DLG4-related synaptopathy: a new rare brain disorder

Agustí Rodríguez-Palmero; Melissa Maria Boerrigter; David Gómez-Andrés; Kimberly A Aldinger; Íñigo Marcos-Alcalde; Bernt Popp; David B Everman; Alysia Kern Lovgren; Stephanie Arpin; Vahid Bahrambeigi; Gea Beunders; Anne-Marie Bisgaard; V A Bjerregaard; Ange-Line Bruel; Thomas D Challman; Benjamin Cogné; Christine Coubes; Stella A de Man; Anne-Sophie Denommé-Pichon; Thomas J Dye; Frances Elmslie; Lars Feuk; Sixto García-Miñaúr; Tracy Gertler; Elisa Giorgio; Nicolas Gruchy; Tobias B Haack; Chad R Haldeman-Englert; Bjørn Ivar Haukanes; Juliane Hoyer; Anna C E Hurst; Bertrand Isidor; Maria Johansson Soller; Sulagna Kushary; Malin Kvarnung; Yuval E Landau; Kathleen A Leppig; Anna Lindstrand; Lotte Kleinendorst; Alex MacKenzie; Giorgia Mandrile; Bryce A Mendelsohn; Setareh Moghadasi; Jenny E Morton; Sebastien Moutton; Amelie J Müller; Melanie O'Leary; Marta Pacio-Míguez; Maria Palomares-Bralo; Sumit Parikh; Rolph Pfundt; Ben Pode-Shakked; Anita Rauch; Elena Repnikova; Anya Revah-Politi; Meredith J Ross; Claudia A L Ruivenkamp; Elisabeth Sarrazin; Juliann M Savatt; Agatha Schlüter; Bitten Schönewolf-Greulich; Zohra Shad; Charles Shaw-Smith; Joseph T Shieh; Motti Shohat; Stephanie Spranger; Heidi Thiese; Frederic Tran Mau-Them; Bregje van Bon; Ineke van de Burgt; Ingrid M B H van de Laar; Esmée van Drie; Mieke M van Haelst; Conny M van Ravenswaaij-Arts; Edgard Verdura; Antonio Vitobello; Stephan Waldmüller; Sharon Whiting; Christiane Zweier; Carlos E Prada; Bert B A de Vries; William B Dobyns; Simone F Reiter; Paulino Gómez-Puertas; Aurora Pujol; Zeynep Tümer

doi:10.1038/s41436-020-01075-9

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DLG4-related synaptopathy: a new rare brain disorder

Journal article

Peer reviewed

DLG4-related synaptopathy: a new rare brain disorder

Agustí Rodríguez-Palmero, Melissa Maria Boerrigter, David Gómez-Andrés, Kimberly A Aldinger, Íñigo Marcos-Alcalde, Bernt Popp, David B Everman, Alysia Kern Lovgren, Stephanie Arpin, Vahid Bahrambeigi, …

Genetics in medicine, Vol.23(5), pp.888-899

05/01/2021

DOI: https://doi.org/10.1038/s41436-020-01075-9

PMID: 33597769

Abstract

Autism Spectrum Disorder - diagnosis

Autism Spectrum Disorder - genetics

Brain

Brain Diseases

Disks Large Homolog 4 Protein - genetics

Humans

Intellectual Disability

Neurodevelopmental Disorders - diagnosis

Neurodevelopmental Disorders - genetics

Phenotype

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. 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. 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. 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.

