Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.

Humans Phenotype Neurodevelopmental Disorders / genetics Wnt Signaling Pathway / genetics Intellectual Disability / genetics Genomics beta Catenin / genetics
Autism Cerebral palsy Familial exudative vitreoretinopathy Microcephaly Wnt beta catenin signaling pathway

Journal

Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831

Informations de publication

Date de publication:
11 2022
Historique:
received: 23 05 2022
revised: 01 08 2022
accepted: 01 08 2022
pubmed: 10 9 2022
medline: 9 11 2022
entrez: 9 9 2022
Statut: ppublish

Résumé

Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP. Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay. The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants. NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.

Identifiants

DOI: 10.1016/j.gim.2022.08.006 PMID: 36083290 PMC: PMC9939054
pubmed: 36083290
pii: S1098-3600(22)00897-8
doi: 10.1016/j.gim.2022.08.006
pmc: PMC9939054
mid: NIHMS1865456
pii:
doi:

Substances chimiques

CTNNB1 protein, human 0
beta Catenin 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2351-2366

Subventions

Organisme : NICHD NIH HHS
ID : R01 HD104938
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS106298
Pays : United States

Informations de copyright

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of Interest F.M. and M.M.M. are employees of GeneDX, Inc. All other authors declare no conflict of interest.

Références

Science. 2002 Jul 19;297(5580):365-9
pubmed: 12130776
Development. 2011 Feb;138(4):667-76
pubmed: 21228006
JAMA. 2021 Feb 2;325(5):467-475
pubmed: 33528536
Dev Med Child Neurol. 2018 Feb;60(2):209-210
pubmed: 29336076
Hum Mutat. 2019 Aug;40(8):1030-1038
pubmed: 31116477
Dev Med Child Neurol. 2014 Apr;56(4):323-8
pubmed: 24111874
JAMA. 2014 Nov 12;312(18):1880-7
pubmed: 25326637
N Engl J Med. 2012 Nov 15;367(20):1921-9
pubmed: 23033978
Stem Cell Res. 2020 Dec;49:102091
pubmed: 33264726
NPJ Genom Med. 2021 Sep 16;6(1):74
pubmed: 34531397
Nucleic Acids Res. 2018 Jan 4;46(D1):D1062-D1067
pubmed: 29165669
Science. 1992 Aug 21;257(5073):1142-4
pubmed: 1509266
Am J Hum Genet. 2009 Apr;84(4):524-33
pubmed: 19344873
Dev Biol. 2005 Mar 1;279(1):155-68
pubmed: 15708565
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
Hum Genet. 2015 Jan;134(1):97-109
pubmed: 25326669
Nat Genet. 2020 Oct;52(10):1046-1056
pubmed: 32989326
Dev Med Child Neurol. 2000 Dec;42(12):816-24
pubmed: 11132255
Mov Disord. 2018 Apr;33(4):656-657
pubmed: 29436745
Mol Genet Genomic Med. 2021 Jan;9(1):e1542
pubmed: 33350591
Oncogene. 2003 Sep 11;22(39):7923-30
pubmed: 12970740
Hum Mol Genet. 2008 Jun 1;17(11):1605-12
pubmed: 18263894
Neuroscience. 2003;122(1):129-43
pubmed: 14596855
Clin Genet. 2016 Jun;89(6):700-7
pubmed: 26757139
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
Cell. 2009 Oct 16;139(2):299-311
pubmed: 19837033
Trends Genet. 2021 Jul;37(7):657-668
pubmed: 33277042
J Clin Invest. 2014 Apr;124(4):1468-82
pubmed: 24614104
Nature. 2017 Feb 23;542(7642):433-438
pubmed: 28135719
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Nat Genet. 2017 Apr;49(4):515-526
pubmed: 28191889
Ann Clin Transl Neurol. 2018 Mar 26;5(5):538-551
pubmed: 29761117
Curr Biol. 2003 Apr 15;13(8):680-5
pubmed: 12699626
Cell. 2004 Mar 19;116(6):883-95
pubmed: 15035989
J Cell Biol. 2000 Feb 7;148(3):567-78
pubmed: 10662781
Am J Hum Genet. 2017 Jun 1;100(6):960-968
pubmed: 28575650
J Med Genet. 2023 Feb;60(2):174-182
pubmed: 35361685
Genet Med. 2017 Sep;19(9):1055-1063
pubmed: 28333917
Eur J Med Genet. 2017 Feb;60(2):130-135
pubmed: 27915094
Ann Clin Transl Neurol. 2022 Feb;9(2):193-205
pubmed: 35076175
Hum Mutat. 2015 Oct;36(10):928-30
pubmed: 26220891
Development. 1995 Nov;121(11):3529-37
pubmed: 8582267
EMBO J. 2012 Jun 13;31(12):2714-36
pubmed: 22617422
Nucleic Acids Res. 2014 Jan;42(Database issue):D986-92
pubmed: 24174537
Science. 2012 Dec 21;338(6114):1619-22
pubmed: 23160955
Am J Hum Genet. 2019 Jun 6;104(6):1182-1201
pubmed: 31130284
Neurol Genet. 2022 Jan 25;8(1):e652
pubmed: 35097204
Eye (Lond). 2015 Jan;29(1):1-14
pubmed: 25323851

Auteurs

Sayaka Kayumi (S)

Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia; Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia.

