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

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

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer 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
DOI
Stato di pubblicazionePubblicato - 2021

Keywords

  • KMT2A variants
  • Rubinstein–Taybi syndromes
  • Wiedemann–Steiner

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