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Title: DLG4-related synaptopathy: a new rare brain disorder
Creators - without role: Agustí Rodríguez-Palmero - Hospital Universitari Germans Trias i Pujol
Melissa Maria Boerrigter - Radboud University Nijmegen
David Gómez-Andrés - Vall d'Hebron Institut de Recerca
Kimberly A Aldinger - Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA
Íñigo Marcos-Alcalde - Centro de Biología Molecular Severo Ochoa
Bernt Popp - University Hospital Leipzig
David B Everman - Greenwood Genetic Center
Alysia Kern Lovgren - Broad Institute
Stephanie Arpin - Inserm
Vahid Bahrambeigi - Greenwood Genetic Center
Gea Beunders - University Medical Center Groningen
Anne-Marie Bisgaard - Copenhagen University Hospital
V A Bjerregaard - Kennedy Center
Ange-Line Bruel - CHU Dijon Bourgogne
Thomas D Challman - Autism & Developmental Medicine Institute
Benjamin Cogné - Génétique Médicale & Génomique Fonctionelle
Christine Coubes - Génétique Médicale & Génomique Fonctionelle
Stella A de Man - Department of Pediatrics, Amphia Hospital, Breda, The Netherlands
Anne-Sophie Denommé-Pichon - CHU Dijon Bourgogne
Thomas J Dye - University of Cincinnati Medical Center
Frances Elmslie - St George's, University of London
Lars Feuk - Uppsala University
Sixto García-Miñaúr - Hospital Universitario La Paz
Tracy Gertler - Lurie Children's Hospital
Elisa Giorgio - University of Turin
Nicolas Gruchy - Université de Caen Normandie
Tobias B Haack - University of Tübingen
Chad R Haldeman-Englert - Nashotah House Theological Seminary
Bjørn Ivar Haukanes - Haukeland University Hospital
Juliane Hoyer - Friedrich-Alexander-Universität Erlangen-Nürnberg
Anna C E Hurst - University of Alabama at Birmingham
Bertrand Isidor - Inserm
Maria Johansson Soller - Karolinska University Hospital
Sulagna Kushary - Columbia University
Malin Kvarnung - Karolinska University Hospital
Yuval E Landau - Clalit Health Services
Kathleen A Leppig - Kaiser Permanente
Anna Lindstrand - Karolinska Institutet
Lotte Kleinendorst - Amsterdam University Medical Centers
Alex MacKenzie - University of Ottawa
Giorgia Mandrile - Thalassemia Centre and Genetic Unit, San Luigi University Hospital, Orbassano, Italy
Bryce A Mendelsohn - University of California, San Francisco
Setareh Moghadasi - Leiden University Medical Center
Jenny E Morton - Birmingham Women's Hospital
Sebastien Moutton - Infirmerie Protestante
Amelie J Müller - University of Tübingen
Melanie O'Leary - Broad Institute
Marta Pacio-Míguez - Hospital Universitario La Paz
Maria Palomares-Bralo - Hospital Universitario La Paz
Sumit Parikh - Cleveland Clinic
Rolph Pfundt - Sheba Medical Center
Ben Pode-Shakked - Sheba Medical Center
Anita Rauch - University of Zurich
Elena Repnikova - Children's Mercy Hospital
Anya Revah-Politi - Columbia University Irving Medical Center
Meredith J Ross - Columbia University Irving Medical Center
Claudia A L Ruivenkamp - Leiden University Medical Center
Elisabeth Sarrazin - Centre Hospitalier Universitaire de Martinique
Juliann M Savatt - Autism & Developmental Medicine Institute
Agatha Schlüter - Institut d'Investigació Biomédica de Bellvitge
Bitten Schönewolf-Greulich - Rigshospitalet
Zohra Shad - Cook Children's Medical Center
Charles Shaw-Smith - Royal Devon & Exeter NHS Foundation Trust
Joseph T Shieh - University of California, San Francisco
Motti Shohat - Sheba Medical Center
Stephanie Spranger - Klinikum Bremen-Mitte
Heidi Thiese - Kaiser Permanente
Frederic Tran Mau-Them - Inserm
Bregje van Bon - Radboud University Medical Center
Ineke van de Burgt - Radboud University Medical Center
Ingrid M B H van de Laar - Erasmus MC
Esmée van Drie - Amsterdam University Medical Centers
Mieke M van Haelst - University of Amsterdam
Conny M van Ravenswaaij-Arts - University Medical Center Groningen
Edgard Verdura - Institut d'Investigació Biomédica de Bellvitge
Antonio Vitobello - Université de Bourgogne
Stephan Waldmüller - University of Tübingen
Sharon Whiting - Children's Hospital of Eastern Ontario
Christiane Zweier - Friedrich-Alexander-Universität Erlangen-Nürnberg
Carlos E Prada - University of Cincinnati Medical Center
Bert B A de Vries - Radboud University Medical Center
William B Dobyns - University of Washington
Simone F Reiter - Haukeland University Hospital
Paulino Gómez-Puertas - Centro de Biología Molecular Severo Ochoa
Aurora Pujol - Institut d'Investigació Biomédica de Bellvitge
Zeynep Tümer - University of Copenhagen
Publication Details: Genetics in medicine, Vol.23(5), pp.888-899
Grant note: UM1 HG008900 / NHGRI NIH HHS
Identifiers: 9913701209631
Academic Unit: Genomic Health; Pediatrics
Language: English
Resource Type: Journal article