Dmitrijs Rots, Sanaa Choufani, Victor Faundes, Alexander J M Dingemans, Shelagh Joss, Nicola Foulds, Elizabeth A Jones, Sarah Stewart, Pradeep Vasudevan, Tabib Dabir, Soo-Mi Park, Rosalyn Jewell, Natasha Brown, Lynn Pais, Sébastien Jacquemont, Khadijé Jizi, Conny M A van Ravenswaaij-Arts, Hester Y Kroes, Constance T R M Stumpel, Charlotte W Ockeloen, Illja J Diets, Mathilde Nizon, Marie Vincent, Benjamin Cogné, Thomas Besnard, Marios Kambouris, Emily Anderson, Elaine H Zackai, Carey McDougall, Sarah Donoghue, Anne O'Donnell-Luria, Zaheer Valivullah, Melanie O'Leary, Siddharth Srivastava, Heather Byers, Nancy Leslie, Sarah Mazzola, George E Tiller, Moin Vera, Joseph J Shen, Richard Boles, Vani Jain, Elise Brischoux-Boucher, Esther Kinning, Brittany N Simpson, Jacques C Giltay, Jacqueline Harris, Boris Keren, Anne Guimier, Pierre Marijon, Bert B A de Vries, Constance S Motter, Bryce A Mendelsohn, Samantha Coffino, Erica H Gerkes, Alexandra Afenjar, Paola Visconti, Elena Bacchelli, Elena Maestrini, Andree Delahaye-Duriez, Catherine Gooch, Yvonne Hendriks, Hieab Adams, Christel Thauvin-Robinet, Sarah Josephi-Taylor, Marta Bertoli, Michael J Parker, Julie W Rutten, Oana Caluseriu, Hilary J Vernon, Jonah Kaziyev, Jia Zhu, Jessica Kremen, Zoe Frazier, Hailey Osika, David Breault, Sreelata Nair, Suzanne M E Lewis, Fabiola Ceroni, Marta Viggiano, Annio Posar, Helen Brittain, Traficante Giovanna, Gori Giulia, Lina Quteineh, Russia Ha-Vinh Leuchter, Evelien Zonneveld-Huijssoon, Cecilia Mellado, Isabelle Marey, Alicia Coudert, Mariana Inés Aracena Alvarez, Milou G P Kennis, Arianne Bouman, Maian Roifman, María Inmaculada Amorós Rodríguez, Juan Dario Ortigoza-Escobar, Vivian Vernimmen, Margje Sinnema, Rolph Pfundt, Han G Brunner, Lisenka E L M Vissers, Tjitske Kleefstra, Rosanna Weksberg, Siddharth Banka
{"title":"KMT2C 的致病变体会导致一种不同于 Kleefstra 和 Kabuki 综合征的神经发育障碍。","authors":"Dmitrijs Rots, Sanaa Choufani, Victor Faundes, Alexander J M Dingemans, Shelagh Joss, Nicola Foulds, Elizabeth A Jones, Sarah Stewart, Pradeep Vasudevan, Tabib Dabir, Soo-Mi Park, Rosalyn Jewell, Natasha Brown, Lynn Pais, Sébastien Jacquemont, Khadijé Jizi, Conny M A van Ravenswaaij-Arts, Hester Y Kroes, Constance T R M Stumpel, Charlotte W Ockeloen, Illja J Diets, Mathilde Nizon, Marie Vincent, Benjamin Cogné, Thomas Besnard, Marios Kambouris, Emily Anderson, Elaine H Zackai, Carey McDougall, Sarah Donoghue, Anne O'Donnell-Luria, Zaheer Valivullah, Melanie O'Leary, Siddharth Srivastava, Heather Byers, Nancy Leslie, Sarah Mazzola, George E Tiller, Moin Vera, Joseph J Shen, Richard Boles, Vani Jain, Elise Brischoux-Boucher, Esther Kinning, Brittany N Simpson, Jacques C Giltay, Jacqueline Harris, Boris Keren, Anne Guimier, Pierre Marijon, Bert B A de Vries, Constance S Motter, Bryce A Mendelsohn, Samantha Coffino, Erica H Gerkes, Alexandra Afenjar, Paola Visconti, Elena Bacchelli, Elena Maestrini, Andree Delahaye-Duriez, Catherine Gooch, Yvonne Hendriks, Hieab Adams, Christel Thauvin-Robinet, Sarah Josephi-Taylor, Marta Bertoli, Michael J Parker, Julie W Rutten, Oana Caluseriu, Hilary J Vernon, Jonah Kaziyev, Jia Zhu, Jessica Kremen, Zoe Frazier, Hailey Osika, David Breault, Sreelata Nair, Suzanne M E Lewis, Fabiola Ceroni, Marta Viggiano, Annio Posar, Helen