Refining the Phenotypic Spectrum of KMT5B-Associated Developmental Delay

Aviva Eliyahu, Ortal Barel, Lior Greenbaum, Gal Zaks Hoffer, Yael Goldberg, Annick Raas-Rothschild, Amihood Singer, Ifat Bar-Joseph, Vered Kunik, Elisheva Javasky, Orna Staretz-Chacham, Naomi Pode-Shakked, Lily Bazak, Noa Ruhrman-Shahar, Elon Pras, Moshe Frydman, Mordechai Shohat, Ben Pode-Shakked

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8 Scopus citations


The role of lysine methyltransferases (KMTs) and demethylases (KDMs) in the regulation of chromatin modification is well-established. Recently, deleterious heterozygous variants in KMT5B were implicated in individuals with intellectual disability (ID) and/or autism spectrum disorder. We describe three unrelated patients with global developmental delay (GDD) or ID, macrocephaly and additional features. Using whole exome sequencing, each of the probands was found to harbor a distinct de novo heterozygous disease-causing variant in KMT5B: c.541C > G (p.His181Asp); c.833A > T (p.Asn278Ile); or c.391_394delAAAG (p.Lys131GlufsTer6). We discuss herein their clinical presentations, and compare them to those of previously reported patients. Furthermore, using a three-dimensional computational model of the KMT5B protein, we demonstrate the predicted structural effects of the two missense variants. Our findings support the role of de novo missense and nonsense variants in KMT5B-associated GDD/ID, and suggest that this gene should be considered in the differential diagnosis of neurodevelopmental disorders accompanied by macrocephaly and/or overgrowth.

Original languageEnglish
Article number844845
JournalFrontiers in Pediatrics
StatePublished - 30 Mar 2022

Bibliographical note

Publisher Copyright:
Copyright © 2022 Eliyahu, Barel, Greenbaum, Zaks Hoffer, Goldberg, Raas-Rothschild, Singer, Bar-Joseph, Kunik, Javasky, Staretz-Chacham, Pode-Shakked, Bazak, Ruhrman-Shahar, Pras, Frydman, Shohat and Pode-Shakked.


The authors wish to thank the patients and their families for their kind assistance. Clinical whole exome sequencing was supported by the Department of Human Genetics, Israeli Ministry of Health (MOH) Pilot Program.

FundersFunder number
Ministry of Health -Singapore
Ministry of Health, State of Israel


    • KMT5B
    • de novo
    • developmental delay
    • intellectual disability
    • macrocephaly


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