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Lookup NU author(s): Dr Marta Bertoli
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© 2024 American Society of Human Genetics. Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition.
Author(s): Rots D, Choufani S, Faundes V, Dingemans AJM, Joss S, Foulds N, Jones EA, Stewart S, Vasudevan P, Dabir T, Park S-M, Jewell R, Brown N, Pais L, Jacquemont S, Jizi K, Ravenswaaij-Arts CMAV, Kroes HY, Stumpel CTRM, Ockeloen CW, Diets IJ, Nizon M, Vincent M, Cogne B, Besnard T, Kambouris M, Anderson E, Zackai EH, McDougall C, Donoghue S, O'Donnell-Luria A, Valivullah Z, O'Leary M, Srivastava S, Byers H, Leslie N, Mazzola S, Tiller GE, Vera M, Shen JJ, Boles R, Jain V, Brischoux-Boucher E, Kinning E, Simpson BN, Giltay JC, Harris J, Keren B, Guimier A, Marijon P, Vries BBAD, Motter CS, Mendelsohn BA, Coffino S, Gerkes EH, Afenjar A, Visconti P, Bacchelli E, Maestrini E, Delahaye-Duriez A, Gooch C, Hendriks Y, Adams H, Thauvin-Robinet C, Josephi-Taylor S, Bertoli M, Parker MJ, Rutten JW, Caluseriu O, Vernon HJ, Kaziyev J, Zhu J, Kremen J, Frazier Z, Osika H, Breault D, Nair S, Lewis SME, Ceroni F, Viggiano M, Posar A, Brittain H, Giovanna T, Giulia G, Quteineh L, Ha-Vinh Leuchter R, Zonneveld-Huijssoon E, Mellado C, Marey I, Coudert A, Aracena Alvarez MI, Kennis MGP, Bouman A, Roifman M, Amoros Rodriguez MI, Ortigoza-Escobar JD, Vernimmen V, Sinnema M, Pfundt R, Brunner HG, Vissers LELM, Kleefstra T, Weksberg R, Banka S
Publication type: Article
Publication status: Published
Journal: American Journal of Human Genetics
Year: 2024
Pages: ePub ahead of Print
Online publication date: 15/07/2024
Acceptance date: 19/06/2024
ISSN (print): 0002-9297
ISSN (electronic): 1537-6605
Publisher: Cell Press
URL: https://doi.org/10.1016/j.ajhg.2024.06.009
DOI: 10.1016/j.ajhg.2024.06.009
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