Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome,Nature Genetics

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Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome
Nature Genetics ( IF 31.7 ) Pub Date : 2021-07-01 , DOI: 10.1038/s41588-021-00886-z
Margot A Cousin _{1,

2} , Blake A Creighton ₃ , Keith A Breau ₃ , Rebecca C Spillmann ₄ , Erin Torti ₅ , Sruthi Dontu ₃ , Swarnendu Tripathi ₆ , Deepa Ajit ₃ , Reginald J Edwards ₃ , Simone Afriyie ₃ , Julia C Bay ₃ , Kathryn M Harper _{7,

8} , Alvaro A Beltran _{9,

10} , Lorena J Munoz ₁₀ , Liset Falcon Rodriguez ₃ , Michael C Stankewich ₁₁ , Richard E Person ₅ , Yue Si ₅ , Elizabeth A Normand ₅ , Amy Blevins ₅ , Alison S May ₁₂ , Louise Bier ₁₃ , Vimla Aggarwal _{13,

14} , Grazia M S Mancini ₁₅ , Marjon A van Slegtenhorst ₁₅ , Kirsten Cremer ₁₆ , Jessica Becker ₁₆ , Hartmut Engels ₁₆ , Stefan Aretz ₁₆ , Jennifer J MacKenzie ₁₇ , Eva Brilstra ₁₈ , Koen L I van Gassen ₁₈ , Richard H van Jaarsveld ₁₈ , Renske Oegema ₁₈ , Gretchen M Parsons ₁₉ , Paul Mark ₁₉ , Ingo Helbig _{20,

21,

22,

23} , Sarah E McKeown _{20,

21} , Robert Stratton ₂₄ , Benjamin Cogne _{25,

26} , Bertrand Isidor _{25,

26} , Pilar Cacheiro ₂₇ , Damian Smedley ₂₇ , Helen V Firth _{28,

29} , Tatjana Bierhals ₃₀ , Katja Kloth ₃₀ , Deike Weiss ₃₁ , Cecilia Fairley ₃₂ , Joseph T Shieh _{32,

33} , Amy Kritzer ₃₄ , Parul Jayakar ₃₅ , Evangeline Kurtz-Nelson ₃₆ , Raphael A Bernier ₃₆ , Tianyun Wang ₃₇ , Evan E Eichler _{37,

38} , Ingrid M B H van de Laar ₁₅ , Allyn McConkie-Rosell ₄ , Marie T McDonald ₄ , Jennifer Kemppainen _{1,

39} , Brendan C Lanpher _{1,

39} , Laura E Schultz-Rogers _{1,

2} , Lauren B Gunderson _{1,

39} , Pavel N Pichurin ₁ , Grace Yoon ₄₀ , Michael Zech _{41,

42} , Robert Jech ₄₃ , Juliane Winkelmann _{41,

42,

44,

45} , , , Adriana S Beltran _{10,

46,

47} , Michael T Zimmermann _{6,

48,

49} , Brenda Temple ₅₀ , Sheryl S Moy _{7,

8} , Eric W Klee _{1,

2,

39} , Queenie K-G Tan ₄ , Damaris N Lorenzo _{3,

8,

9}

Affiliation

Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Pediatrics, Duke University Medical Center, Duke University, Durham, NC, USA.
GeneDx, Gaithersburg, MD, USA.
Bioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Human Pluripotent Stem Cell Core, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Pathology, Yale University, New Haven, CT, USA.
Department of Neurology, Columbia University, New York, NY, USA.
Institute for Genomic Medicine, Columbia University, New York, NY, USA.
Laboratory of Personalized Genomic Medicine, Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
McMaster University, Hamilton, Ontario, Canada.
Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
Spectrum Health Medical Genetics, Grand Rapids, MI, USA.
Division of Neurology, Departments of Neurology and Pediatrics, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
The Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
Genetics, Driscoll Children's Hospital, Corpus Christi, TX, USA.
Service de Génétique Médicale, CHU Nantes, Nantes, France.
Université de Nantes, CNRS, INSERM, L'Institut du Thorax, Nantes, France.
William Harvey Research Institute, School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Department of Clinical Genetics, Cambridge University Hospitals, Cambridge, UK.
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Neuropediatrics, Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
Nicklaus Children's Hospital, Miami, FL, USA.
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
Divisions of Clinical/Metabolic Genetics and Neurology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
Institute of Human Genetics, Technical University of Munich, Munich, Germany.
Department of Neurology, Charles University, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic.
Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany.
Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.
Clinical and Translational Sciences Institute, Medical College of Wisconsin, Milwaukee, WI, USA.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

SPTBN1 encodes βII-spectrin, the ubiquitously expressed β-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal βII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of βII-spectrin in the central nervous system.

中文翻译：

致病性 SPTBN1 变异导致常染色体显性神经发育综合征

SPTBN1编码 βII-血影蛋白，这种普遍表达的 β-血影蛋白形成与质膜相关的微米级网络。神经元βII-血影蛋白缺陷的小鼠存在皮质组织缺陷、发育迟缓和行为缺陷。这些表型虽然不太严重，但在单倍体不足的动物中观察到，这表明携带杂合SPTBN1变异的个体也可能表现出神经发育和功能的可测量的损害。在这里，我们在 29 名患有发育、语言和运动迟缓的个体中发现了杂合SPTBN1变异；轻度至重度智力障碍；自闭症特征；癫痫发作；行为和运动异常；肌张力减退;以及多变的畸形面部特征。我们发现这些SPTBN1变异会导致影响 βII 血影蛋白稳定性、破坏与关键分子伙伴的结合以及扰乱细胞骨架组织和动力学的影响。我们的研究将SPTBN1变异定义为神经发育综合征的遗传基础，扩大了影响大脑的血影蛋白病的范围，并强调了 βII-血影蛋白在中枢神经系统中的关键作用。

更新日期：2021-07-01

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