Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

Sarah E Sheppard; Laura Bryant; Rochelle N Wickramasekara; Courtney Vaccaro; Brynn Robertson; Jodi Hallgren; Jason Hulen; Cynthia J Watson; Victor Faundes; Yannis Duffourd; Pearl Lee; M Celeste Simon; Xavier de la Cruz; Natália Padilla; Marco Flores-Mendez; Naiara Akizu; Jacqueline Smiler; Renata Pellegrino Da Silva; Dong Li; Michael March; Abdias Diaz-Rosado; Isabella Peixoto de Barcelos; Zhao Xiang Choa; Chin Yan Lim; Christèle Dubourg; Hubert Journel; Florence Demurger; Maureen Mulhern; Cigdem Akman; Natalie Lippa; Marisa Andrews; Dustin Baldridge; John Constantino; Arie van Haeringen; Irina Snoeck-Streef; Penny Chow; Anne Hing; John M Graham, Jr; Margaret Au; Laurence Faivre; Wei Shen; Rong Mao; Janice Palumbos; David Viskochil; William Gahl; Cynthia Tifft; Ellen Macnamara; Natalie Hauser; Rebecca Miller; Jessica Maffeo; Alexandra Afenjar; Diane Doummar; Boris Keren; Pamela Arn; Sarah Macklin-Mantia; Ilse Meerschaut; Bert Callewaert; André Reis; Christiane Zweier; Carole Brewer; Anand Saggar; Marie F Smeland; Ajith Kumar; Frances Elmslie; Charu Deshpande; Mathilde Nizon; Benjamin Cogne; Yvette van Ierland; Martina Wilke; Marjon van Slegtenhorst; Suzanne Koudijs; Jin Yun Chen; David Dredge; Danielle Pier; Saskia Wortmann; Erik-Jan Kamsteeg; Johannes Koch; Devon Haynes; Lynda Pollack; Hannah Titheradge; Kara Ranguin; Anne-Sophie Denommé-Pichon; Sacha Weber; Rubén Pérez de la Fuente; Jaime Sánchez Del Pozo; Jose Miguel Lezana Rosales; Pascal Joset; Katharina Steindl; Anita Rauch; Davide Mei; Francesco Mari; Renzo Guerrini; James Lespinasse; Frédéric Tran Mau-Them; Christophe Philippe; Benjamin Dauriat; Laure Raymond; Sébastien Moutton; Anna M Cueto-González; Tiong Yang Tan; Cyril Mignot; Sarah Grotto; Florence Renaldo; Theodore G Drivas; Laura Hennessy; Anna Raper; Ilaria Parenti; Frank J Kaiser; Alma Kuechler; Øyvind L Busk; Lily Islam; Jacob A Siedlik; Lindsay B Henderson; Jane Juusola; Richard Person; Rhonda E Schnur; Antonio Vitobello; Siddharth Banka; Elizabeth J Bhoj; Holly A F Stessman

doi:10.1126/sciadv.ade1463

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Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

Journal article

Peer reviewed

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

Sarah E Sheppard, Laura Bryant, Rochelle N Wickramasekara, Courtney Vaccaro, Brynn Robertson, Jodi Hallgren, Jason Hulen, Cynthia J Watson, Victor Faundes, Yannis Duffourd, …

Science advances, Vol.9(10), pp.eade1463-eade1463

03/10/2023

DOI: https://doi.org/10.1126/sciadv.ade1463

PMID: 36897941

Abstract

Animals

Haploinsufficiency

Humans

Megalencephaly

Methyltransferases - genetics

Mice

Mice, Knockout

Neurodevelopmental Disorders - genetics

Phenotype

Pathogenic variants in , a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest ( = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in -related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

