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

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De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2019-11-14 , DOI: 10.1038/s41436-019-0693-9
Ghayda M Mirzaa _{1,

2,

3} , Jessica X Chong _{2,

3} , Amélie Piton _{4,

5} , Bernt Popp ₆ , Kimberly Foss ₁ , Hui Guo ₇ , Ricardo Harripaul _{8,

9} , Kun Xia ₇ , Joshua Scheck ₁ , Kimberly A Aldinger ₁ , Samin A Sajan ₁₀ , Sha Tang ₁₁ , Dominique Bonneau _{12,

13} , Anita Beck ₂ , Janson White ₁₄ , Sonal Mahida ₁₅ , Jacqueline Harris ₁₅ , Constance Smith-Hicks ₁₅ , Juliane Hoyer ₆ , Christiane Zweier ₆ , André Reis ₆ , Christian T Thiel ₆ , Rami Abou Jamra ₁₆ , Natasha Zeid ₁₇ , Amy Yang ₁₈ , Laura S Farach ₁₉ , Laurence Walsh ₂₀ , Katelyn Payne ₂₀ , Luis Rohena _{21,

22} , Milen Velinov ₂₃ , Alban Ziegler _{12,

24} , Elise Schaefer ₂₅ , Vincent Gatinois _{26,

27,

28} , David Geneviève _{26,

27,

28} , Marleen E H Simon ₂₉ , Jennefer Kohler ₃₀ , Joshua Rotenberg ₃₁ , Patricia Wheeler ₃₂ , Austin Larson ₃₃ , Michelle E Ernst ₃₄ , Cigdem I Akman _{34,

35} , Rachel Westman ₃₆ , Patricia Blanchet ₂₇ , Lori-Anne Schillaci ₃₇ , Catherine Vincent-Delorme ₃₈ , Karen W Gripp ₃₉ , Francesca Mattioli ₄₀ , Gwenaël Le Guyader ₄₁ , Bénédicte Gerard ₄ , Michèle Mathieu-Dramard ₄₂ , Gilles Morin ₄₃ , Roksana Sasanfar ₄₃ , Muhammad Ayub ₄₄ , Nasim Vasli ₄₅ , Sandra Yang ₄₆ , Rick Person ₄₆ , Kristin G Monaghan ₄₆ , Deborah A Nickerson ₁₄ , Ellen van Binsbergen ₂₉ , Gregory M Enns _{30,

47} , Annika M Dries ₃₀ , Leah J Rowe ₃₃ , Anne C H Tsai ₃₃ , Shayna Svihovec ₃₃ , Jennifer Friedman _{48,

49} , Zehra Agha ₅₀ , Raheel Qamar ₅₀ , Lance H Rodan _{51,

52} , Julian Martinez-Agosto ₅₃ , Charlotte W Ockeloen ₅₄ , Marie Vincent ₅₅ , William James Sunderland ₅₆ , Jonathan A Bernstein _{30,

