J.2,Elloumi Houda Zghal3,Haack Tobias4,Hildebrant Clara5,Martínez‐Gil Núria67,Mathews Jennifer5,Müller Amelie Johanna4,Valenzuela Palafoll Irene67,Steigerwald Connolly2,Chung Wendy K.8

Affiliation:

1. Department of Pediatrics Columbia University New York New York USA

2. Department of Neurology NYU Grossman School of Medicine New York New York USA

3. GeneDx Gaithersburg Maryland USA

4. Institute of Medical Genetics and Applied Genomics, University of Tübingen Tübingen Germany

5. Department of Pediatrics University of North Carolina Chapel Hill North Carolina USA

6. Department of Clinical and Molecular Genetics Vall d'Hebron University Hospital Barcelona Spain

7. Medical Genetics Group, Vall d'Hebron Research Institute Barcelona Spain

8. Boston Children's Hospital, Harvard Medical School Boston Massachusetts USA

Abstract

AbstractFEZF2 encodes a transcription factor critical to neurodevelopment that regulates other neurodevelopment genes. Rare variants in FEZF2 have previously been suggested to play a role in autism, and cases of 3p14 microdeletions that include FEZF2 share a neurodevelopmental phenotype including mild dysmorphic features and intellectual disability. We identified seven heterozygous predicted deleterious variants in FEZF2 (three frameshifts, one recurrent missense in two independent cases, one nonsense, and one complete gene deletion) in unrelated individuals with neurodevelopmental disorders including developmental delay/intellectual disability, autism, and/or attention‐deficit/hyperactivity. Variants were confirmed to be de novo in five of seven cases and paternally inherited from an affected father in one. Predicted deleterious variants in FEZF2 may affect the expression of genes that are involved in fate choice pathways in developing neurons, and thus contribute to the neurodevelopmental phenotype. Future studies are needed to clarify the mechanism by which FEZF2 leads to this neurodevelopmental disorder.

Funder

National Institutes of Health

National Center for Advancing Translational Sciences

National Institute on Aging

Wellcome Trust

Ministerio de Ciencia e Innovación

Publisher

Wiley

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