. 2020 Mar;22(3):538-546.

doi: 10.1038/s41436-019-0693-9. Epub 2019 Nov 14.

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

Ghayda M Mirzaa^{1

2

3}, Jessica X Chong^{4

5}, Amélie Piton^{6

7}, Bernt Popp⁸, Kimberly Foss⁹, Hui Guo¹⁰, Ricardo Harripaul^{11

12}, Kun Xia¹⁰, Joshua Scheck⁹, Kimberly A Aldinger⁹, Samin A Sajan¹³, Sha Tang¹⁴, Dominique Bonneau^{15

16}, Anita Beck⁴, Janson White¹⁷, Sonal Mahida¹⁸, Jacqueline Harris¹⁸, Constance Smith-Hicks¹⁸, Juliane Hoyer⁸, Christiane Zweier⁸, André Reis⁸, Christian T Thiel⁸, Rami Abou Jamra¹⁹, Natasha Zeid²⁰, Amy Yang²¹, Laura S Farach²², Laurence Walsh²³, Katelyn Payne²³, Luis Rohena^{24

25}, Milen Velinov²⁶, Alban Ziegler^{15

27}, Elise Schaefer²⁸, Vincent Gatinois^{29

30

31}, David Geneviève^{29

30

31}, Marleen E H Simon³², Jennefer Kohler³³, Joshua Rotenberg³⁴, Patricia Wheeler³⁵, Austin Larson³⁶, Michelle E Ernst³⁷, Cigdem I Akman^{37

38}, Rachel Westman³⁹, Patricia Blanchet³⁰, Lori-Anne Schillaci⁴⁰, Catherine Vincent-Delorme⁴¹, Karen W Gripp⁴², Francesca Mattioli⁴³, Gwenaël Le Guyader⁴⁴, Bénédicte Gerard⁶, Michèle Mathieu-Dramard⁴⁵, Gilles Morin⁴⁶, Roksana Sasanfar⁴⁶, Muhammad Ayub⁴⁷, Nasim Vasli⁴⁸, Sandra Yang⁴⁹, Rick Person⁴⁹, Kristin G Monaghan⁴⁹, Deborah A Nickerson¹⁷, Ellen van Binsbergen³², Gregory M Enns^{33

50}, Annika M Dries³³, Leah J Rowe³⁶, Anne C H Tsai³⁶, Shayna Svihovec³⁶, Jennifer Friedman^{51

52}, Zehra Agha⁵³, Raheel Qamar⁵³, Lance H Rodan^{54

55}, Julian Martinez-Agosto⁵⁶, Charlotte W Ockeloen⁵⁷, Marie Vincent⁵⁸, William James Sunderland⁵⁹, Jonathan A Bernstein^{33

50}; Undiagnosed Diseases Network,; Evan E Eichler^{17

60}, John B Vincent^{11

12}; University of Washington Center for Mendelian Genomics (UW-CMG),; Michael J Bamshad^{4