47} , , Evan E Eichler _{14,

57} , John B Vincent _{8,

9} , , Michael J Bamshad _{2,

3}

Affiliation

Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
Brotman Baty Institute for Precision Medicine, Seattle, Washington, USA.
Molecular Genetic Unit, Strasbourg University Hospital, Strasbourg, France.
Institute of Genetics and Molecular and Cellular Biology, Université de Strasbourg, Illkirch, France.
Institute of Human Genetics, University Hospital Elrangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
The Campbell Family Mental Health Research Institute, Centre for Addiction & Mental Health (CAMH), Toronto, ON, Canada.
Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA.
WuXi NextCODE, Cambridge, MA, USA.
Département de Biochimie et de Génétique, CHU d'Angers, Angers, France.
UMR INSERM 1083 CNRS 6015, Angers, France.
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany.
Yale New Haven Health, New Haven, CT, USA.
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
Department of Pediatrics, McGovern Medical School at the University of Texas Health Sciences Center, Houston, TX, USA.
Indiana University Health at Riley Hospital for Children, Indianapolis, IN, USA.
Division of Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, TX, USA.
Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
New York State Institute for Basic Research in Developmental Disability, NY, Staten Island, USA.
Service de Génétique Médicale, Centre hospitalier, Le Mans, France.
Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Institut de Génétique Médicale d'Alsace, Strasbourg, France.
Service de génétique clinique, Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Strasbourg, France.
Centre de Référence Maladies Rares Anomalies du Développement et Syndromes Malformatifs Sud-Ouest Occitanie Réunion, Hôpital Arnaud de Villeneuve, Montpellier, France.
Université Montpellier, Unité Inserm U1183, Montpellier, France.
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA, USA.
Memorial Hermann Memorial City Medical Center, Houston, TX, USA.
Arnold Palmer Hospital for Children, Orlando, FL, USA.
Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA.
Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Division of Pediatric Neurology, Columbia University Irving Medical Center, New York, NY, USA.
Division of Genetics, St. Luke's Clinic, Boise, ID, USA.
Department of Genetics and Genome Sciences, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
Service de Génétique Clinique Guy Fontaine Centre de référence maladies rares Anomalies du dévelopement, Hôpital Jeanne de Flandre Lille, Lille, France.
Department of Pediatrics, AI duPont Hospital, DE, Wilmington, USA.
Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch-Graffenstaden, Lille, France.
Service de Génétique Clinique, Centre de compétence Maladies rares Anomalies du dévelopement, CHU de Poitiers, Poitiers, France.
Service de Génétique Clinique Centre de référence maladies rares Anomalies du dévelopement, CHU Amiens-Picardie, Amiens, France.
Children's Medical Center, UMass Memorial Medical Center, Worcester, MA, USA.
Department of Psychiatry, Queen's University, Kingston, ON, Canada.
Division of Clinical & Metabolic Genetics, Hospital for Sick Children, Toronto, ON, Canada.
GeneDx, Gaithersburg, MD, USA.
Division of Medical Genetics, Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University, Stanford, CA, USA.
Departments of Neurosciences and Pediatrics, University of California San Diego and Division of Neurology, Rady Children's Hospital, San Diego, CA, USA.
Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
Department of Biosciences, COMSATS University, Islamabad, Pakistan.
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
CHU de Nantes, Service de génétique médicale, Nantes, France.
University of Washington Foundation Board, University of Washington, Seattle, WA, USA.
Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.

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.

中文翻译：

ZNF292 中的从头和遗传变异是具有自闭症谱系障碍特征的神经发育障碍的基础。

目的智力障碍 (ID) 和自闭症谱系障碍 (ASD) 是遗传异质性神经发育障碍。我们试图描述一种由锌指蛋白 292 基因 (ZNF292) 变异引起的新型神经发育障碍的临床、分子和神经影像谱。方法我们确定了一个由 28 个 ID 家族组成的队列，这些家族是通过靶向和外显子组测序鉴定的假定致病性 ZNF292 变体。分析可用数据以表征典型表型并检查基因型 - 表型关系。结果先证者出现 ID 以及一系列神经发育特征，包括 ASD 等。除一个具有显性遗传的家族外，所有 ZNF292 变体都是从头发生的。ZNF292 编码一种高度保守的锌指蛋白，可作为转录因子，在发育中的人脑中高度表达，支持其在神经发育中的关键作用。结论 ZNF292 中的从头和显性遗传变异与包括 ID 和 ASD 在内的一系列神经发育特征相关。临床范围很广，大多数个体表现为轻度至中度 ID，伴有或不伴有其他综合征特征。我们的研究结果表明，ZNF292 中的变异可能是神经发育障碍的复发原因，表现为伴有或不伴有 ASD 的 ID。结论 ZNF292 中的从头和显性遗传变异与包括 ID 和 ASD 在内的一系列神经发育特征相关。临床范围很广，大多数个体表现为轻度至中度 ID，伴有或不伴有其他综合征特征。我们的研究结果表明，ZNF292 中的变异可能是神经发育障碍的复发原因，表现为伴有或不伴有 ASD 的 ID。结论 ZNF292 中的从头和显性遗传变异与包括 ID 和 ASD 在内的一系列神经发育特征相关。临床范围很广，大多数个体表现为轻度至中度 ID，伴有或不伴有其他综合征特征。我们的研究结果表明，ZNF292 中的变异可能是神经发育障碍的复发原因，表现为伴有或不伴有 ASD 的 ID。

更新日期：2019-11-14

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