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
Dipartimento di Scienze della vita e sanità pubblica
Facoltà di Medicina e Chirurgia "A.Gemelli"
Ambito disciplinare: Clinica Pediatrica
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.
European Journal of Human Genetics
KMT2A variants
Rubinstein–Taybi syndromes
Wiedemann–Steiner
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KMT2A Biochemistry, Genetics and Molecular Biology 100%
Nested Gene Biochemistry, Genetics and Molecular Biology 60%
Epigenetics Biochemistry, Genetics and Molecular Biology 60%
Mutation Biochemistry, Genetics and Molecular Biology 40%
Phenotype Biochemistry, Genetics and Molecular Biology 40%
EP300 Biochemistry, Genetics and Molecular Biology 40%
Methylation Biochemistry, Genetics and Molecular Biology 20%
Screening Biochemistry, Genetics and Molecular Biology 20%
Zampino, G., Milani, D., Di Fede, E., Massa, V., Augello, B., Squeo, G., Scarano, E., Perri, A. M., Fischetto, R., Causio, F. A., Piccione, M., Curridori, E., Mazza, T., Castellana, S., Larizza, L., Ghelma, F., Colombo, E. A., Gandini, M. C., Castori, M., ... Gervasini, C. (2021). Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann–Steiner and Rubinstein–Taybi syndromes. European Journal of Human Genetics, 29, 88-98. https://doi.org/10.1038/s41431-020-0679-8
Zampino, Giuseppe ; Milani, Daniela ; Di Fede, Elisabetta et al. / Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann–Steiner and Rubinstein–Taybi syndromes. In: European Journal of Human Genetics. 2021 ; Vol. 29. pagg. 88-98.
@article{fda17d928a2c45868dfb49f4e07c7eaf,
title = "Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann–Steiner and Rubinstein–Taybi syndromes",
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.",
keywords = "KMT2A variants, Rubinstein–Taybi syndromes, Wiedemann–Steiner, KMT2A variants, Rubinstein–Taybi syndromes, Wiedemann–Steiner",
author = "Giuseppe Zampino and Daniela Milani and {Di Fede}, Elisabetta and Valentina Massa and Bartolomeo Augello and Gabriella Squeo and Emanuela Scarano and Perri, {Anna Maria} and Rita Fischetto and Causio, {Francesco Andrea} and Maria Piccione and Elena Curridori and Tommaso Mazza and Stefano Castellana and Lidia Larizza and Filippo Ghelma and Colombo, {Elisa Adele} and Gandini, {Maria Chiara} and Marco Castori and Giuseppe Merla and Donatella Milani and Cristina Gervasini",
journal = "European Journal of Human Genetics",
publisher = "-NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON, ENGLAND, N1 9XW -S Karger AG:Allschwilerstrasse 10, CH-4009 Basel Switzerland:011 41 61 3061111, EMAIL: orders@karger.ch, INTERNET: http://www.karger.com, Fax: 011 41 61 3061234",
Zampino, G, Milani, D, Di Fede, E, Massa, V, Augello, B, Squeo, G, Scarano, E, Perri, AM, Fischetto, R, Causio, FA, Piccione, M, Curridori, E, Mazza, T, Castellana, S, Larizza, L, Ghelma, F, Colombo, EA, Gandini, MC, Castori, M, Merla, G, Milani, D & Gervasini, C 2021, 'Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann–Steiner and Rubinstein–Taybi syndromes', European Journal of Human Genetics, vol. 29, pagg. 88-98. https://doi.org/10.1038/s41431-020-0679-8
Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann–Steiner and Rubinstein–Taybi syndromes. / Zampino, Giuseppe; Milani, Daniela; Di Fede, Elisabetta et al.
In: European Journal of Human Genetics, Vol. 29, 2021, pag. 88-98.
T1 - Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann–Steiner and Rubinstein–Taybi syndromes
AU - Zampino, Giuseppe
AU - Milani, Daniela
AU - Di Fede, Elisabetta
AU - Massa, Valentina
AU - Augello, Bartolomeo
AU - Squeo, Gabriella
AU - Scarano, Emanuela
AU - Perri, Anna Maria
AU - Fischetto, Rita
AU - Causio, Francesco Andrea
AU - Piccione, Maria
AU - Curridori, Elena
AU - Mazza, Tommaso
AU - Castellana, Stefano
AU - Larizza, Lidia
AU - Ghelma, Filippo
AU - Colombo, Elisa Adele
AU - Gandini, Maria Chiara
AU - Castori, Marco
AU - Merla, Giuseppe
AU - Milani, Donatella
AU - Gervasini, Cristina
N2 - 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.
AB - 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.
KW - KMT2A variants
KW - Rubinstein–Taybi syndromes
KW - Wiedemann–Steiner
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
Zampino G, Milani D, Di Fede E, Massa V, Augello B, Squeo G et al. Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann–Steiner and Rubinstein–Taybi syndromes. European Journal of Human Genetics. 2021;29:88-98. doi: 10.1038/s41431-020-0679-8