Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

Sheppard SE, Bryant L, Wickramasekara RN, Vaccaro C, Robertson B, Hallgren J, Hulen J, Watson CJ, Faundes V, Duffourd Y, Lee P, Celeste Simon M, de la Cruz X, Padilla N, Flores-Mendez M, Akizu N, Smiler J, Da Silva RP, Li D, March M, Diaz-Rosado A, de Barcelos IP, Choa ZX, Lim CY, Dubourg C, Journel H, Demurger F, Mulhern M, Akman C, Lippa N, Andrews M, Baldridge D, Constantino J, van Haeringen A, Snoeck-Streef I, Chow P, Hing A, Graham JM, Au M, Faivre L, Shen W, Mao R, Palumbos J, Viskochil D, Gahl W, Tifft C, Macnamara E, Hauser N, Miller R, Maffeo J, Afenjar A, Doummar D, Keren B, Arn P, Macklin-Mantia S, Meerschaut I, Callewaert B, Reis A, Zweier C, Brewer C, Saggar A, Smeland MF, Kumar A, Elmslie F, Deshpande C, Nizon M, Cogne B, van Ierland Y, Wilke M, van Slegtenhorst M, Koudijs S, Chen JY, Dredge D, Pier D, Wortmann S, Kamsteeg EJ, Koch J, Haynes D, Pollack L, Titheradge H, Ranguin K, Denommé-Pichon AS, Weber S, de la Fuente RP, del Pozo JS, Rosales JML, Joset P, Steindl K, Rauch A, Mei D, Mari F, Guerrini R, Lespinasse J, Mau-Them FT, Philippe C, Dauriat B, Raymond L, Moutton S, Cueto-González AM, Tan TY, Mignot C, Grotto S, Renaldo F, Drivas TG, Hennessy L, Raper A, Parenti I, Kaiser FJ, Kuechler A, Busk ØL, Islam L, Siedlik JA, Henderson LB, Juusola J, Person R, Schnur RE, Vitobello A, Banka S, Bhoj EJ, Stessman HA (2023)

Publication Type: Journal article

Publication year: 2023


Book Volume: 9

Article Number: eade1463

Journal Issue: 10

DOI: 10.1126/sciadv.ade1463


Pathogenic variants in KMT5B, 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 (n = 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 Kmt5b 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 KMT5Brelated neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

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Involved external institutions

Penn Medicine US United States (USA) (US) Washington University US United States (USA) (US) Massachusetts General Hospital US United States (USA) (US) Creighton University US United States (USA) (US) Hôpital Armand-Trousseau (AP-HP) FR France (FR) University Hospital Ghent BE Belgium (BE) Birmingham Women's and Children's NHS Foundation Trust GB United Kingdom (GB) Children's Hospital of Philadelphia US United States (USA) (US) University of Manchester GB United Kingdom (GB) Centre hospitalier universitaire (CHU) de Dijon Bourgogne FR France (FR) Autonomous University of Barcelona (UAB) / Universitat Autònoma de Barcelona ES Spain (ES) Agency for Science, Technology and Research (A*STAR) SG Singapore (SG) Centre hospitalier universitaire de Rennes / CHU Rennes FR France (FR) Hospital Chubert FR France (FR) Columbia University Irving Medical Center (CUIMC) US United States (USA) (US) Leiden University Medical Center NL Netherlands (NL) University Medical Centre Utrecht (UMC Utrecht) NL Netherlands (NL) University of Washington US United States (USA) (US) University of California Los Angeles (UCLA) US United States (USA) (US) Université Bourgogne Franche-Comté FR France (FR) University of Utah US United States (USA) (US) National Human Genome Research Institute (NHGRI) US United States (USA) (US) Inova Fairfax Hospital (IFH) US United States (USA) (US) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière FR France (FR) Nemours Children's Hospital US United States (USA) (US) Mayo Clinic Hospital US United States (USA) (US) Royal Devon & Exeter NHS Foundation Trust GB United Kingdom (GB) St George's Hospital GB United Kingdom (GB) University Hospital of North Norway / Universitetssykehuset Nord-Norge (UNN) NO Norway (NO) Great Ormond Street Hospital (GOSH) GB United Kingdom (GB) St George’s University Hospitals NHS Foundation Trust GB United Kingdom (GB) Guy's Hospital GB United Kingdom (GB) Nantes University Hospital / Centre hospitalier universitaire de Nantes (CHU) FR France (FR) Erasmus University Medical Center (MC) NL Netherlands (NL) Universitätskliniken Salzburg AT Austria (AT) Orlando Health Arnold Palmer Hospital for Children US United States (USA) (US) CHU de Caen Normandie FR France (FR) Hospital Universitario 12 de Octubre ES Spain (ES) University of Zurich / Universität Zürich (UZH) CH Switzerland (CH) Azienda Ospedaliera Universitaria Meyer IT Italy (IT) Hôpital Chambéry - Centre Hospitalier de Chambéry - Hôpital Savoie FR France (FR) Hospital Center University De Limoges Dupuytren FR France (FR) Eurofins GSC Luxembourg LU Luxembourg (LU) Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron ES Spain (ES) Murdoch Childrens Research Institute AU Australia (AU) Sorbonne Université FR France (FR) Perelman School of Medicine University of Pennsylvania US United States (USA) (US) Universitätsklinikum Essen DE Germany (DE) Telemark Hospital Trust NO Norway (NO) GeneDX US United States (USA) (US)

How to cite


Sheppard, S.E., Bryant, L., Wickramasekara, R.N., Vaccaro, C., Robertson, B., Hallgren, J.,... Stessman, H.A. (2023). Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice. Science Advances, 9(10).


Sheppard, Sarah E., et al. "Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice." Science Advances 9.10 (2023).

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