De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder
2 Détoxication et réparation tissulaire
3 HUS - Hôpitaux Universitaires de Strasbourg
4 FAU - Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg
5 University of Washington [Seattle]
6 Central South University [Changsha]
7 CAMH - Centre for Addiction and Mental Health [Toronto]
8 Center for Integrative Brain Research
9 Ambry Genetics [Aliso Viejo, CA, USA]
10 CAU - China Agricultural University
11 BNMI - Biologie Neurovasculaire et Mitochondriale Intégrée
12 CHU Angers - Centre Hospitalier Universitaire d'Angers
13 Washington University School of Medicine in St. Louis
14 Kennedy Krieger Institute [Baltimore]
15 Institute of Human Genetics [Erlangen, Allemagne]
16 Leipzig University / Universität Leipzig
17 Yale University [New Haven]
18 OHSU - Oregon Health and Science University [Portland]
19 IUPUI - Indiana University - Purdue University Indianapolis
20 Indiana University [South Bend]
21 UTSA - The University of Texas at San Antonio
22 New York State Psychiatric Institute
23 Service de génétique médicale
24 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]
25 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
26 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
27 UMCU - University Medical Center [Utrecht]
28 Stanford University
29 UCF - University of Central Florida [Orlando]
30 UC San Diego - Department of Pediatrics [Univ California San Diego]
31 University of Colorado Anschutz Medical Campus [Aurora]
32 CUIMC - Columbia University Irving Medical Center
33 Signal Processing Lab [Boise - Idaho]
34 UH Cleveland Medical Center - University Hospitals Case Medical Center
35 Hôpital Jeanne de Flandres
36 Department of Psychology [University North Carolina Wilmington]
37 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
38 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
39 Service d'hématologie et immunologie
40 Unité de génétique médicale et oncogénétique [CHU Amiens Picardie]
41 IHTP - Institut d'histoire du temps présent
42 UMASS - University of Massachusetts Medical School [Worcester]
43 Queen's University [Kingston, Canada]
44 Department of Molecular Genetics [Toronto]
45 GeneDx [Gaithersburg, MD, USA]
46 GS - Department of Genome Sciences [Seattle]
47 Department of Pediatrics [Stanford]
48 Stanford School of Medicine [Stanford]
49 UC San Diego - University of California [San Diego]
50 CIIT - COMSATS Institute of Information Technology [Islamabad]
51 Boston Children's Hospital
52 UCLA - University of California [Los Angeles]
53 RadboudUMC - Radboud University Medical Center [Nijmegen]
54 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
55 Department of Psychiatry
56 Seattle University [Seattle]
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Résumé
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.