Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Mirzaa GM

PROVIDER: S-EPMC7060121 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Mirzaa Ghayda M GM Chong Jessica X JX Piton Amélie A Popp Bernt B Foss Kimberly K Guo Hui H Harripaul Ricardo R Xia Kun K Scheck Joshua J Aldinger Kimberly A KA Sajan Samin A SA Tang Sha S Bonneau Dominique D Beck Anita A White Janson J Mahida Sonal S Harris Jacqueline J Smith-Hicks Constance C Hoyer Juliane J Zweier Christiane C Reis André A Reis André A Thiel Christian T CT Jamra Rami Abou RA Zeid Natasha N Yang Amy A Farach Laura S LS Walsh Laurence L Payne Katelyn K Rohena Luis L Velinov Milen M Ziegler Alban A Schaefer Elise E Gatinois Vincent V Geneviève David D Simon Marleen E H MEH Kohler Jennefer J Rotenberg Joshua J Wheeler Patricia P Larson Austin A Ernst Michelle E ME Akman Cigdem I CI Westman Rachel R Blanchet Patricia P Schillaci Lori-Anne LA Vincent-Delorme Catherine C Gripp Karen W KW Mattioli Francesca F Guyader Gwenaël Le GL Gerard Bénédicte B Mathieu-Dramard Michèle M Morin Gilles G Sasanfar Roksana R Ayub Muhammad M Vasli Nasim N Yang Sandra S Person Rick R Monaghan Kristin G KG Nickerson Deborah A DA van Binsbergen Ellen E Enns Gregory M GM Dries Annika M AM Rowe Leah J LJ Tsai Anne C H ACH Svihovec Shayna S Friedman Jennifer J Agha Zehra Z Qamar Raheel R Rodan Lance H LH Martinez-Agosto Julian J Ockeloen Charlotte W CW Vincent Marie M Sunderland William James WJ Bernstein Jonathan A JA Eichler Evan E EE Vincent John B JB Bamshad Michael J MJ

Genetics in medicine : official journal of the American College of Medical Genetics 20191114 3

<h4>Purpose</h4>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).<h4>Methods</h4>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 ...[more]

PMID: 31723249

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Project description:BackgroundBoth de novo variants and recessive inherited variants were associated with autism spectrum disorder (ASD). This study aimed to use exome data to prioritize recessive inherited genes (RIGs) with biallelically inherited variants in autosomes or X-linked inherited variants in males and investigate the functional relationships between RIGs and genes with de novo variants (DNGs).MethodsWe used a bioinformatics pipeline to analyze whole-exome sequencing data from 1799 ASD quads (containing one proband, one unaffected sibling, and their parents) from the Simons Simplex Collection and prioritize candidate RIGs with rare biallelically inherited variants in autosomes or X-linked inherited variants in males. The relationships between RIGs and DNGs were characterized based on different genetic perspectives, including genetic variants, functional networks, and brain expression patterns.ResultsAmong the biallelically or hemizygous constrained genes that were expressed in the brain, ASD probands carried significantly more biallelically inherited protein-truncating variants (PTVs) in autosomes (p = 0.038) and X-linked inherited PTVs in males (p = 0.026) than those in unaffected siblings. We prioritized eight autosomal, and 13 X-linked candidate RIGs, including 11 genes already associated with neurodevelopmental disorders. In total, we detected biallelically inherited variants or X-linked inherited variants of these 21 candidate RIGs in 26 (1.4%) of 1799 probands. We then integrated previously reported known or candidate genes in ASD, ultimately obtaining 70 RIGs and 87 DNGs for analysis. We found that RIGs were less likely to carry multiple recessive inherited variants than DNGs were to carry multiple de novo variants. Additionally, RIGs and DNGs were significantly co-expressed and interacted with each other, forming a network enriched in known functional ASD clusters, although RIGs were less likely to be enriched in these functional clusters compared with DNGs. Furthermore, although RIGs and DNGs presented comparable expression patterns in the human brain, RIGs were less likely to be associated with prenatal brain regions, the middle cortical layers, and excitatory neurons than DNGs.LimitationsThe RIGs analyzed in this study require functional validation, and the results should be replicated in more patients with ASD.ConclusionsASD RIGs were functionally associated with DNGs; however, they exhibited higher heterogeneity than DNGs.

Dataset Information

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

Publications

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

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