Pathogenic variants in <i>KMT2C</i> result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes

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dc.contributor.authorRots, Dmitrijs
dc.contributor.authorChoufani, Sanaa
dc.contributor.authorFaundes, Victor
dc.contributor.authorDingemans, Alexander J. M.
dc.contributor.authorJoss, Shelagh
dc.contributor.authorFoulds, Nicola
dc.contributor.authorJones, Elizabeth A.
dc.contributor.authorStewart, Sarah
dc.contributor.authorVasudevan, Pradeep
dc.contributor.authorDabir, Tabib
dc.contributor.authorPark, Soo-Mi
dc.contributor.authorJewell, Rosalyn
dc.contributor.authorBrown, Natasha
dc.contributor.authorPais, Lynn
dc.contributor.authorJacquemont, Sebastien
dc.contributor.authorJizi, Khadije
dc.contributor.authorvan Ravenswaaij-Arts, Conny M. A.
dc.contributor.authorKroes, Hester Y.
dc.contributor.authorStumpel, Constance T. R. M.
dc.contributor.authorOckeloen, Charlotte W.
dc.contributor.authorDiets, Illja J.
dc.contributor.authorNizon, Mathilde
dc.contributor.authorVincent, Marie
dc.contributor.authorCogne, Benjamin
dc.contributor.authorBesnard, Thomas
dc.contributor.authorKambouris, Marios
dc.contributor.authorAnderson, Emily
dc.contributor.authorZackai, Elaine H.
dc.contributor.authorMcDougall, Carey
dc.contributor.authorDonoghue, Sarah
dc.contributor.authorO'Donnell-Luria, Anne
dc.contributor.authorValivullah, Zaheer
dc.contributor.authorO'Leary, Melanie
dc.contributor.authorSrivastava, Siddharth
dc.contributor.authorByers, Heather
dc.contributor.authorLeslie, Nancy
dc.contributor.authorMazzola, Sarah
dc.contributor.authorTiller, George E.
dc.contributor.authorVera, Moin
dc.contributor.authorShen, Joseph J.
dc.contributor.authorBoles, Richard
dc.contributor.authorJain, Vani
dc.contributor.authorBrischoux-Boucher, Elise
dc.contributor.authorKinning, Esther
dc.contributor.authorSimpson, Brittany N.
dc.contributor.authorGiltay, Jacques C.
dc.contributor.authorHarris, Jacqueline
dc.contributor.authorKeren, Boris
dc.contributor.authorGuimier, Anne
dc.contributor.authorMarijon, Pierre
dc.contributor.authorde Vries, Bert B. A.
dc.contributor.authorMotter, Constance S.
dc.contributor.authorMendelsohn, Bryce A.
dc.contributor.authorCoffino, Samantha
dc.contributor.authorGerkes, Erica H.
dc.contributor.authorAfenjar, Alexandra
dc.contributor.authorVisconti, Paola
dc.contributor.authorBacchelli, Elena
dc.contributor.authorMaestrini, Elena
dc.contributor.authorDelahaye-Duriez, Andree
dc.contributor.authorGooch, Catherine
dc.contributor.authorHendriks, Yvonne
dc.contributor.authorAdams, Hieab
dc.contributor.authorThauvin-Robinet, Christel
dc.contributor.authorJosephi-Taylor, Sarah
dc.contributor.authorBertoli, Marta
dc.contributor.authorParker, Michael J.
dc.contributor.authorRutten, Julie W.
dc.contributor.authorCaluseriu, Oana
dc.contributor.authorVernon, Hilary J.
dc.contributor.authorKaziyev, Jonah
dc.contributor.authorZhu, Jia
dc.contributor.authorKremen, Jessica
dc.contributor.authorFrazier, Zoe
dc.contributor.authorOsika, Hailey
dc.contributor.authorBreault, David
dc.contributor.authorNair, Sreelata
dc.contributor.authorLewis, Suzanne M. E.
dc.contributor.authorCeroni, Fabiola
dc.contributor.authorViggiano, Marta
dc.contributor.authorPosar, Annio
dc.contributor.authorBrittain, Helen
dc.contributor.authorGiovanna, Traficante
dc.contributor.authorGiulia, Gori
dc.contributor.authorQuteineh, Lina
dc.contributor.authorLeuchter, Russia Ha-Vinh
dc.contributor.authorZonneveld-Huijssoon, Evelien
dc.contributor.authorMellado, Cecilia
dc.contributor.authorMarey, Isabelle
dc.contributor.authorCoudert, Alicia
dc.contributor.authorAracena Alvarez, Mariana Ines
dc.contributor.authorKennis, Milou G. P.
dc.contributor.authorBouman, Arianne
dc.contributor.authorRoifman, Maian
dc.contributor.authorAmoros Rodriguez, Maria Inmaculada
dc.contributor.authorDario Ortigoza-Escobar, Juan
dc.contributor.authorVernimmen, Vivian
dc.contributor.authorSinnema, Margje
dc.contributor.authorPfundt, Rolph
dc.contributor.authorBrunner, Han G.
dc.contributor.authorVissers, Lisenka E. L. M.
dc.contributor.authorKleefstra, Tjitske
dc.contributor.authorWeksberg, Rosanna
dc.contributor.authorBanka, Siddharth
dc.date.accessioned2025-01-20T16:06:26Z
dc.date.available2025-01-20T16:06:26Z
dc.date.issued2024
dc.description.abstractTrithorax-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.
dc.fuente.origenWOS
dc.identifier.doi10.1016/j.ajhg.2024.06.009.
dc.identifier.eissn1537-6605
dc.identifier.issn0002-9297
dc.identifier.urihttps://doi.org/10.1016/j.ajhg.2024.06.009.
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/89955
dc.identifier.wosidWOS:001318815700001
dc.issue.numero8
dc.language.isoen
dc.pagina.final1642
dc.pagina.inicio1626
dc.revistaAmerican journal of human genetics
dc.rightsacceso restringido
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titlePathogenic variants in <i>KMT2C</i> result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes
dc.typeartículo
dc.volumen111
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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