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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)88-98
JournalEuropean Journal of Human Genetics
Volume29
Issue number1
DOIs
Publication statusPublished - 2021

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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