Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome,Genetics in Medicine

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Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome
Genetics in Medicine ( IF 6.6 ) Pub Date : 2021-08-03 , DOI: 10.1038/s41436-021-01246-2
Marjolein J A Weerts ₁ , Kristina Lanko ₁ , Francisco J Guzmán-Vega ₂ , Adam Jackson _{3,

4} , Reshmi Ramakrishnan ₂ , Kelly J Cardona-Londoño ₂ , Karla A Peña-Guerra ₂ , Yolande van Bever ₁ , Barbara W van Paassen ₁ , Anneke Kievit ₁ , Marjon van Slegtenhorst ₁ , Nicholas M Allen ₅ , Caroline M Kehoe ₅ , Hannah K Robinson ₆ , Lewis Pang ₆ , Selina H Banu ₇ , Mashaya Zaman ₇ , Stephanie Efthymiou ₈ , Henry Houlden ₈ , Irma Järvelä ₉ , Leena Lauronen ₁₀ , Tuomo Määttä ₁₁ , Isabelle Schrauwen ₁₂ , Suzanne M Leal ₁₂ , Claudia A L Ruivenkamp ₁₃ , Daniela Q C M Barge-Schaapveld ₁₃ , Cacha M P C D Peeters-Scholte ₁₄ , Hamid Galehdari ₁₅ , Neda Mazaheri ₁₅ , Sanjay M Sisodiya _{16,

17} , Victoria Harrison ₁₈ , Angela Sun ₁₉ , Jenny Thies ₂₀ , Luis Alberto Pedroza ₂₁ , Yana Lara-Taranchenko ₂₂ , Ivan K Chinn _{23,

24} , James R Lupski _{25,

26,

27} , Alexandra Garza-Flores ₂₈ , Jeffery McGlothlin ₂₉ , Lin Yang ₃₀ , Shaoping Huang ₃₀ , Xiaodong Wang ₃₁ , Tamison Jewett ₃₂ , Gretchen Rosso ₃₂ , Xi Lin ₃₃ , Shehla Mohammed ₃₄ , J Lawrence Merritt ₁₉ , Ghayda M Mirzaa _{19,

35,

36} , Andrew E Timms ₃₇ , Joshua Scheck ₃₅ , Mariet W Elting ₃₈ , Abeltje M Polstra ₃₈ , Lauren Schenck ₃₉ , Maura R Z Ruzhnikov _{39,

40} , Annalisa Vetro ₄₁ , Martino Montomoli ₄₁ , Renzo Guerrini ₄₁ , Daniel C Koboldt ₄₂ , Theresa Mihalic Mosher ₄₂ , Matthew T Pastore ₄₂ , Kim L McBride ₄₂ , Jing Peng ₄₃ , Zou Pan ₄₃ , Marjolein Willemsen ₄₄ , Susanne Koning ₄₅ , Peter D Turnpenny ₄₆ , Bert B A de Vries ₄₄ , Christian Gilissen ₄₄ , Rolph Pfundt ₄₄ , Melissa Lees ₄₇ , Stephen R Braddock ₄₈ , Kara C Klemp ₄₈ , Fleur Vansenne ₄₉ , Marielle E van Gijn ₄₉ , Catherine Quindipan ₅₀ , Matthew A Deardorff _{50,

51} , J Austin Hamm ₅₂ , Abbey M Putnam ₅₂ , Rebecca Baud ₅₃ , Laurence Walsh _{53,

54} , Sally A Lynch ₅₅ , Julia Baptista _{6,

56} , Richard E Person ₅₇ , Kristin G Monaghan ₅₇ , Amy Crunk ₅₇ , Jennifer Keller-Ramey ₅₇ , Adi Reich ₅₇ , Houda Zghal Elloumi ₅₇ , Marielle Alders ₅₈ , Jennifer Kerkhof ₅₉ , Haley McConkey ₅₉ , Sadegheh Haghshenas ₆₀ , , Reza Maroofian ₈ , Bekim Sadikovic _{59,