5}

Affiliations

¹ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA. ghayda.mirzaa@seattlechildrens.org.
² Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA. ghayda.mirzaa@seattlechildrens.org.
³ Brotman Baty Institute for Precision Medicine, Seattle, Washington, USA. ghayda.mirzaa@seattlechildrens.org.
⁴ Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
⁵ Brotman Baty Institute for Precision Medicine, Seattle, Washington, USA.
⁶ Molecular Genetic Unit, Strasbourg University Hospital, Strasbourg, France.
⁷ Institute of Genetics and Molecular and Cellular Biology, Université de Strasbourg, Illkirch, France.
⁸ Institute of Human Genetics, University Hospital Elrangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
⁹ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
¹⁰ Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
¹¹ The Campbell Family Mental Health Research Institute, Centre for Addiction & Mental Health (CAMH), Toronto, ON, Canada.
¹² Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
¹³ Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA.
¹⁴ WuXi NextCODE, Cambridge, MA, USA.
¹⁵ Département de Biochimie et de Génétique, CHU d'Angers, Angers, France.
¹⁶ UMR INSERM 1083 CNRS 6015, Angers, France.
¹⁷ Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
¹⁸ Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
¹⁹ Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany.
²⁰ Yale New Haven Health, New Haven, CT, USA.
²¹ Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
²² Department of Pediatrics, McGovern Medical School at the University of Texas Health Sciences Center, Houston, TX, USA.
²³ Indiana University Health at Riley Hospital for Children, Indianapolis, IN, USA.
²⁴ Division of Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, TX, USA.
²⁵ Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
²⁶ New York State Institute for Basic Research in Developmental Disability, NY, Staten Island, USA.
²⁷ Service de Génétique Médicale, Centre hospitalier, Le Mans, France.
²⁸ Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Institut de Génétique Médicale d'Alsace, Strasbourg, France.
²⁹ Service de génétique clinique, Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Strasbourg, France.
³⁰ Centre de Référence Maladies Rares Anomalies du Développement et Syndromes Malformatifs Sud-Ouest Occitanie Réunion, Hôpital Arnaud de Villeneuve, Montpellier, France.
³¹ Université Montpellier, Unité Inserm U1183, Montpellier, France.
³² Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
³³ Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA, USA.
³⁴ Memorial Hermann Memorial City Medical Center, Houston, TX, USA.
³⁵ Arnold Palmer Hospital for Children, Orlando, FL, USA.
³⁶ Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA.
³⁷ Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.
³⁸ Division of Pediatric Neurology, Columbia University Irving Medical Center, New York, NY, USA.
³⁹ Division of Genetics, St. Luke's Clinic, Boise, ID, USA.
⁴⁰ Department of Genetics and Genome Sciences, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
⁴¹ Service de Génétique Clinique Guy Fontaine Centre de référence maladies rares Anomalies du dévelopement, Hôpital Jeanne de Flandre Lille, Lille, France.
⁴² Department of Pediatrics, AI duPont Hospital, DE, Wilmington, USA.
⁴³ Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch-Graffenstaden, Lille, France.
⁴⁴ Service de Génétique Clinique, Centre de compétence Maladies rares Anomalies du dévelopement, CHU de Poitiers, Poitiers, France.
⁴⁵ Service de Génétique Clinique Centre de référence maladies rares Anomalies du dévelopement, CHU Amiens-Picardie, Amiens, France.
⁴⁶ Children's Medical Center, UMass Memorial Medical Center, Worcester, MA, USA.
⁴⁷ Department of Psychiatry, Queen's University, Kingston, ON, Canada.
⁴⁸ Division of Clinical & Metabolic Genetics, Hospital for Sick Children, Toronto, ON, Canada.
⁴⁹ GeneDx, Gaithersburg, MD, USA.
⁵⁰ Division of Medical Genetics, Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University, Stanford, CA, USA.
⁵¹ Departments of Neurosciences and Pediatrics, University of California San Diego and Division of Neurology, Rady Children's Hospital, San Diego, CA, USA.
⁵² Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
⁵³ Department of Biosciences, COMSATS University, Islamabad, Pakistan.
⁵⁴ Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁵⁵ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁵⁶ David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
⁵⁷ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
⁵⁸ CHU de Nantes, Service de génétique médicale, Nantes, France.
⁵⁹ University of Washington Foundation Board, University of Washington, Seattle, WA, USA.
⁶⁰ Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.

PMID: 31723249
PMCID: PMC7060121
DOI: 10.1038/s41436-019-0693-9

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

Ghayda M Mirzaa et al. Genet Med. 2020 Mar.

. 2020 Mar;22(3):538-546.

doi: 10.1038/s41436-019-0693-9. Epub 2019 Nov 14.

