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

Undiagnosed Diseases Network,; University of Washington Center for Mendelian Genomics (UW-CMG),

doi:10.1038/s41436-019-0693-9

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

Undiagnosed Diseases Network,
, University of Washington Center for Mendelian Genomics (UW-CMG),

Department of Pediatrics, Delaware Valley

National Institutes of Health
Department of Genome Sciences
University of Washington
Seattle Children’s Research Institute
Brotman Baty Institute for Precision Medicine
Université de Strasbourg
Friedrich-Alexander University Erlangen-Nürnberg
Central South University
Centre for Addiction & Mental Health (CAMH)
University of Toronto
Ambry Genetics
WuXi NextCODE
Université d'Angers
Institut national de la santé et de la recherche médicale
Kennedy Krieger Institute
Leipzig University
Yale New Haven Health System
Oregon Health and Science University
University of Texas Health Science Center at Houston
Indiana University Health
United States Army
University of Texas Health Science Center at San Antonio
New York State Office for People with Developmental Disabilities
Centre Hospitalier, France
Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée
CHU Montpellier
Université Montpellier
Utrecht University
Stanford University
Memorial Hermann Healthcare System
Orlando Regional Medical Center
University of Colorado School of Medicine
Columbia University
Division of Genetics
Case Western Reserve University
Université de Lille
Illkirch-Graffenstaden
CHU de Poitiers
CHU Amiens-Picardie

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

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.

Original language	English
Pages (from-to)	538-546
Number of pages	9
Journal	Genetics in Medicine
Volume	22
Issue number	3
DOIs	https://doi.org/10.1038/s41436-019-0693-9
State	Published - 1 Mar 2020

Keywords

ZNF292
autism spectrum disorders
exome sequencing
intellectual disability
next-generation sequencing

Access to Document

10.1038/s41436-019-0693-9

Cite this

@article{fbb0fd7ddbf74ff398320e8eeed089ae,

title = "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{\textendash}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.",

keywords = "ZNF292, autism spectrum disorders, exome sequencing, intellectual disability, next-generation sequencing",

author = "\{Undiagnosed Diseases Network,\} and \{University of Washington Center for Mendelian Genomics (UW-CMG),\} and Mirzaa, \{Ghayda M.\} and Chong, \{Jessica X.\} and Am{\'e}lie Piton and Bernt Popp and Kimberly Foss and Hui Guo and Ricardo Harripaul and Kun Xia and Joshua Scheck and Aldinger, \{Kimberly A.\} and Sajan, \{Samin A.\} and Sha Tang and Dominique Bonneau and Anita Beck and Janson White and Sonal Mahida and Jacqueline Harris and Constance Smith-Hicks and Juliane Hoyer and Christiane Zweier and Andr{\'e} Reis and Thiel, \{Christian T.\} and Jamra, \{Rami Abou\} and Natasha Zeid and Amy Yang and Farach, \{Laura S.\} and Laurence Walsh and Katelyn Payne and Luis Rohena and Milen Velinov and Alban Ziegler and Elise Schaefer and Vincent Gatinois and David Genevi{\`e}ve and Simon, \{Marleen E.H.\} and Jennefer Kohler and Joshua Rotenberg and Patricia Wheeler and Austin Larson and Ernst, \{Michelle E.\} and Akman, \{Cigdem I.\} and Rachel Westman and Patricia Blanchet and Schillaci, \{Lori Anne\} and Catherine Vincent-Delorme and Gripp, \{Karen W.\} and Francesca Mattioli and Guyader, \{Gwena{\"e}l Le\} and B{\'e}n{\'e}dicte Gerard and Mich{\`e}le Mathieu-Dramard",

note = "Publisher Copyright: {\textcopyright} 2019, American College of Medical Genetics and Genomics.",

year = "2020",

month = mar,

day = "1",

doi = "10.1038/s41436-019-0693-9",

language = "English",

volume = "22",

pages = "538--546",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier B.V.",

number = "3",

}

TY - JOUR

T1 - De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder

AU - Undiagnosed Diseases Network,

AU - University of Washington Center for Mendelian Genomics (UW-CMG),

AU - Mirzaa, Ghayda M.

AU - Chong, Jessica X.

AU - Piton, Amélie

AU - Popp, Bernt

AU - Foss, Kimberly

AU - Guo, Hui

AU - Harripaul, Ricardo

AU - Xia, Kun

AU - Scheck, Joshua

AU - Aldinger, Kimberly A.

AU - Sajan, Samin A.

AU - Tang, Sha

AU - Bonneau, Dominique

AU - Beck, Anita

AU - White, Janson

AU - Mahida, Sonal

AU - Harris, Jacqueline

AU - Smith-Hicks, Constance

AU - Hoyer, Juliane

AU - Zweier, Christiane

AU - Reis, André

AU - Thiel, Christian T.

AU - Jamra, Rami Abou

AU - Zeid, Natasha

AU - Yang, Amy

AU - Farach, Laura S.

AU - Walsh, Laurence

AU - Payne, Katelyn

AU - Rohena, Luis

AU - Velinov, Milen

AU - Ziegler, Alban

AU - Schaefer, Elise

AU - Gatinois, Vincent

AU - Geneviève, David

AU - Simon, Marleen E.H.

AU - Kohler, Jennefer

AU - Rotenberg, Joshua

AU - Wheeler, Patricia

AU - Larson, Austin

AU - Ernst, Michelle E.

AU - Akman, Cigdem I.

AU - Westman, Rachel

AU - Blanchet, Patricia

AU - Schillaci, Lori Anne

AU - Vincent-Delorme, Catherine

AU - Gripp, Karen W.

AU - Mattioli, Francesca

AU - Guyader, Gwenaël Le

AU - Gerard, Bénédicte

AU - Mathieu-Dramard, Michèle

PY - 2020/3/1

Y1 - 2020/3/1

N2 - 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.

AB - 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.

KW - ZNF292

KW - autism spectrum disorders

KW - exome sequencing

KW - intellectual disability

KW - next-generation sequencing

UR - https://www.scopus.com/pages/publications/85075030020

U2 - 10.1038/s41436-019-0693-9

DO - 10.1038/s41436-019-0693-9

M3 - Article

C2 - 31723249

AN - SCOPUS:85075030020

SN - 1098-3600

VL - 22

SP - 538

EP - 546

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 3

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this