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

TitleDe novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder.
Publication TypeJournal Article
Year of Publication2020
AuthorsMirzaa, 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, CT, Jamra, RAbou, Zeid, N, Yang, A, Farach, LS, Walsh, L, Payne, K, Rohena, L, Velinov, M, Ziegler, A, Schaefer, E, Gatinois, V, Geneviève, D, Simon, MEH, Kohler, J, Rotenberg, J, Wheeler, P, Larson, A, Ernst, ME, Akman, CI, Westman, R, Blanchet, P, Schillaci, L-A, Vincent-Delorme, C, Gripp, KW, Mattioli, F, Le Guyader, G, 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, ACH, Svihovec, S, Friedman, J, Agha, Z, Qamar, R, Rodan, LH, Martinez-Agosto, J, Ockeloen, CW, Vincent, M, Sunderland, WJames, Bernstein, JA, Eichler, EE, Vincent, JB, Bamshad, MJ
Corporate AuthorsUndiagnosed Diseases Network,, University of Washington Center for Mendelian Genomics (UW-CMG),
JournalGenet Med
Volume22
Issue3
Pagination538-546
Date Published2020 Mar
ISSN1530-0366
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.

DOI10.1038/s41436-019-0693-9
Alternate JournalGenet. Med.
PubMed ID31723249
PubMed Central IDPMC7060121
Grant ListUM1 HL098162 / HL / NHLBI NIH HHS / United States
U01 HG007690 / HG / NHGRI NIH HHS / United States
UM1 HL098123 / HL / NHLBI NIH HHS / United States
U01 HG007674 / HG / NHGRI NIH HHS / United States
U01 HG007672 / HG / NHGRI NIH HHS / United States
K08 NS092898 / NS / NINDS NIH HHS / United States
K08NS092898 / NS / NINDS NIH HHS / United States
UL1 TR001085 / TR / NCATS NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
UM1 HL128711 / HL / NHLBI NIH HHS / United States
UM1 HL098147 / HL / NHLBI NIH HHS / United States
U01 HG007942 / HG / NHGRI NIH HHS / United States
U01 HL131003 / HL / NHLBI NIH HHS / United States
U01 HG007708 / HG / NHGRI NIH HHS / United States
U01 TR001395 / TR / NCATS NIH HHS / United States
U01 HG007709 / HG / NHGRI NIH HHS / United States
31671114 / / the Agence de la Biomédecine and the CREGEMES, the Canadian Institutes of Health Research /
U01 HG010218 / HG / NHGRI NIH HHS / United States
UM1 HL128761 / HL / NHLBI NIH HHS / United States
U01 HG007943 / HG / NHGRI NIH HHS / United States
U54 NS093793 / NS / NINDS NIH HHS / United States
U01 HG007530 / HG / NHGRI NIH HHS / United States
U24 HG008956 / HG / NHGRI NIH HHS / United States
U01 HG007703 / HG / NHGRI NIH HHS / United States
R01 MH101221 / MH / NIMH NIH HHS / United States