Authors

Affiliations

¹ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA. ghayda.mirzaa@seattlechildrens.org.
² Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA. ghayda.mirzaa@seattlechildrens.org.
³ Brotman Baty Institute for Precision Medicine, Seattle, Washington, USA. ghayda.mirzaa@seattlechildrens.org.
⁴ Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
⁵ Brotman Baty Institute for Precision Medicine, Seattle, Washington, USA.
⁶ Molecular Genetic Unit, Strasbourg University Hospital, Strasbourg, France.
⁷ Institute of Genetics and Molecular and Cellular Biology, Université de Strasbourg, Illkirch, France.
⁸ Institute of Human Genetics, University Hospital Elrangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
⁹ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
¹⁰ Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
¹¹ The Campbell Family Mental Health Research Institute, Centre for Addiction & Mental Health (CAMH), Toronto, ON, Canada.
¹² Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
¹³ Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA.
¹⁴ WuXi NextCODE, Cambridge, MA, USA.
¹⁵ Département de Biochimie et de Génétique, CHU d'Angers, Angers, France.
¹⁶ UMR INSERM 1083 CNRS 6015, Angers, France.
¹⁷ Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
¹⁸ Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
¹⁹ Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany.
²⁰ Yale New Haven Health, New Haven, CT, USA.
²¹ Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
²² Department of Pediatrics, McGovern Medical School at the University of Texas Health Sciences Center, Houston, TX, USA.
²³ Indiana University Health at Riley Hospital for Children, Indianapolis, IN, USA.
²⁴ Division of Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, TX, USA.
²⁵ Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
²⁶ New York State Institute for Basic Research in Developmental Disability, NY, Staten Island, USA.
²⁷ Service de Génétique Médicale, Centre hospitalier, Le Mans, France.
²⁸ Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Institut de Génétique Médicale d'Alsace, Strasbourg, France.
²⁹ Service de génétique clinique, Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Strasbourg, France.
³⁰ Centre de Référence Maladies Rares Anomalies du Développement et Syndromes Malformatifs Sud-Ouest Occitanie Réunion, Hôpital Arnaud de Villeneuve, Montpellier, France.
³¹ Université Montpellier, Unité Inserm U1183, Montpellier, France.
³² Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
³³ Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA, USA.
³⁴ Memorial Hermann Memorial City Medical Center, Houston, TX, USA.
³⁵ Arnold Palmer Hospital for Children, Orlando, FL, USA.
³⁶ Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA.
³⁷ Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.
³⁸ Division of Pediatric Neurology, Columbia University Irving Medical Center, New York, NY, USA.
³⁹ Division of Genetics, St. Luke's Clinic, Boise, ID, USA.
⁴⁰ Department of Genetics and Genome Sciences, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
⁴¹ Service de Génétique Clinique Guy Fontaine Centre de référence maladies rares Anomalies du dévelopement, Hôpital Jeanne de Flandre Lille, Lille, France.
⁴² Department of Pediatrics, AI duPont Hospital, DE, Wilmington, USA.
⁴³ Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch-Graffenstaden, Lille, France.
⁴⁴ Service de Génétique Clinique, Centre de compétence Maladies rares Anomalies du dévelopement, CHU de Poitiers, Poitiers, France.
⁴⁵ Service de Génétique Clinique Centre de référence maladies rares Anomalies du dévelopement, CHU Amiens-Picardie, Amiens, France.
⁴⁶ Children's Medical Center, UMass Memorial Medical Center, Worcester, MA, USA.
⁴⁷ Department of Psychiatry, Queen's University, Kingston, ON, Canada.
⁴⁸ Division of Clinical & Metabolic Genetics, Hospital for Sick Children, Toronto, ON, Canada.
⁴⁹ GeneDx, Gaithersburg, MD, USA.
⁵⁰ Division of Medical Genetics, Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University, Stanford, CA, USA.
⁵¹ Departments of Neurosciences and Pediatrics, University of California San Diego and Division of Neurology, Rady Children's Hospital, San Diego, CA, USA.
⁵² Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
⁵³ Department of Biosciences, COMSATS University, Islamabad, Pakistan.
⁵⁴ Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁵⁵ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁵⁶ David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
⁵⁷ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
⁵⁸ CHU de Nantes, Service de génétique médicale, Nantes, France.
⁵⁹ University of Washington Foundation Board, University of Washington, Seattle, WA, USA.
⁶⁰ Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.

PMID: 31723249
PMCID: PMC7060121
DOI: 10.1038/s41436-019-0693-9

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.

Keywords: ZNF292; autism spectrum disorders; exome sequencing; intellectual disability; next-generation sequencing.