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Title: Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice
Creators: Sarah E Sheppard - Children's Hospital of Philadelphia
Laura Bryant - Children's Hospital of Philadelphia
Rochelle N Wickramasekara - Creighton University
Courtney Vaccaro - Children's Hospital of Philadelphia
Brynn Robertson - Creighton University
Jodi Hallgren - Creighton University
Jason Hulen - Creighton University
Cynthia J Watson - Creighton University
Victor Faundes - University of Manchester
Yannis Duffourd - Centre Hospitalier Universitaire Dijon Bourgogne
Pearl Lee - Cancer Research Institute
M Celeste Simon - Cancer Research Institute
Xavier de la Cruz - Vall d'Hebron Institut de Recerca
Natália Padilla - Vall d'Hebron Institut de Recerca
Marco Flores-Mendez - Children's Hospital of Philadelphia
Naiara Akizu - Children's Hospital of Philadelphia
Jacqueline Smiler - Children's Hospital of Philadelphia
Renata Pellegrino Da Silva - Children's Hospital of Philadelphia
Dong Li - Children's Hospital of Philadelphia
Michael March - Children's Hospital of Philadelphia
Abdias Diaz-Rosado - Children's Hospital of Philadelphia
Isabella Peixoto de Barcelos - Children's Hospital of Philadelphia
Zhao Xiang Choa - National Skin Centre
Chin Yan Lim - National Skin Centre
Christèle Dubourg - Centre Hospitalier Universitaire de Rennes
Hubert Journel - Centre hospitalier Bretagne Atlantique
Florence Demurger - Centre Hospitalier Universitaire de Rennes
Maureen Mulhern - Columbia University Irving Medical Center
Cigdem Akman - Columbia University Irving Medical Center
Natalie Lippa - Columbia University
Marisa Andrews - Washington University in St. Louis
Dustin Baldridge - Washington University in St. Louis
John Constantino - Washington University in St. Louis
Arie van Haeringen - Leiden University Medical Center
Irina Snoeck-Streef - University Medical Center Utrecht
Penny Chow - University of Washington
Anne Hing - University of Washington
John M Graham, Jr - Cedars-Sinai Medical Center
Margaret Au - Cedars-Sinai Medical Center
Laurence Faivre - University of Burgundy
Wei Shen - University of Utah
Rong Mao - University of Utah
Janice Palumbos - University of Utah
David Viskochil - University of Utah
William Gahl - National Human Genome Research Institute
Cynthia Tifft - National Human Genome Research Institute
Ellen Macnamara - National Human Genome Research Institute
Natalie Hauser - Inova Fairfax Hospital
Rebecca Miller - Inova Fairfax Hospital
Jessica Maffeo - Inova Fairfax Hospital
Alexandra Afenjar - Hôpital Armand-Trousseau
Diane Doummar - Hôpital Armand-Trousseau
Boris Keren - Pitié-Salpêtrière Hospital
Pamela Arn - Department of Pediatrics, Nemours Children's Specialty Care, Jacksonville, FL, USA.
Sarah Macklin-Mantia - Department of Clinical Genomics, Mayo Clinic Florida, Jacksonville, FL, USA
Ilse Meerschaut - Ghent University Hospital
Bert Callewaert - Ghent University Hospital
André Reis - Friedrich-Alexander-Universität Erlangen-Nürnberg
Christiane Zweier - Friedrich-Alexander-Universität Erlangen-Nürnberg
Carole Brewer - Heavitree Hospital
Anand Saggar - St George's Hospital
Marie F Smeland - University Hospital of North Norway
Ajith Kumar - Great Ormond Street Hospital
Frances Elmslie - St George’s University Hospitals NHS Foundation Trust
Charu Deshpande - Guy's Hospital
Mathilde Nizon - Medical Genetics & Functional Genomics
Benjamin Cogne - Medical Genetics & Functional Genomics
Yvette van Ierland - Erasmus MC
Martina Wilke - Erasmus MC
Marjon van Slegtenhorst - Erasmus MC
Suzanne Koudijs - Erasmus MC
Jin Yun Chen - Massachusetts General Hospital
David Dredge - Paracelsus Medical University
Danielle Pier - Massachusetts General Hospital
Saskia Wortmann - Paracelsus Medical University
Erik-Jan Kamsteeg - Paracelsus Medical University
Johannes Koch - Paracelsus Medical University
Devon Haynes - Arnold Palmer Hospital for Children
Lynda Pollack - Arnold Palmer Hospital for Children
Hannah Titheradge - Birmingham Women’s and Children’s NHS Foundation Trust
Kara Ranguin - Université de Caen Normandie
Anne-Sophie Denommé-Pichon - Centre Hospitalier Universitaire Dijon Bourgogne
Sacha Weber - Université de Caen Normandie
Rubén Pérez de la Fuente - UDISGEN (Unidad de Dismorfología y Genética) 12 de Octubre University Hospital, Madrid, Spain
Jaime Sánchez Del Pozo - UDISGEN (Unidad de Dismorfología y Genética) 12 de Octubre University Hospital, Madrid, Spain
Jose Miguel Lezana Rosales - UDISGEN (Unidad de Dismorfología y Genética) 12 de Octubre University Hospital, Madrid, Spain
Pascal Joset - University of Zurich
Katharina Steindl - University of Zurich
Anita Rauch - University of Zurich
Davide Mei - Meyer Children's Hospital
Francesco Mari - Meyer Children's Hospital
Renzo Guerrini - Meyer Children's Hospital
James Lespinasse - Centre Hospitalier de Chambéry
Frédéric Tran Mau-Them - Inserm
Christophe Philippe - Centre Hospitalier Universitaire Dijon Bourgogne
Benjamin Dauriat - Centre Hospitalier Universitaire de Limoges
Laure Raymond - Eurofins
Sébastien Moutton - Eurofins
Anna M Cueto-González - Vall d'Hebron Hospital Universitari
Tiong Yang Tan - Victorian Clinical Genetics Services
Cyril Mignot - Assistance Publique – Hôpitaux de Paris
Sarah Grotto - Assistance Publique – Hôpitaux de Paris
Florence Renaldo - Hôpital Armand-Trousseau
Theodore G Drivas - University of Pennsylvania
Laura Hennessy - University of Pennsylvania
Anna Raper - University of Pennsylvania
Ilaria Parenti - University of Duisburg-Essen
Frank J Kaiser - University of Duisburg-Essen
Alma Kuechler - University of Duisburg-Essen
Øyvind L Busk - Telemark Hospital
Lily Islam - Birmingham Women’s and Children’s NHS Foundation Trust
Jacob A Siedlik - Creighton University
Lindsay B Henderson - GeneDx, Gaithersburg, MD, USA.
Jane Juusola - GeneDx, Gaithersburg, MD, USA.
Richard Person - GeneDx, Gaithersburg, MD, USA.
Rhonda E Schnur - Rowan University
Antonio Vitobello - Centre Hospitalier Universitaire Dijon Bourgogne
Siddharth Banka - University of Manchester
Elizabeth J Bhoj - Children's Hospital of Philadelphia
Holly A F Stessman - Creighton University
Publication Details: Science advances, Vol.9(10), pp.eade1463-eade1463
Identifiers: 991005969882202656
Academic Unit: Pharmacology and Neuroscience
Language: English
Resource Type: Journal article

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

Abstract

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