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.
- Mendelian chromatin disorders
- next generation sequencing
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Contributors GM and CG conceived and designed the study. GM and BA designed the NGS panel. GMS, BA, NM and MR performed the NGS experiments and Sanger validation. GM, GMS and VM revised the literature. TM and SC performed the bioinformatics analysis. CG, DoM, PP, MC, AP, MP, MA, SM, MDM, MCDG, DaM, AS, SG, RF, EAC and EDF provided samples and clinical data. GM wrote the manuscript, with contributions from GMS, MC, VM and CG. GM, CG and VM provided funding. All authors contributed to and approved the final version of the manuscript.
Funding This work has been in part supported by Telethon - Italy (grant no GGP13231), the Italian Ministry of Health, Jerome Lejeune Foundation, Daunia Plast, Circolo Unione Apricena, Fidapa Apricena, and Associazione Italiana Sindrome Kabuki (AISK) to GM; Fondazione Cariplo (2015-0783 to VM); and intramural fundings from Università degli Studi di Milano (to CG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests GM reports personal fees from Takeda, outside the submitted work.
Patient consent for publication Not required.
Ethics approval Patients and their relatives were enrolled after appropriate informed consent was obtained by the physicians in charge and approval obtained from the local ethics committees.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Deidentified participant data.