De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder

Mirzaa GM, Chong JX, Piton A, Popp B, Foss K, Guo H, Harripaul R, Xia K, Scheck J, Aldinger KA, Sajan SA, Tang S, Bonneau D, Beck A, White J, Mahida S, Harris J, Smith-Hicks C, Hoyer J, Zweier C, Reis A, Thiel C, Jamra RA, Zeid N, Yang A, Farach LS, Walsh L, Payne K, Rohena L, Velinov M, Ziegler A, Schaefer E, Gatinois V, Geneviève D, Simon ME, Kohler J, Rotenberg J, Wheeler P, Larson A, Ernst ME, Akman CI, Westman R, Blanchet P, Schillaci LA, Vincent-Delorme C, Gripp KW, Mattioli F, Guyader GL, Gerard B, Mathieu-Dramard M, Morin G, Sasanfar R, Ayub M, Vasli N, Yang S, Person R, Monaghan KG, Nickerson DA, van Binsbergen E, Enns GM, Dries AM, Rowe LJ, Tsai AC, Svihovec S, Friedman J, Agha Z, Qamar R, Rodan LH, Martinez-Agosto J, Ockeloen CW, Vincent M, Sunderland WJ, Bernstein JA, Eichler EE, Vincent JB, Bamshad MJ (2019)

Publication Type: Journal article

Publication year: 2019


DOI: 10.1038/s41436-019-0693-9


Purpose: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292). Methods: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype–phenotype relationships. Results: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment. Conclusion: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.

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Involved external institutions

Universitätsklinikum Leipzig DE Germany (DE) Kennedy Krieger Institute US United States (USA) (US) Centre hospitalier universitaire (CHU) d'Angers FR France (FR) University of Washington US United States (USA) (US) Oregon Health and Science University (OSHU) US United States (USA) (US) Yale New Haven Health US United States (USA) (US) Center for Integrative Brain Research US United States (USA) (US) Central South University CN China (CN) University of Colorado Anschutz Medical Campus US United States (USA) (US) University of California Los Angeles (UCLA) US United States (USA) (US) Centre for Addiction and Mental Health (CAMH) CA Canada (CA) Nantes University Hospital / Centre hospitalier universitaire de Nantes (CHU) FR France (FR) Centre hospitalier universitaire de Poitiers (CHU de Poitiers) FR France (FR) UMass Memorial Health Care US United States (USA) (US) Stanford University US United States (USA) (US) San Antonio Military Health System US United States (USA) (US) WuXi NextCODE US United States (USA) (US) Centre Hospitalier Régional Universitaire de Lille (CHRU de Lille) FR France (FR) University Medical Centre Utrecht (UMC Utrecht) NL Netherlands (NL) Arnaud de Villeneuve FR France (FR) Département Génétique Médicale, Maladies rares et médecine personnalisée FR France (FR) University Hospitals of Cleveland / Case Western Reserve University Hospital US United States (USA) (US) Office of Mental Retardation and Developmental Disabilities US United States (USA) (US) University of Texas Health Science Center at Houston (UTHealth) US United States (USA) (US) Riley Hospital for Children at Indiana University Health US United States (USA) (US) Memorial Hermann US United States (USA) (US) DuPont DE Germany (DE) Institute of Genetics and Molecular and Cellular Biology / Institut de génétique et de biologie moléculaire et cellulaire (IGBMC) FR France (FR) Orlando Health Arnold Palmer Hospital for Children US United States (USA) (US) Columbia University US United States (USA) (US) GeneDX US United States (USA) (US) COMSATS University Islamabad (CUI) / / COMSATS Institute of Information Technology (CIIT) PK Pakistan (PK) Hôpitaux universitaires de Strasbourg (HUS) / University Hospital Strasbourg FR France (FR) Ambry Genetics US United States (USA) (US) Queen's University CA Canada (CA) Centre Hospitalier Universitaire Amiens-Picardie (CHU Amiens-Picardie) FR France (FR) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) NL Netherlands (NL) Boston Children's Hospital US United States (USA) (US) The Hospital for Sick Children (SickKids) CA Canada (CA)

How to cite


Mirzaa, G.M., Chong, J.X., Piton, A., Popp, B., Foss, K., Guo, H.,... Bamshad, M.J. (2019). De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder. Genetics in Medicine.


Mirzaa, Ghayda M., et al. "De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder." Genetics in Medicine (2019).

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