Portrait of a spectrum: clinical and genetic characterization of a large cohort of chromatinopathies—30 years' experience from a third level center

Chromatinopathies (CPs) are an expanding group of rare genetic disorders affecting epigenetic machinery. Besides an intricate genotypic spectrum, these conditions share overlapping phenotypes characterized by neurocognitive impairment, growth defects and distinctive, but often convergent, facial features. Although individually rare, the landscape of CPs is increasingly growing and represents an emerging and possibly underestimated cause of disability. Due to their complexity and rarity, accurate diagnosis and management pose significant difficulties. To address these challenges and gain a deeper overview of these diseases' spectrum, we retrospectively collected clinical characteristics of 239 patients diagnosed with CPs and critically analyzed their diagnostic journey, growth charts, neurological and gestaltic features. Starting from the largest collection of CPs to date, our data point to wide sequencing analyses as the best shortcut to diagnosis. We have also demonstrated the importance of growth defects in this group of disorders that require dedicated growth tables, and we have delved into the great variability of neurological and clinical burden in these conditions. This retrospective study provides a significant advance in our understanding of these rare diseases and will help to improve diagnostic, therapeutic, and clinical approaches to CPs and to develop personalized multidisciplinary care plans for affected patients.