Journal

Journal of medical genetics
ISSN: 1468-6244
Titre abrégé: J Med Genet
Pays: England
ID NLM: 2985087R

Informations de publication

Date de publication:
Oct 2022
Historique:
received: 28 01 2021
accepted: 09 11 2021
pubmed: 22 12 2021
medline: 28 9 2022
entrez: 21 12 2021
Statut: ppublish

Résumé

High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD). This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). Our study establishes that de novo coding variants in

Sections du résumé

BACKGROUND
High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD).
METHODS
This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous
RESULTS
A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del).
CONCLUSION
Our study establishes that de novo coding variants in

Identifiants

pubmed: 34930816
pii: jmedgenet-2021-107751
doi: 10.1136/jmedgenet-2021-107751
pmc: PMC9241146
mid: NIHMS1793510
doi:

Substances chimiques

Amino Acids 0
RNA, Messenger 0
AGO1 protein, human 0
Argonaute Proteins 0

Types de publication

Journal Article Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

965-975

Subventions

Organisme : NIAAA NIH HHS
ID : R01 AA026834
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH119689
Pays : United States

Informations de copyright

© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: KMW, ET, FM, AD and MJT are employees of GeneDx. ZP and KM are employees of Ambry Genetics.

Auteurs

Audrey Schalk (A)

Institut de génétique médicale d'Alsace (IGMA), Laboratoire de Diagnostic Génétique, Hôpitaux universitaires de Strasbourg, Strasbourg, Alsace, France.

Margot A Cousin (MA)

Department of Quantitative Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Nikita R Dsouza (NR)

Bioinformatics Research and Development Laboratory, Genomics Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Thomas D Challman (TD)

Autism & Developmental Medicine Institute, Geisinger-Lewistown Hospital, Lewistown, Pennsylvania, USA.

Karen E Wain (KE)

Autism & Developmental Medicine Institute, Geisinger-Lewistown Hospital, Lewistown, Pennsylvania, USA.

Zoe Powis (Z)

Department of Clinical Genomics, Ambry Genetics Corp, Aliso Viejo, California, USA.

Kelly Minks (K)

Department of Clinical Genomics, Ambry Genetics Corp, Aliso Viejo, California, USA.

Aurélien Trimouille (A)

Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, Aquitaine, France.
Maladies rares: Génétique et Métabolisme (MRGM), INSERM U1211, Université de Bordeaux Centre de Génomique Fonctionnelle de Bordeaux, Bordeaux, Nouvelle-Aquitaine, France.

Eulalie Lasseaux (E)

Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, Aquitaine, France.

Didier Lacombe (D)

Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, Aquitaine, France.
Maladies rares: Génétique et Métabolisme (MRGM), INSERM U1211, Université de Bordeaux Centre de Génomique Fonctionnelle de Bordeaux, Bordeaux, Nouvelle-Aquitaine, France.

Chloé Angelini (C)

Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, Aquitaine, France.
Maladies rares: Génétique et Métabolisme (MRGM), INSERM U1211, Université de Bordeaux Centre de Génomique Fonctionnelle de Bordeaux, Bordeaux, Nouvelle-Aquitaine, France.

Vincent Michaud (V)

Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, Aquitaine, France.
Maladies rares: Génétique et Métabolisme (MRGM), INSERM U1211, Université de Bordeaux Centre de Génomique Fonctionnelle de Bordeaux, Bordeaux, Nouvelle-Aquitaine, France.

Julien Van-Gils (J)

Département de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, Aquitaine, France.

Nino Spataro (N)

Genetics Laboratory, UDIAT-Centre Diagnòstic, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí, Sabadell, Catalunya, Spain.

Anna Ruiz (A)

Genetics Laboratory, UDIAT-Centre Diagnòstic, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí, Sabadell, Catalunya, Spain.

Elizabeth Gabau (E)

Paediatric Unit, Parc Tauli Foundation-UAB University Institute, Sabadell, Catalunya, Spain.

Elliot Stolerman (E)

106 Gregor Mendel Cir, Greenwood Genetic Center Inc, Greenwood, South Carolina, USA.

Camerun Washington (C)

106 Gregor Mendel Cir, Greenwood Genetic Center Inc, Greenwood, South Carolina, USA.

Ray Louie (R)

106 Gregor Mendel Cir, Greenwood Genetic Center Inc, Greenwood, South Carolina, USA.

Brendan C Lanpher (BC)

Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA.

Jennifer L Kemppainen (JL)

Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA.

Micheil Innes (M)

Department of Medical Genetics and Alberta Children's Hospital Research Institute, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada.

Frank Kooy (F)

Center Medical Genetics, University Hospital Antwerp, Antwerp, Belgium.

Marije Meuwissen (M)

Center Medical Genetics, University Hospital Antwerp, Antwerp, Belgium.

Alice Goldenberg (A)

Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, Centre Hospitalier Universitaire de Rouen, Rouen, Normandie, France.

Francois Lecoquierre (F)

Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, Centre Hospitalier Universitaire de Rouen, Rouen, Normandie, France.

Gabriella Vera (G)

Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, Centre Hospitalier Universitaire de Rouen, Rouen, Normandie, France.

Karin E M Diderich (KEM)

Erasmus Medical Center Department of Clinical Genetics, Rotterdam, Netherlands.

Beth Sheidley (B)

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.

Christelle Moufawad El Achkar (CM)

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.

Meredith Park (M)

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.

Fadi F Hamdan (FF)

Division of Medical Genetics, Department of Pediatrics, Saint Justine Hospital, Montreal, Quebec, Canada.

Jacques L Michaud (JL)

Division of Medical Genetics, Department of Pediatrics, Saint Justine Hospital, Montreal, Quebec, Canada.