Luis A Pérez-Jurado (LA)

Genetics Service, Hospital del Mar Medical Research Institute (IMIM), Network Research Centre for Rare Diseases (CIBERER), Barcelona, Spain; Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.

María Palomares (M)

Instituto de Genética Médica y Molecular (INGEMM), La Paz University Hospital, Network Research Centre for Rare Diseases (CIBERER), Madrid, Spain.

Sneha Rangu (S)

Albert Einstein College of Medicine, Bronx, NY; Section of Dermatology, Children's Hospital of Philadelphia, Philadelphia, PA.

Sarah E Sheppard (SE)

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.

Wendy K Chung (WK)

Departments of Pediatrics and Medicine, Columbia University Irving Medical Center, New York, NY.

Michael C Kruer (MC)

Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ; Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ.

Mira Kharbanda (M)

Wessex Clinical Genetics Service, Southampton University Hospitals NHS Foundation Trust, Princess Anne Hospital, Southampton, United Kingdom.

David J Amor (DJ)

Department of Paediatrics, Melbourne Medical School, The University of Melbourne, Parkville, Victoria, Australia; Murdoch Children's Research Institute, Parkville, Victoria, Australia.

George McGillivray (G)

Murdoch Children's Research Institute, Parkville, Victoria, Australia.

Julie S Cohen (JS)

Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD; Department of Neurology, Johns Hopkins University School of Medicine, Kennedy Krieger Institute, Baltimore, MD.

Sixto García-Miñaúr (S)

Instituto de Genética Médica y Molecular (INGEMM), La Paz University Hospital, Network Research Centre for Rare Diseases (CIBERER), Madrid, Spain.

Clare L van Eyk (CL)

Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia; Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia.

Kelly Harper (K)

Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia; Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia.

Lachlan A Jolly (LA)

Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia; Adelaide Biomedical School, The University of Adelaide, Adelaide, South Australia, Australia.

Dani L Webber (DL)

Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia; Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia.

Christopher P Barnett (CP)

Paediatric and Reproductive Genetics Unit, Women's and Children's Hospital, Adelaide, South Australia, Australia.

Fernando Santos-Simarro (F)

Instituto de Genética Médica y Molecular (INGEMM), La Paz University Hospital, Network Research Centre for Rare Diseases (CIBERER), Madrid, Spain.

Marta Pacio-Míguez (M)

Instituto de Genética Médica y Molecular (INGEMM), La Paz University Hospital, Network Research Centre for Rare Diseases (CIBERER), Madrid, Spain.

Angela Del Pozo (AD)

Instituto de Genética Médica y Molecular (INGEMM), La Paz University Hospital, Network Research Centre for Rare Diseases (CIBERER), Madrid, Spain.

Somayeh Bakhtiari (S)

Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ; Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ.

Matthew Deardorff (M)

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Robert's Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA; Departments of Pathology and Laboratory Medicine and Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine of the University of Southern California, Los Angeles, CA.

Holly A Dubbs (HA)

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA.

Kosuke Izumi (K)

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Robert's Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Katheryn Grand (K)

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, CA.

Christopher Gray (C)

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Robert's Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA.

Paul R Mark (PR)

Spectrum Health Medical Genetics, Grand Rapids, MI.

Elizabeth J Bhoj (EJ)

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Dong Li (D)

Center for Applied Genomics, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA.

Xilma R Ortiz-Gonzalez (XR)

Paediatric and Reproductive Genetics Unit, Women's and Children's Hospital, Adelaide, South Australia, Australia; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Beth Keena (B)

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA.

Elaine H Zackai (EH)

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Ethan M Goldberg (EM)

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Guiomar Perez de Nanclares (G)

Molecular (epi)genetics lab, Bioaraba Research Health Institute, Araba University Hospital, Vitoria-Gasteiz, Spain.

Arrate Pereda (A)

Molecular (epi)genetics lab, Bioaraba Research Health Institute, Araba University Hospital, Vitoria-Gasteiz, Spain.

Isabel Llano-Rivas (I)

Department of Genetics, Hospital de Cruces, Barakaldo, Spain.

Ignacio Arroyo (I)

Servicio de Neonatología, Hospital San Pedro de Alcántara, Cáceres, Spain.

María Ángeles Fernández-Cuesta (MÁ)

Neuropediatrics, Hospital Universitario de Basurto, Bilbao, Vizcaya, Spain.

