TY - JOUR
T1 - Customised next-generation sequencing multigene panel to screen a large cohort of individuals with chromatin-related disorder
AU - Piccione, Maria
AU - Prontera, Paolo
AU - Augello, Bartolomeo
AU - Castori, Marco
AU - Maitz, Silvia
AU - Castellana, Stefano
AU - Colombo, Elisa Adele
AU - Accadia, Maria
AU - Malerba, Natascia
AU - Petracca, Antonio
AU - Squeo, Gabriella Maria
AU - Di Fede, Elisabetta
AU - Giglio, Sabrina
AU - Russo, Matteo
AU - Fischetto, Rita
AU - Merla, Giuseppe
AU - Melis, Daniela
AU - Gervasini, Cristina
AU - Di Giacomo, Marilena Carmela
AU - Massa, Valentina
AU - Della Monica, Matteo
AU - Selicorni, Angelo
AU - Milani, Donatella
AU - Mazza, Tommaso
AU - Augello, Bernardo
PY - 2020
Y1 - 2020
N2 - 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.
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.
UR - http://hdl.handle.net/10447/472474
M3 - Article
VL - 57
SP - 760
EP - 768
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
SN - 0022-2593
ER -