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Conflict of interest statement

Conflict of interest notification page

Sandra Yang, Rick Person, and Kristin G. Monaghan are employees of GeneDx, Inc., a wholly owned subsidiary of OPKO Health, Inc. Evan E. Eichler. is on the scientific advisory board (SAB) of DNAnexus, Inc. Jennifer Friedman’s spouse is founder and principal of Friedman Bioventure which holds a variety of publicly traded and private biotechnology interests. The remaining authors have no competing financial interests.

Figures

**Figure 1.. Genomic structure and distribution of variants in *ZNF292*.**
Most of the identified variants in *ZNF292* are truncating (frameshift, nonsense) located within the largest and most terminal exon (8) of the gene that encodes a ZNF292 DNA binding domain. Several of these variants lie within zinc finger regions (depicted in gray) and coiled coil domains (depicted in pink) upstream of the nuclear localization signal (NLS, depicted in black). The cDNA panel shows the coding and non-coding regions of the gene (in blue and yellow, respectively). The bottom panel shows the predicted protein domains including the zinc finger (C2H2 type) regions (shown in gray), the coiled coil domain (pink) and the nuclear localization signal (black). *ZNF292* variants in the main cohort are shown, color-coded by type with nonsense variants shown in yellow, and frameshift variants in green. C-terminal coiled coil regions were calculated using multicoil2 (http://cb.csail.mit.edu/cb/multicoil2/cgi-bin/multicoil2.cgi), and NLS regions were mapped using cNLS mapper (http://nls-mapper.iab.keio.ac.jp/cgi-bin/NLS_Mapper_form.cgi)

**Figure 2.. Facial features of individuals with pathogenic *ZNF292* variants.**
(**A, B**) Photos of 17–027 showing a thin upper lip, smooth philtral folds, upturned nasal tip, sparse but long eyebrows with synophrys; (**C-D**) Photos of 18–007 at age 3.5 years showing epicanthal folds, mildly upslanted palpebral fissures, prominent forehead, and bulbous nose. D, hand photographs of the child showing ichthyosis; (**E, F**) Photo of 17–013 as a child (E) and as a teenager (F) showing laterally prominent ears, thick lips with a tented upper lip, short philtrum, prominent eyebrows with very prominent brow ridge and deep set eyes; (**G, H**) Frontal and lateral facial photograph of 17–005 at age 4 years 1 month showing mild micrognathia, short philtrum, and mildly downslanting palpebral fissures. All affected individuals have a prominent chin.

**Figure 3.. Brain MRI images of individuals with pathogenic variants in *ZNF292*.**
(**A-B**) T1-weighted and T2-weighted brain MR images of patient 17–003 showing mildly prominent ventricles (asterisks, image F); (**C-D**) T1-weighted sagittal and axial images of 17–008 showing paucity of the white matter due to an in utero vascular insult and a thin corpus callosum (arrowhead; image G); (**E-H**) T1-weighted and constructive interference in steady state (CISS) images of patient 17–009 showing multiple abnormalities including hypoplasia of the cerebellar vermis and hemispheres, with marked asymmetry (arrow, image I; asterisks, image G), with possible clefting OF the cerebellum (arrow, image G), as well as a deep infold within the cortical surface (arrowhead, image F). Patient also has evidence of possible hemosiderin deposition that is asymmetric, suggesting a previous vascular insult/injury.

**Figure 4.. Expression of *ZNF292* in developing human and mouse brains.**
A, *ZNF292* expression in the developing human brain (normalized RPKM data) showing high expression during early prenatal development that diminishes in the postnatal brain. *Data obtained from BrainSpan* http://www.brainspan.org. Codes: AMY, amygdala; CBC, cerebellum; HIP, hippocampus; MD, medial dorsal nucleus of the thalamus; NCTX, neocortex; NCTX, neocortex. B, *Zpf292* expression in the adult mouse brain showing the highest expression (indicated by higher intensity staining) in hippocampus and Purkinje cells of the cerebellum.

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases