Browsing by Author "Faundes, Victor"

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    Clustered variants in the 5′ coding region of TRA2B cause a distinctive neurodevelopmental syndrome
    (2023) Ramond, Francis; Dalgliesh, Caroline; Grimmel, Mona; Wechsberg, Oded; Vetro, Annalisa; Guerrini, Renzo; FitzPatrick, David; Poole, Rebecca L.; Lebrun, Marine; Bayat, Allan; Grasshoff, Ute; Bertrand, Miriam; Witt, Dennis; Turnpenny, Peter D.; Faundes, Victor; Santa Maria, Lorena; Fuentes, Carolina Mendoza; Mabe, Paulina; Hussain, Shaun A.; Mullegama, Sureni V.; Torti, Erin; Oehl-Jaschkowitz, Barbara; Salmon, Lina Basel; Orenstein, Naama; Shahar, Noa Ruhrman; Hagari, Ofir; Bazak, Lily; Hoffjan, Sabine; Prada, Carlos E.; Haack, Tobias; Elliott, David J.
    Purpose: Transformer2 proteins (Tra2a and Tra2(3) control splicing patterns in human cells, and no human phenotypes have been associated with germline variants in these genes. The aim of this work was to associate germline variants in the TRA2B gene to a novel neurodevelopmental disorder.Methods: A total of 12 individuals from 11 unrelated families who harbored predicted loss-of -function monoallelic variants, mostly de novo, were recruited. RNA sequencing and western blot analyses of Tra2(3-1 and Tra2(3-3 isoforms from patient-derived cells were performed. Tra2(31-GFP, Tra2(33-GFP and CHEK1 exon 3 plasmids were transfected into HEK-293 cells.Results: All variants clustered in the 5 ' part of TRA2B, upstream of an alternative translation start site responsible for the expression of the noncanonical Tra2(3-3 isoform. All affected in-dividuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature. Experimental studies showed that these variants decreased the expression of the canonical Tra2(3-1 isoform, whereas they increased the expression of the Tra2(3-3 isoform, which is shorter and lacks the N-terminal RS1 domain. Increased expression of Tra2(3-3-GFP were shown to interfere with the incorporation of CHEK1 exon 3 into its mature transcript, normally incorporated by Tra2(3-1.Conclusion: Predicted loss-of-function variants clustered in the 5 ' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2(3 protein.(c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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    Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes
    (2024) 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, Sebastien; Jizi, Khadije; van Ravenswaaij-Arts, Conny M. A.; Kroes, Hester Y.; Stumpel, Constance T. R. M.; Ockeloen, Charlotte W.; Diets, Illja J.; Nizon, Mathilde; Vincent, Marie; Cogne, 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; de Vries, Bert B. A.; 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; Leuchter, Russia Ha-Vinh; Zonneveld-Huijssoon, Evelien; Mellado, Cecilia; Marey, Isabelle; Coudert, Alicia; Aracena Alvarez, Mariana Ines; Kennis, Milou G. P.; Bouman, Arianne; Roifman, Maian; Amoros Rodriguez, Maria Inmaculada; Dario Ortigoza-Escobar, Juan; Vernimmen, Vivian; Sinnema, Margje; Pfundt, Rolph; Brunner, Han G.; Vissers, Lisenka E. L. M.; Kleefstra, Tjitske; Weksberg, Rosanna; Banka, Siddharth
    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, similar to 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.