GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder.,Genetics in Medicine

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GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder.
Genetics in Medicine ( IF 8.8 ) Pub Date : 2020-01-17 , DOI: 10.1038/s41436-019-0747-z
Christine Shieh ₁ , Natasha Jones ₂ , Brigitte Vanle _{3,

4} , Margaret Au ₅ , Alden Y Huang ₆ , Ana P G Silva ₂ , Hane Lee ₇ , Emilie D Douine ₈ , Maria G Otero ₉ , Andrew Choi ₉ , Katheryn Grand ₁₀ , Ingrid P Taff ₁₁ , Mauricio R Delgado ₁₂ , M J Hajianpour ₁₃ , Andrea Seeley ₁₄ , Luis Rohena _{15,

16} , Hilary Vernon ₁₇ , Karen W Gripp ₁₈ , Samantha A Vergano ₁₉ , Sonal Mahida ₂₀ , Sakkubai Naidu _{21,

22} , Ana Berta Sousa ₂₃ , Karen E Wain ₂₄ , Thomas D Challman ₂₄ , Geoffrey Beek ₂₅ , Donald Basel ₂₆ , Judith Ranells ₂₇ , Rosemarie Smith ₂₈ , Roman Yusupov ₂₉ , Mary-Louise Freckmann ₃₀ , Lisa Ohden ₃₁ , Laura Davis-Keppen ₃₂ , David Chitayat _{33,

34} , James J Dowling ₃₅ , Richard Finkel ₃₆ , Andrew Dauber ₃₇ , Rebecca Spillmann ₃₈ , Loren D M Pena _{39,

40} , , Kay Metcalfe ₄₁ , Miranda Splitt ₄₂ , Katherine Lachlan _{43,

44} , Shane A McKee ₄₅ , Jane Hurst ₄₆ , David R Fitzpatrick ₄₇ , Jenny E V Morton _{48,

49,

50} , Helen Cox _{48,

49,

50} , Sunita Venkateswaran ₅₁ , Juan I Young ₅₂ , Eric D Marsh ₅₃ , Stanley F Nelson ₈ , Julian A Martinez ₅₄ , John M Graham ₅₅ , Usha Kini ₅₆ , Joel P Mackay ₂ , Tyler Mark Pierson _{10,

57,

58}

Affiliation

David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, Australia.
Department of Psychiatry & Behavioral Neurosciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Medical College of Wisconsin-Central Wisconsin, Wausau, WI, USA.
Department of Pediatrics Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Institute for Precision Health, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Department of Human Genetics and Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Board of Governor's Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Neurology, Hofstra School of Medicine, Great Neck, NY, USA.
Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center and Texas Scottish Rite Hospital for Children, Dallas, TX, USA.
Department of Pediatrics, Division of Medical Genetics, East Tennessee State University, Quillen College of Medicine, Mountain Home, TN, USA.
Geisinger Medical Center, Danville, PA, USA.
Division of Genetics, Department of Pediatrics, Brooke Army Medical Center, Fort Sam Houston, TX, USA.
Department of Pediatrics, UT Health San Antonio, Long School of Medicine, San Antonio, TX, USA.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Balitmore, MD, USA.
Division of Medical Genetics, Al DuPont Hospital for Children, Wilmington, DE, USA.
Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA, USA.
Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
Department of Neurology and Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Hugo Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD, USA.
Serviço de Genética Médica, Hospital Santa Maria, CHULN, Lisboa, Portugal and Faculdade de Medicina de Lisboa, Universidade de Lisboa, Lisboa, Portugal.
Autism & Developmental Medicine Institute, Geisinger, Lewisburg, PA, USA.
Children's Hospitals and Clinics of Minnesota Department of Genetics, Minneapolis, MN, USA.
Department of Pediatrics, Division of Genetics; Children's Hospital of Wisconsin, Milwaukee, WI, USA.
Division of Genetics and Metabolism, Department of Pediatrics, University of South Florida, Tampa, FL, USA.
Department of Pediatrics, Division of Genetics, Maine Medical Center, Portland, ME, USA.
Division of Clinical Genetics, Joe DiMaggio Children's Hospital, Hollywood, FlL, USA.
Royal North Shore Hospital, St Leonards, NSW, Australia.
Department of Genetic Counseling, Sanford Children's Specialty Clinic, Sioux Falls, SD, USA.
Department of Pediatrics, Sanford School of Medicine of the University of South Dakota, Sioux Falls, SD, USA.
The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada.
Division of Pediatric Neurology, Department of Pediatrics, Nemours Children's Hospital, Orlando, FL, USA.
Division of Endocrinology, Children's National Health System, Washington, DC, USA.
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA.
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Manchester Centre for Genomic Medicine, Manchester University NHS FT, Manchester, UK.
Institute of Genetic Medicine, Northern Genetics Service, Newcastle upon Tyne Hospitals Trust, Newcastle, UK.
Faculty of Medicine, University of Southampton, Southampton, UK.
Human Development and Health Division, Wessex Clinical Genetics Service, University Hospitals of Southampton NHS Trust, Southampton, UK.
Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK.
Department of Clinical Genetics, NE Thames Genetics Service, Great Ormond Street Hospital, London, UK.
Medical Research Council Human Genetics Unit, University of Edinburgh, Edinburgh, UK.
West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham, UK.
Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UK.
Birmingham Women's Hospital, Edgbaston, Birmingham, UK.
Division of Neurology, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada.
John P Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
Division of Neurology, Children's Hospital of Philadelphia and Department of Neurology and Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Department of Human Genetics; Division of Medical Genetics, Department of Pediatrics; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Pediatrics, Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Oxford Centre for Genomic Medicine, Oxford University Hospital NHS Foundation Trust, Oxford, UK.
Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

PURPOSE Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND). METHODS Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex. RESULTS Subjects had clinical findings that included macrocephaly, hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novelGATAD2B variants were identified with multiple variant types (nonsense, truncating frameshift, splice-site variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region domains (CR1 or CR2) of the GATAD2B protein. Immunoprecipitation assays revealed several of these missense variants disrupted GATAD2B interactions with its NuRD complex binding partners. CONCLUSIONS A consistent GAND phenotype was caused by a range of genetic variants in GATAD2B that include loss-of-function and missense subtypes. Missense variants were present in conserved region domains that disrupted assembly of NuRD complex proteins. GAND's clinical phenotype had substantial clinical overlap with other disorders associated with the NuRD complex that involve CHD3 and CHD4, with clinical features of hypotonia, intellectual disability, cardiac defects, childhood apraxia of speech, and macrocephaly.

中文翻译：

GATAD2B 相关神经发育障碍 (GAND)：对 NuRD 相关障碍的临床和分子见解。

目的确定 GATAD2B 相关神经发育障碍 (GAND) 的基因型/表型特征。方法评估了 50 名 GAND 受试者以确定一致的基因型/表型特征。利用体外转录翻译产物的免疫沉淀测定用于评估 GATAD2B 错义变体与核小体重塑和脱乙酰酶 (NuRD) 复合物中的结合伙伴相互作用的能力。结果受试者的临床发现包括大头畸形、肌张力减退、智力残疾、新生儿喂养问题、羊水过多、言语失用、癫痫和二叶主动脉瓣。41 个新的 GATAD2B 变体被鉴定为具有多种变体类型（无义、截断移码、剪接位点变体、缺失和错义）。七名受试者被鉴定为具有定位在 GATAD2B 蛋白的两个保守区域结构域（CR1 或 CR2）内的错义变体。免疫沉淀分析显示，其中一些错义变体破坏了 GATAD2B 与其 NuRD 复合物结合伙伴的相互作用。结论一致的 GAND 表型是由 GATAD2B 中的一系列遗传变异引起的，包括功能丧失和错义亚型。错义变体存在于破坏 NuRD 复合蛋白组装的保守区域结构域中。GAND 的临床表型与涉及 CHD3 和 CHD4 的其他与 NuRD 复合体相关的疾病有实质性的临床重叠，具有张力减退、智力残疾、心脏缺陷、儿童言语失用和大头畸形的临床特征。

更新日期：2020-01-17

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