DLG4 -related synaptopathy: a new rare brain disorder,Genetics in Medicine

当前位置： X-MOL 学术 › Genet. Med. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

DLG4 -related synaptopathy: a new rare brain disorder
Genetics in Medicine ( IF 6.6 ) Pub Date : 2021-02-17 , DOI: 10.1038/s41436-020-01075-9
Agustí Rodríguez-Palmero _{1,

2} , Melissa Maria Boerrigter _{3,

4} , David Gómez-Andrés ₅ , Kimberly A Aldinger ₆ , Íñigo Marcos-Alcalde _{7,

8} , Bernt Popp _{9,

10} , David B Everman ₁₁ , Alysia Kern Lovgren ₁₂ , Stephanie Arpin ₁₃ , Vahid Bahrambeigi _{11,

14} , Gea Beunders ₁₅ , Anne-Marie Bisgaard ₁₆ , V A Bjerregaard ₃ , Ange-Line Bruel ₁₇ , Thomas D Challman ₁₈ , Benjamin Cogné _{19,

20} , Christine Coubes ₂₁ , Stella A de Man ₂₂ , Anne-Sophie Denommé-Pichon ₁₇ , Thomas J Dye _{23,

24} , Frances Elmslie ₂₅ , Lars Feuk ₂₆ , Sixto García-Miñaúr ₂₇ , Tracy Gertler ₂₈ , Elisa Giorgio ₂₉ , Nicolas Gruchy ₃₀ , Tobias B Haack ₃₁ , Chad R Haldeman-Englert ₃₂ , Bjørn Ivar Haukanes ₃₃ , Juliane Hoyer ₉ , Anna C E Hurst ₃₄ , Bertrand Isidor _{19,

20} , Maria Johansson Soller _{35,

36} , Sulagna Kushary ₃₇ , Malin Kvarnung _{35,

36} , Yuval E Landau _{38,

39,

40} , Kathleen A Leppig ₄₁ , Anna Lindstrand _{35,

36} , Lotte Kleinendorst ₄₂ , Alex MacKenzie ₄₃ , Giorgia Mandrile ₄₄ , Bryce A Mendelsohn ₄₅ , Setareh Moghadasi ₄₆ , Jenny E Morton ₄₇ , Sebastien Moutton _{17,

48} , Amelie J Müller ₃₁ , Melanie O'Leary ₁₂ , Marta Pacio-Míguez ₂₇ , Maria Palomares-Bralo ₂₇ , Sumit Parikh ₄₉ , Rolph Pfundt ₅₀ , Ben Pode-Shakked _{40,

50,

51,

52} , Anita Rauch ₅₃ , Elena Repnikova ₅₄ , Anya Revah-Politi _{36,

55} , Meredith J Ross ₅₆ , Claudia A L Ruivenkamp ₄₆ , Elisabeth Sarrazin ₅₇ , Juliann M Savatt ₁₈ , Agatha Schlüter ₁ , Bitten Schönewolf-Greulich ₃ , Zohra Shad ₅₈ , Charles Shaw-Smith ₅₉ , Joseph T Shieh ₆₀ , Motti Shohat ₆₁ , Stephanie Spranger ₆₂ , Heidi Thiese ₄₁ , Frederic Tran Mau-Them ₁₇ , Bregje van Bon ₆₃ , Ineke van de Burgt ₆₃ , Ingrid M B H van de Laar ₆₄ , Esmée van Drie ₄₂ , Mieke M van Haelst ₄₂ , Conny M van Ravenswaaij-Arts ₁₅ , Edgard Verdura ₁ , Antonio Vitobello ₁₇ , Stephan Waldmüller ₃₁ , Sharon Whiting ₄₃ , Christiane Zweier ₉ , Carlos E Prada _{24,

