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

    Research output: Contribution to journalArticlepeer-review

    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


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

    ASJC Scopus subject areas

    • Pediatrics, Perinatology, and Child Health


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