Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann\u2013Steiner and Rubinstein\u2013Taybi syndromes

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

doi:10.1038/s41431-020-0679-8

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.

Highlights

IntroductionOpening, acting as “writer” of the epigenetic machinery
Lysine-specific methyltransferase 2A (KMT2A, OMIM +159555) located at 11q23.3 contributes to chromatin10 Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy11 Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy12 UOSD Pediatria ad alta intensità di cura, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milano, Milano, ItalyExpanding the phenotype associated to KMT2A variants: overlapping clinical signs between. . .opening, acting as “writer” of the epigenetic machinery
Chromatinopathies define a group of diseases caused by alterations in genes coding for components of the epigenetic apparatus termed “writers, erasers, readers, and remodelers”

Summary

Introduction

Opening, acting as “writer” of the epigenetic machinery This gene encodes for a DNA-binding protein that methylates lysine 4 of histone H3 (K4H3me), which positively regulates transcription of multiple genes, including those involved in hematopoiesis and neuronal development [1]. Heterozygous KMT2A loss-of-function and missense variants have been associated to Wiedemann–Steiner syndrome (WDSTS, OMIM #605130), described for the first time in 1989 by Wiedemann et al [3] and characterized by hypertrichosis cubiti, intellectual disability (ID) and developmental delay, a distinctive facial appearance and short stature [4]. Studies in large cohorts of syndromic/non-syndromic ID and neurodevelopmental disorders with heterogeneous phenotype have led to the identification of further 32 KMT2A novel variants [12,13,14,15]. Besides WDSTS, deleterious variants in KMT2A were described in association with epilepsy [17], primary immunodeficiency [18], and eosinophilia [19]

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