PT - JOURNAL ARTICLE AU - Gabriella Maria Squeo AU - Bartolomeo Augello AU - Valentina Massa AU - Donatella Milani AU - Elisa Adele Colombo AU - Tommaso Mazza AU - Stefano Castellana AU - Maria Piccione AU - Silvia Maitz AU - Antonio Petracca AU - Paolo Prontera AU - Maria Accadia AU - Matteo Della Monica AU - Marilena Carmela Di Giacomo AU - Daniela Melis AU - Angelo Selicorni AU - Sabrina Giglio AU - Rita Fischetto AU - Elisabetta Di Fede AU - Natascia Malerba AU - Matteo Russo AU - Marco Castori AU - Cristina Gervasini AU - Giuseppe Merla TI - Customised next-generation sequencing multigene panel to screen a large cohort of individuals with chromatin-related disorder AID - 10.1136/jmedgenet-2019-106724 DP - 2020 Nov 01 TA - Journal of Medical Genetics PG - 760--768 VI - 57 IP - 11 4099 - http://jmg.bmj.com/content/57/11/760.short 4100 - http://jmg.bmj.com/content/57/11/760.full SO - J Med Genet2020 Nov 01; 57 AB - Background The regulation of the chromatin state by epigenetic mechanisms plays a central role in gene expression, cell function, and maintenance of cell identity. Hereditary disorders of chromatin regulation are a group of conditions caused by abnormalities of the various components of the epigenetic machinery, namely writers, erasers, readers, and chromatin remodelers. Although neurological dysfunction is almost ubiquitous in these disorders, the constellation of additional features characterizing many of these genes and the emerging clinical overlap among them indicate the existence of a community of syndromes. The introduction of high-throughput next generation sequencing (NGS) methods for testing multiple genes simultaneously is a logical step for the implementation of diagnostics of these disorders.Methods We screened a heterogeneous cohort of 263 index patients by an NGS-targeted panel, containing 68 genes associated with more than 40 OMIM entries affecting chromatin function.Results This strategy allowed us to identify clinically relevant variants in 87 patients (32%), including 30 for which an alternative clinical diagnosis was proposed after sequencing analysis and clinical re-evaluation.Conclusion Our findings indicate that this approach is effective not only in disorders with locus heterogeneity, but also in order to anticipate unexpected misdiagnoses due to clinical overlap among cognate disorders. Finally, this work highlights the utility of a prompt diagnosis in such a clinically and genetically heterogeneous group of disorders that we propose to group under the umbrella term of chromatinopathies.