Brittain, Traficante Giovanna, Gori Giulia, Lina Quteineh, Russia Ha-Vinh Leuchter, Evelien Zonneveld-Huijssoon, Cecilia Mellado, Isabelle Marey, Alicia Coudert, Mariana Inés Aracena Alvarez, Milou G P Kennis, Arianne Bouman, Maian Roifman, María Inmaculada Amorós Rodríguez, Juan Dario Ortigoza-Escobar, Vivian Vernimmen, Margje Sinnema, Rolph Pfundt, Han G Brunner, Lisenka E L M Vissers, Tjitske Kleefstra, Rosanna Weksberg, Siddharth Banka","doi":"10.1016/j.ajhg.2024.06.009","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"1626-1642"},"PeriodicalIF":8.1000,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11339626/pdf/","citationCount":"0","resultStr":"{\"title\":\"Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes.\",\"authors\":\"Dmitrijs Rots, Sanaa Choufani, Victor Faundes, Alexander J M Dingemans, Shelagh Joss, Nicola Foulds, Elizabeth A Jones, Sarah Stewart, Pradeep Vasudevan, Tabib Dabir, Soo-Mi Park, Rosalyn Jewell, Natasha Brown, Lynn Pais, Sébastien Jacquemont, Khadijé Jizi, Conny M A van Ravenswaaij-Arts, Hester Y Kroes, Constance T R M Stumpel, Charlotte W Ockeloen, Illja J Diets, Mathilde Nizon, Marie Vincent, Benjamin Cogné, Thomas Besnard, Marios Kambouris, Emily Anderson, Elaine H Zackai, Carey McDougall, Sarah Donoghue, Anne O'Donnell-Luria, Zaheer Valivullah, Melanie O'Leary, Siddharth Srivastava, Heather Byers, Nancy Leslie, Sarah Mazzola, George E Tiller, Moin Vera, Joseph J Shen, Richard Boles, Vani Jain, Elise Brischoux-Boucher, Esther Kinning, Brittany N Simpson, Jacques C Giltay, Jacqueline Harris, Boris Keren, Anne Guimier, Pierre Marijon, Bert B A de Vries, Constance S Motter, Bryce A Mendelsohn, Samantha Coffino, Erica H Gerkes, Alexandra Afenjar, Paola Visconti, Elena Bacchelli, Elena Maestrini, Andree Delahaye-Duriez, Catherine Gooch, Yvonne Hendriks, Hieab Adams, Christel Thauvin-Robinet, Sarah Josephi-Taylor, Marta Bertoli, Michael J Parker, Julie W Rutten, Oana Caluseriu, Hilary J Vernon, Jonah Kaziyev, Jia Zhu, Jessica Kremen, Zoe Frazier, Hailey Osika, David Breault, Sreelata Nair, Suzanne M E Lewis, Fabiola Ceroni, Marta Viggiano, Annio Posar, Helen Brittain, Traficante Giovanna, Gori Giulia, Lina Quteineh, Russia Ha-Vinh Leuchter, Evelien Zonneveld-Huijssoon, Cecilia Mellado, Isabelle Marey, Alicia Coudert, Mariana Inés Aracena Alvarez, Milou G P Kennis, Arianne Bouman, Maian Roifman, María Inmaculada Amorós Rodríguez, Juan Dario Ortigoza-Escobar, Vivian Vernimmen, Margje Sinnema, Rolph Pfundt, Han G Brunner, Lisenka E L M Vissers, Tjitske Kleefstra, Rosanna Weksberg, Siddharth Banka\",\"doi\":\"10.1016/j.ajhg.2024.06.009\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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. 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Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes.
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.
期刊介绍:
The American Journal of Human Genetics (AJHG) is a monthly journal published by Cell Press, chosen by The American Society of Human Genetics (ASHG) as its premier publication starting from January 2008. AJHG represents Cell Press's first society-owned journal, and both ASHG and Cell Press anticipate significant synergies between AJHG content and that of other Cell Press titles.