Refining the Phenotypic Spectrum of KMT5B-Associated Developmental Delay

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

doi:10.3389/fped.2022.844845

Cited by 11 publications

(9 citation statements)

References 22 publications

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“…Growth abnormalities (macrocephaly and/or tall stature) were common in our cohort and have been reported in previous KMT5B patient studies ( 11 , 14 – 16 , 40 ). Eight patients in the study had both macrocephaly and tall stature, whereas 22 patients had macrocephaly without tall stature.…”

Section: Discussionsupporting

confidence: 87%

“…This is supported by multiple lines of evidence. First, macrocephaly appears more often in this cohort independent of tall stature, arguing against a broad overgrowth phenotype that has been previously suggested (11,16). Primary fibroblasts isolated from KMT5B patients grow significantly slower without increased cell death compared to controls including cells from patient 10 who presented with both macrocephaly and tall stature.…”

Section: Discussionmentioning

confidence: 52%

“…Similar to previous reports, all participants in this study had ID/DD, and many had unique facial characteristics and autism (fig. S9) ( 11 , 14 – 16 ). Furthermore, our large cohort identified a high prevalence of hypotonia and congenital heart defects among this population.…”

Section: Discussionmentioning

confidence: 99%

“…Disruptive variants in lysine methyl transferases (KMTs) and lysine demethylases (KDMs) lead to various neurodevelopmental syndromes that share similar phenotypes including developmental delay (DD), intellectual disability (ID), and craniofacial anomalies (4,(8)(9)(10)(11). Computational analysis (12) and large-scale sequencing studies have highlighted the importance of the lysine methyltransferase gene, KMT5B, in the pathogenesis of neurodevelopmental disorders (11,(13)(14)(15)(16). KMT5B (OMIM: 610881), also denominated suppressor of variegation 4-20 (SUV420H1), is located on chromosome 11q13.2 and contains 13 exons (17).…”

Section: Introductionmentioning

confidence: 99%

“…Pathogenic variants in KMT5B cause neurodevelopmental delay with multisystemic involvement (OMIM# 617788) (11,13,14,16,18,21). Clinical features reported include ID, autism spectrum disorder, DD, macrocephaly, febrile seizures, hypotonia, attention deficits, failure to thrive, sleep problems, tall stature, gastrointestinal issues, and characteristic facial features (11,14,16,18,21). Similar to other KMTs and KDMs, haploinsufficiency has been proposed as the most likely pathogenic mechanism for KMT5B (11); although, functional studies remain limited.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

et al. 2023

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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 KMT5B -related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

et al. 2023

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Epigenetic regulation of craniofacial development and disease

Shull,

Artinger

2023

Birth Defects Research

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BackgroundThe formation of the craniofacial complex relies on proper neural crest development. The gene regulatory networks (GRNs) and signaling pathways orchestrating this process have been extensively studied. These GRNs and signaling cascades are tightly regulated as alterations to any stage of neural crest development can lead to common congenital birth defects, including multiple syndromes affecting facial morphology as well as nonsyndromic facial defects, such as cleft lip with or without cleft palate. Epigenetic factors add a hierarchy to the regulation of transcriptional networks and influence the spatiotemporal activation or repression of specific gene regulatory cascades; however less is known about their exact mechanisms in controlling precise gene regulation.AimsIn this review, we discuss the role of epigenetic factors during neural crest development, specifically during craniofacial development and how compromised activities of these regulators contribute to congenital defects that affect the craniofacial complex.

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