Ann J Lewis (AJ)

Pediatric Neurology, Kaiser Permanente Santa Clara Medical Center, Santa Clara, California, USA.

Christiane Zweier (C)

Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Department of Human Genetics, Inselspital University Hospital Bern, Bern, BE, Switzerland.

André Reis (A)

Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Matias Wagner (M)

Institute of Human Genetics, Technische Universitat Munchen, Munchen, Bayern, Germany.
Institute of Neurogenomics, Helmholtz Zentrum Munchen Deutsches Forschungszentrum fur Umwelt und Gesundheit, Neuherberg, Bayern, Germany.

Heike Weigand (H)

Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr von Hauner Children's Hospital, Munich University Hospital (Ludwig Maximilians University), Munchen, Bayern, Germany.

Hubert Journel (H)

Service de Génétique Médicale, Hopital Chubert, Vannes, Bretagne, France.

Boris Keren (B)

Département de Génétique et de Cytogénétique, Centre de Reference Déficience Intellectuelle de Causes Rares, GRC UPMC « Déficience Intellectuelle et Autisme », Hôpital Universitaire Pitié Salpêtrière, Paris, Île-de-France, France.
INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Épinière, Paris, Île-de-France, France.

Sandrine Passemard (S)

APHP, Hopital Universitaire Robert-Debre Departement de genetique, Paris, Île-de-France, France.
NeuroDiderot, UMR1141, INSERM, Paris, France.

Cyril Mignot (C)

Département de Génétique et de Cytogénétique, Centre de Reference Déficience Intellectuelle de Causes Rares, GRC UPMC « Déficience Intellectuelle et Autisme », Hôpital Universitaire Pitié Salpêtrière, Paris, Île-de-France, France.
INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Épinière, Paris, Île-de-France, France.

Koen van Gassen (K)

Department of Genetics, University Medical Centre Utrecht Center for Molecular Medicine, Utrecht, The Netherlands.

Eva H Brilstra (EH)

Department of Genetics, University Medical Centre Utrecht Center for Molecular Medicine, Utrecht, The Netherlands.

Gina Itzikowitz (G)

Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, Rondebosch, Western Cape, South Africa.

Emily O'Heir (E)

Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute for Genome Research, Cambridge, Massachusetts, USA.
Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.

Jake Allen (J)

Stanley Center for Psychiatric Research, Broad Institute Stanley Center for Psychiatric Research, Cambridge, Massachusetts, USA.

Kirsten A Donald (KA)

Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, Rondebosch, Western Cape, South Africa.
Neuroscience Institute, University of Cape Town, Rondebosch, Western Cape, South Africa.

Bruce Richard Korf (BR)

Department of Genetics, The University of Alabama at Birmingham, Birmingham, Alabama, USA.

Tammi Skelton (T)

Department of Genetics, The University of Alabama at Birmingham, Birmingham, Alabama, USA.

Michelle Thompson (M)

Department of Genetics, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
HudsonAlpha Institute, HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.

Nathaniel H Robin (NH)

Department of Genetics, The University of Alabama at Birmingham, Birmingham, Alabama, USA.

Natasha L Rudy (NL)

Department of Genetics, The University of Alabama at Birmingham, Birmingham, Alabama, USA.

William B Dobyns (WB)

Department of Pediatrics (Genetics) and Neurology, University of Washington, Seattle Children's Research Institute, Seattle, Washington, USA.

Kimberly Foss (K)

Department of Pediatrics (Genetics) and Neurology, University of Washington, Seattle Children's Research Institute, Seattle, Washington, USA.

Yuri Alexander Zarate (YA)

Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

Katherine A Bosanko (KA)

Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

Yves Alembik (Y)

Institut de génétique médicale d'Alsace (IGMA), Service de Génétique Médicale, Hôpitaux universitaires de Strasbourg, Strasbourg, Alsace, France.

Benjamin Durand (B)

Institut de génétique médicale d'Alsace (IGMA), Service de Génétique Médicale, Hôpitaux universitaires de Strasbourg, Strasbourg, Alsace, France.

Frederic Tran Mau-Them (F)

Institut de génétique médicale d'Alsace (IGMA), Laboratoire de Diagnostic Génétique, Hôpitaux universitaires de Strasbourg, Strasbourg, Alsace, France.

Emmanuelle Ranza (E)

Medigenome, Swiss Institute of Medicine, Bern, Bern, Switzerland.

Xavier Blanc (X)

Medigenome, Swiss Institute of Medicine, Bern, Bern, Switzerland.

Stylianos E Antonarakis (SE)

Medigenome, Swiss Institute of Medicine, Bern, Bern, Switzerland.

Kirsty McWalter (K)

GeneDx, GeneDx, Gaithersburg, Maryland, USA.

Erin Torti (E)

GeneDx, GeneDx, Gaithersburg, Maryland, USA.

Francisca Millan (F)

GeneDx, GeneDx, Gaithersburg, Maryland, USA.

Amy Dameron (A)

GeneDx, GeneDx, Gaithersburg, Maryland, USA.

Mari Tokita (M)

GeneDx, GeneDx, Gaithersburg, Maryland, USA.

Michael T Zimmermann (MT)

Bioinformatics Research and Development Laboratory, Genomics Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Eric W Klee (EW)

Department of Quantitative Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA.

Amelie Piton (A)

Neurogenetics and Translational Medecine, Institut of Genetics and Molecular and Cellular Biology, Illkirch-Grafenstaden, Grand Est, France piton@igbmc.fr.

Benedicte Gerard (B)

Institut de génétique médicale d'Alsace (IGMA), Laboratoire de Diagnostic Génétique, Hôpitaux universitaires de Strasbourg, Strasbourg, Alsace, France.

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