Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann–Steiner and Rubinstein–Taybi syndromes

Maria Piccione, Bartolomeo Augello, Marco Castori, Stefano Castellana, Elisa Adele Colombo, Anna Maria Perri, Giuseppe Merla, Gabriella Squeo, Elisabetta Di Fede, Maria Chiara Gandini, Elena Curridori, Francesco Andrea Causio, Filippo Ghelma, Rita Fischetto, Giuseppe Merla, Cristina Gervasini, Valentina Massa, Giuseppe Zampino, Francesco Andrea Causio, Donatella MilaniEmanuela Scarano, Lidia Larizza, Tommaso Mazza, Bernardo Augello

Risultato della ricerca: Articlepeer review

2 Citazioni (Scopus)

Abstract

Lysine-specific methyltransferase 2A (KMT2A) is responsible for methylation of histone H3 (K4H3me) and contributes to chromatin remodeling, acting as “writer” of the epigenetic machinery. Mutations in KMT2A were first reported in Wiedemann–Steiner syndrome (WDSTS). More recently, KMT2A variants have been described in probands with a specific clinical diagnosis comprised in the so-called chromatinopathies. Such conditions, including WDSTS, are a group of overlapping disorders caused by mutations in genes coding for the epigenetic machinery. Among them, Rubinstein–Taybi syndrome (RSTS) is mainly caused by heterozygous pathogenic variants in CREBBP or EP300. In this work, we used next generation sequencing (either by custom-made panel or by whole exome) to identify alternative causative genes in individuals with a RSTS-like phenotype negative to CREBBP and EP300 mutational screening. In six patients we identified different novel unreported variants in KMT2A gene. The identified variants are de novo in at least four out of six tested individuals and all of them display some typical RSTS phenotypic features but also WDSTS specific signs. This study reinforces the concept that germline variants affecting the epigenetic machinery lead to a shared molecular effect (alteration of the chromatin state) determining superimposable clinical conditions.
Lingua originaleEnglish
pagine (da-a)88-98
Numero di pagine11
RivistaEUROPEAN JOURNAL OF HUMAN GENETICS
Volume29
Stato di pubblicazionePublished - 2021

All Science Journal Classification (ASJC) codes

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  • ???subjectarea.asjc.2700.2716???

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