Christel Thauvin-Robinet (C)

Centre de Référence Anomalies du Développement et Syndromes Malformatifs et Centre de Référence Déficiences Intellectuelles de Causes Rares, FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France; L'Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, Laboratoire de Génétique Chromosomique et Moléculaire, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France; INSERM - Bourgogne Franche-Comté University, UMR 1231 GAD Team, Genetics of Developmental Disorders, Dijon, France.

Laurence Faivre (L)

Centre de Référence Anomalies du Développement et Syndromes Malformatifs et Centre de Référence Déficiences Intellectuelles de Causes Rares, FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France; L'Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, Laboratoire de Génétique Chromosomique et Moléculaire, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.

Aurore Garde (A)

Centre de Référence Anomalies du Développement et Syndromes Malformatifs et Centre de Référence Déficiences Intellectuelles de Causes Rares, FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France.

Benoit Mazel (B)

Centre de Référence Anomalies du Développement et Syndromes Malformatifs et Centre de Référence Déficiences Intellectuelles de Causes Rares, FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France.

Ange-Line Bruel (AL)

L'Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, Laboratoire de Génétique Chromosomique et Moléculaire, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France; INSERM - Bourgogne Franche-Comté University, UMR 1231 GAD Team, Genetics of Developmental Disorders, Dijon, France.

Michael L Tress (ML)

Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

Eva Brilstra (E)

Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.

Amena Smith Fine (AS)

Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD; Department of Neurology, Johns Hopkins University School of Medicine, Kennedy Krieger Institute, Baltimore, MD.

Kylie E Crompton (KE)

Department of Paediatrics, Melbourne Medical School, The University of Melbourne, Parkville, Victoria, Australia; Murdoch Children's Research Institute, Parkville, Victoria, Australia.

Alexander P A Stegmann (APA)

Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.

Margje Sinnema (M)

Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.

Servi C J Stevens (SCJ)

Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.

Joost Nicolai (J)

Department of Neurology, Maastricht University Medical Center, Maastricht, the Netherlands.

Gaetan Lesca (G)

Department of Medical Genetics, Hospices Civils de Lyon, Lyon, France.

Laurence Lion-François (L)

Department of Pediatric Neurology, Hospices Civils de Lyon, Lyon, France.

Damien Haye (D)

Department of Medical Genetics, Hospices Civils de Lyon, Lyon, France.

Nicolas Chatron (N)

Department of Medical Genetics, Hospices Civils de Lyon, Lyon, France.

Amelie Piton (A)

Department of Medical genetics, Hopitaux Universitaires de Strasbourg, France.

Mathilde Nizon (M)

Service de Génétique Médicale, CHU Nantes, Nantes, France.

Benjamin Cogne (B)

Service de Génétique Médicale, CHU Nantes, Nantes, France.

Siddharth Srivastava (S)

Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA.

Jennifer Bassetti (J)

Department of Pediatrics, Division of Medical Genetics, Weill Cornell Medicine, New York, NY.

Candace Muss (C)

Nemours/A.I duPont Hospital for Children, Wilmington, DE.

Karen W Gripp (KW)

Nemours/A.I duPont Hospital for Children, Wilmington, DE.

Rebecca A Procopio (RA)

Department of Ophthalmology, Wills Eye Hospital, Philadelphia, PA.

Francisca Millan (F)

GeneDX, Gaithersburg, MD.

Michelle M Morrow (MM)

GeneDX, Gaithersburg, MD.

Melissa Assaf (M)

Banner Children's Specialists Neurology Clinic, Glendale, AZ.

Andres Moreno-De-Luca (A)

Department of Radiology, Autism & Developmental Medicine Institute, Genomic Medicine Institute, Geisinger, Danville, PA.

Shelagh Joss (S)

West of Scotland Clinical Genetics Service, Glasgow, United Kingdom.

Mark J Hamilton (MJ)

West of Scotland Clinical Genetics Service, Glasgow, United Kingdom.

Marta Bertoli (M)

Northern Genetics Service, Newcastle upon Tyne, United Kingdom.

Nicola Foulds (N)

Wessex Clinical Genetics Service, Southampton University Hospitals NHS Foundation Trust, Princess Anne Hospital, Southampton, United Kingdom.

Shane McKee (S)

Northern Ireland Regional Genetics Centre, Belfast, United Kingdom.

Alastair H MacLennan (AH)

Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia; Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia.

Jozef Gecz (J)

Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia; Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.

Mark A Corbett (MA)

Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia; Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia. Electronic address: mark.corbett@adelaide.edu.au.

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Genomic and phenotypic characterization of 404...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Genomic and phenotypic characterization of 404...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Genomic and phenotypic characterization of 404...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Voie de signalisation Wnt › Genomic and phenotypic characterization of 404...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Déficience intellectuelle › Genomic and phenotypic characterization of 404...
questionsmedicales.fr › Disciplines des sciences naturelles › Disciplines des sciences biologiques › Biologie › Génétique › Génomique › Genomic and phenotypic characterization of 404...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › bêta-Caténine › Genomic and phenotypic characterization of 404...