65} , Bert B A de Vries ₆₃ , William B Dobyns _{6,

66,

67} , Simone F Reiter ₃₃ , Paulino Gómez-Puertas ₇ , Aurora Pujol _{1,

68} , Zeynep Tümer _{3,

69}

Affiliation

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, and Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
Paediatric Neurology Unit, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain.
Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands.
Child Neurology Unit. Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain.
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
Molecular Modelling Group, Severo Ochoa Molecular Biology Centre (CBM SO, CSIC-UAM), Madrid, Spain.
Bioscience Research Institute, School of Experimental Sciences, Francisco de Vitoria University, Pozuelo de Alarcón, Spain.
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
Greenwood Genetic Center, Greenwood, SC, USA.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Service de génétique, CHU de Tours, UMR 1253, iBrain, Université de Tours, Inserm, Tours, France.
Graduate School of Biomedical Sciences, The University of Texas, MD Anderson Cancer Center UTHealth, Houston, TX, USA.
Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
Center for Rett syndrome, Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Denmark.
INSERM UMR1231, GAD, University of Burgundy, FHU-TRANSLAD, CHU Dijon-Bourgogne, Dijon, France.
Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA, USA.
Service de Génétique Médicale, CHU Nantes, Nantes, France.
Université de Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.
Département de Génétique Médicale, Maladies rares et Médecine personnalisée, CHU Montpellier, France.
Department of Pediatrics, Amphia Hospital, Breda, The Netherlands.
Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
South West Thames Regional Genetics Service, St George's University Hospitals, University of London, London, United Kingdom.
Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain.
Division of Neurology, Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
Department of Medical Sciences, University of Turin, Torino, Italy.
Service de Génétique, CHU Caen Clemenceau, Biotargen, Univ Caen, France.
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Mission Fullerton Genetics Center, Asheville, NC, USA.
Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Leumit Health Care Services, Tel-Aviv, Israel.
Metabolic Disease Service, Schneider Children's Medical Center of Israel, Tel-Aviv, Israel.
Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Genetic Services, Kaiser Permanente of Washington, Seattle, WA, USA.
Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada.
Thalassemia Centre and Genetic Unit, San Luigi University Hospital, Orbassano, Italy.
Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, CA, USA.
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham Women's Hospital, Birmingham, United Kingdom.
CPDPN, Pôle mère enfant, Maison de Santé Protestante Bordeaux Bagatelle, Talence, France.
Mitochondrial Medicine & Neurogenetics, Cleveland Clinic, Cleveland, OH, USA.
Genomic Unit, Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
Institute of Rare Diseases, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
Wohl Institute for Translational Medicine and Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland.
Division of Clinical Laboratory Genetics & Genomics, Children's Mercy Hospital, Kansas City, MO, USA.
Precision Genomics Laboratory, Columbia University Irving Medical Center, New York, NY, USA.
Department of Pediatrics, Columbia University Medical Center, NewYork-Presbyterian Hospital, New York, NY, USA.
Centre de Référence des Maladies rares neuromusculaires AOC, Hôpital Pierre Zobda Quitman, CHU Martinique, Fort de France, Martinique.
Cook Children's Medical Center Genetics, Fort Worth, TX, USA.
Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom.
Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
Bioinformatics unit, Cancer Research Center, Sheba Medical Center and Sackler Medical Center, Tel Aviv University and Maccabi HMO, Tel Aviv, Israel.
Praxis fuer Humangenetik, Klinikum Bremen-Mitte, Bremen, Germany.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Department of Pediatrics, University of Washington, Seattle, WA, USA.
Department of Neurology, University of Washington, Seattle, WA, USA.
Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Purpose

Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.

Methods

The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.

Results

The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit–hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.

Conclusion

The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

中文翻译：

DLG4相关突触病：一种新的罕见脑部疾病

目的

由DLG4编码的突触后密度蛋白 95 (PSD-95)调节大脑中的兴奋性突触功能。在这里，我们介绍了 53 名患有DLG4变体的患者（42 名以前未发表过）的临床和遗传特征。

方法

临床和遗传信息是通过 GeneMatcher 合作收集的。所有个体均由当地临床医生进行调查，并通过临床外显子组/基因组测序鉴定基因变异。

结果

临床表现主要是早发性全球发育迟缓、智力障碍、自闭症谱系障碍和注意力缺陷多动障碍，所有这些都指向脑部疾病。Marfanoid 习性，以前被认为是DLG4相关表型的特征，仅在 9 个人中发现，尽管有一些重叠的特征，但无法确定明显的面部畸形。在 45 种不同的DLG4变体中，预计 39 种会导致蛋白质功能丧失，并且大多数是从头发生的（四种来源不明）。蛋白质建模研究表明，鉴定出的六种错义变体会导致结构或功能变化。