60} , Siddharth Banka _{3,

4} , Stefan T Arold _{2,

61} , Tahsin Stefan Barakat ₁

Affiliation

Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Division of Biological and Environmental Sciences and Engineering (BESE), Thuwal, Saudi Arabia.
Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Department of Paediatrics, National University of Ireland Galway, Galway, Ireland.
Exeter Genomics Laboratory, RILD Building, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
Department of Pediatric Neurology, Dr. M.R. Khan Shishu (Children) Hospital and ICH, Mirpur, Dhaka, Bangladesh.
Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK.
Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
Department of Clinical Neurophysiology, New Children´s Hospital, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital (HUH), Helsinki, Finland.
Disability Services, Joint Authority for Kainuu, Kajaani, Finland.
Center for Statistical Genetics, Sergievsky Center, Taub Institute for Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University Medical Center, New York, NY, USA.
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.
Chalfont Centre for Epilepsy, London, Bucks, UK.
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
Department of Pediatrics, Division of Genetic Medicine, University of Washington School of Medicine, Seattle, Washington, USA.
Department of Pediatrics, Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA, USA.
Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA.
Universidad San Francisco de Quito, Colegio de ciencias de la salud-Hospital de los Valles, Quito, Ecuador.
Department of Pediatrics, Section of Immunology, Allergy, and Retrovirology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.
Cook Children's Genetics, Cook Children's Physician Network, Cook Children's Hospital, Fort Worth, TX, USA.
Cook Children's Neurosciences, Cook Children's Physician Network, Cook Children's Hospital, Fort Worth, TX, USA.
Department of Pediatrics, The Second Affiliated Hospital of Xi 'an Jiaotong University, Xi'an, China.
Cipher Gene Ltd, Beijing, China.
Department of Pediatrics, Section on Medical Genetics, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Pediatrics Department, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
Clinical Genetics, Guy's and St Thomas NHS Foundation Trust, London, UK.
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
Brotman Baty Institute for Precision Medicine, Seattle, WA, USA.
Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA.
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
Department of Pediatrics, Division of Medical Genetics, Stanford Medicine, Stanford, CA, USA.
Department of Neurology and Neurological Sciences, Stanford Medicine, Stanford, CA, USA.
Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital-University of Florence, Florence, Italy.
Nationwide Children's Hospital, Columbus, OH, USA.
Xiangya Hospital of Central South University, Changsha, China.
Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
Clinical Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK.
NE Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Division of Medical Genetics, Department of Pediatrics, SSM Health Cardinal Glennon Children's Hospital, Saint Louis University School of Medicine, Saint Louis, MO, USA.
Department of Clinical Genetics, University Medical Center Groningen, Groningen, The Netherlands.
Center for Personalized Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Departments of Pathology and Pediatrics, Keck School of Medicine of the, University of Southern California, Los Angeles, CA, USA.
East Tennessee Children's Hospital Genetics Center, Knoxville, TN, USA.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Neurology, Indiana University School of Medicine and Riley Hospital for Children, Indianapolis, IN, USA.
Department of Clinical Genetics, Children's Health Ireland at Temple St. Children's Hospital and Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
GeneDx, Gaithersburg, MD, USA.
Amsterdam UMC, Department of Clinical Genetics, Amsterdam Reproduction & Development Research Institute, University of Amsterdam, Amsterdam, The Netherlands.
Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada.
Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
Centre de Biologie Structurale, CNRS, INSERM, Université de Montpellier, Montpellier, France.

Purpose

Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort.

Methods

We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays.

Results

Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants.

Conclusion

Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

中文翻译：

描绘 SETD1B 相关综合征的分子和表型谱

目的

SETD1B的致病性变异与包括智力障碍、语言延迟和癫痫发作在内的综合性神经发育障碍有关。迄今为止，已经描述了 11 名具有（可能）致病性SETD1B序列变异的患者的临床特征。本研究旨在基于扩展患者队列的特征，进一步描述SETD1B相关综合征的谱系。

方法

我们对一组 36 名未发表的具有SETD1B序列变异的个体进行了深入的临床表征，描述了他们的分子和表型谱。使用体外和全基因组甲基化测定对选定的变体进行功能测试。

结果

我们的数据提供了SETD1B变体功能丧失机制的证据，导致全球发育迟缓、语言迟缓（包括退化、智力残疾、自闭症和其他行为问题）以及可变癫痫表型的核心临床表型。发育迟缓似乎先于癫痫发作，这表明即使在没有癫痫活动的情况下，SETD1B 功能障碍也会影响生理神经发育。男性显着过多且受影响更严重，我们推测性相关性状可能会影响外显率的易感性和SETD1B变体的临床谱。