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).
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.
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.
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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We thank the families and referring physicians for their participation in this study. We also thank people from the Unit of Molecular Genetics and the Centre National de Recherche en Génomique Humaine, especially Claire Feger, Elsa Nourrisson, and Céline Cuny for the library preparation, DNA sequencing, and bioinformatics analysis for respective individuals. Analysis of ES data performed at the UW-CMG was funded by NHGRI and NHLBI grants UM1 HG006493 and U24 HG008956 (to D.A.N. and M.J.B.). This work was supported by grants U01HL131003, UM1HL098147, UM1HL098123, UM1HL128761, UM1HL128711, and UM1HL098162 in support of the Pediatric Cardiac Genomics Consortium from the National Heart, Lung, and Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (to D.A.N., and M.J.B.); the Intramural Research Program of the NHGRI and by the National Institutes of Health (NIH) through the Office of Strategic Coordination and Office of the NIH Director under award numbers U01 HG007708, U01 HG007709, U01 HG007703, U01 HG007530, U01 HG007942, U01 HG007690, U01 HG007674, U01 HG007672, U01 TR001395, U01 HG007943, and U54 NS093793, the Stanford Clinical and Translational Science Award (CTSA) to Spectrum (UL1 TR001085); the Center for Addiction and Mental Health (CAMH) Foundation (to J.V.); a National Alliance for Research on Schizophrenia & Depression (NARSAD) New Investigator Award (to N.V.); a Peterborough K.M. Hunter Charitable Foundation Graduate Scholarship (to R.H.); the Special Education Organization of Iran for additional support for family recruitment (to R.S.); the Deutsche Forschungsgemeinschaft (DFG) grant ZW184/6–1 (to C.Z.); the DFG grant PO2366/2–1 (to B.P.); the Agence de la Biomédecine and the CREGEMES, the Canadian Institutes of Health Research (MOP-102758) (to J.B.V.); the National Natural Science Foundation of China (31671114) (to H.G.); the DFG393/2–2 award (to R.A.J.); the National Natural Science Foundation of China (81525007) (to K.X.); the National Institute of Neurological Disorders and Stroke (NINDS) grant K08NS092898 (to G.M.M.); NIH R01 MH101221 (to E.E.E.); and Jordan’s Guardian Angels (to G.M.M.). E.E.E. is an investigator of the Howard Hughes Medical Institute. Members of the Undiagnosed Disease Network (UDN) are listed in the Supplementary Data.
S.Y., R.P., and K.G.M. are employees of GeneDx, Inc., a wholly owned subsidiary of OPKO Health, Inc. E.E.E. is on the scientific advisory board (SAB) of DNAnexus, Inc. J.F.’s spouse is founder and principal of Friedman Bioventure, which holds a variety of publicly traded and private biotechnology interests. The other authors declare no conflicts of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Mirzaa, G.M., Chong, J.X., Piton, A. et al. De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder. Genet Med (2019) doi:10.1038/s41436-019-0693-9
- intellectual disability
- autism spectrum disorders
- next-generation sequencing
- exome sequencing