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DOI 10.1016/j.ajhg.2024.06.009

Медицинская библиотека · American journal of human genetics · 2024

Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes.

Rots Dmitrijs, Choufani Sanaa, Faundes Victor, Dingemans Alexander J M, Joss Shelagh, Foulds Nicola, Jones Elizabeth A, Stewart Sarah, Vasudevan Pradeep, Dabir Tabib, Park Soo-Mi, Jewell Rosalyn, Brown Natasha, Pais Lynn, Jacquemont Sébastien, Jizi Khadijé, Ravenswaaij-Arts Conny M A van, Kroes Hester Y, Stumpel Constance T R M, Ockeloen Charlotte W, Diets Illja J, Nizon Mathilde, Vincent Marie, Cogné Benjamin, Besnard Thomas, Kambouris Marios, Anderson Emily, Zackai Elaine H, McDougall Carey, Donoghue Sarah, O'Donnell-Luria Anne, Valivullah Zaheer, O'Leary Melanie, Srivastava Siddharth, Byers Heather, Leslie Nancy, Mazzola Sarah, Tiller George E, Vera Moin, Shen Joseph J, Boles Richard, Jain Vani, Brischoux-Boucher Elise, Kinning Esther, Simpson Brittany N, Giltay Jacques C, Harris Jacqueline, Keren Boris, Guimier Anne, Marijon Pierre, Vries Bert B A de, Motter Constance S, Mendelsohn Bryce A, Coffino Samantha, Gerkes Erica H, Afenjar Alexandra, Visconti Paola, Bacchelli Elena, Maestrini Elena, Delahaye-Duriez Andree, Gooch Catherine, Hendriks Yvonne, Adams Hieab, Thauvin-Robinet Christel, Josephi-Taylor Sarah, Bertoli Marta, Parker Michael J, Rutten Julie W, Caluseriu Oana, Vernon Hilary J, Kaziyev Jonah, Zhu Jia, Kremen Jessica, Frazier Zoe, Osika Hailey, Breault David, Nair Sreelata, Lewis Suzanne M E, Ceroni Fabiola, Viggiano Marta, Posar Annio, Brittain Helen, Giovanna Traficante, Giulia Gori, Quteineh Lina, Ha-Vinh Leuchter Russia, Zonneveld-Huijssoon Evelien, Mellado Cecilia, Marey Isabelle, Coudert Alicia, Aracena Alvarez Mariana Inés, Kennis Milou G P, Bouman Arianne, Roifman Maian, Amorós Rodríguez María Inmaculada, Ortigoza-Escobar Juan Dario, Vernimmen Vivian, Sinnema Margje, Pfundt Rolph, Brunner Han G, Vissers Lisenka E L M, Kleefstra Tjitske, Weksberg Rosanna, Banka Siddharth

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Аннотация

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.

Для цитирования: Rots Dmitrijs, Choufani Sanaa, Faundes Victor, Dingemans Alexander J M, Joss Shelagh, Foulds Nicola, Jones Elizabeth A, Stewart Sarah, Vasudevan Pradeep, Dabir Tabib, Park Soo-Mi, Jewell Rosalyn, Brown Natasha, Pais Lynn, Jacquemont Sébastien, Jizi Khadijé, Ravenswaaij-Arts Conny M A van, Kroes Hester Y, Stumpel Constance T R M, Ockeloen Charlotte W, Diets Illja J, Nizon Mathilde, Vincent Marie, Cogné Benjamin, Besnard Thomas, Kambouris Marios, Anderson Emily, Zackai Elaine H, McDougall Carey, Donoghue Sarah, O'Donnell-Luria Anne, Valivullah Zaheer, O'Leary Melanie, Srivastava Siddharth, Byers Heather, Leslie Nancy, Mazzola Sarah, Tiller George E, Vera Moin, Shen Joseph J, Boles Richard, Jain Vani, Brischoux-Boucher Elise, Kinning Esther, Simpson Brittany N, Giltay Jacques C, Harris Jacqueline, Keren Boris, Guimier Anne, Marijon Pierre, Vries Bert B A de, Motter Constance S, Mendelsohn Bryce A, Coffino Samantha, Gerkes Erica H, Afenjar Alexandra, Visconti Paola, Bacchelli Elena, Maestrini Elena, Delahaye-Duriez Andree, Gooch Catherine, Hendriks Yvonne, Adams Hieab, Thauvin-Robinet Christel, Josephi-Taylor Sarah, Bertoli Marta, Parker Michael J, Rutten Julie W, Caluseriu Oana, Vernon Hilary J, Kaziyev Jonah, Zhu Jia, Kremen Jessica, Frazier Zoe, Osika Hailey, Breault David, Nair Sreelata, Lewis Suzanne M E, Ceroni Fabiola, Viggiano Marta, Posar Annio, Brittain Helen, Giovanna Traficante, Giulia Gori, Quteineh Lina, Ha-Vinh Leuchter Russia, Zonneveld-Huijssoon Evelien, Mellado Cecilia, Marey Isabelle, Coudert Alicia, Aracena Alvarez Mariana Inés, Kennis Milou G P, Bouman Arianne, Roifman Maian, Amorós Rodríguez María Inmaculada, Ortigoza-Escobar Juan Dario, Vernimmen Vivian, Sinnema Margje, Pfundt Rolph, Brunner Han G, Vissers Lisenka E L M, Kleefstra Tjitske, Weksberg Rosanna, Banka Siddharth. Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes.. American journal of human genetics. 2024. DOI: 10.1016/j.ajhg.2024.06.009.

Предметные рубрики MeSH

HumansAbnormalities, MultipleVestibular DiseasesIntellectual DisabilityFaceDNA-Binding ProteinsMaleFemaleHematologic DiseasesNeurodevelopmental DisordersCraniofacial AbnormalitiesChromosome DeletionChromosomes, Human, Pair 9ChildDNA MethylationChild, PreschoolNeoplasm ProteinsAdolescentHypertrichosisMutationFailure to ThriveHistone-Lysine N-MethyltransferaseHeart Defects, Congenital
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