The past, present, and future for constitutional ring chromosomes: A report of the international consortium for human ring chromosomes

Human ring chromosomes (RCs) are rare diseases with an estimated newborn incidence of 1/50,000 and an annual occurrence of 2,800 patients globally. Over the past 60 years, banding cytogenetics, fluorescence in situ hybridization (FISH), chromosome microarray analysis (CMA), and whole-genome sequencing (WGS) has been used to detect an RC and further characterize its genomic alterations. Ring syndrome featuring sever growth retardation and variable intellectual disability has been considered as general clinical presentations for all RCs due to the cellular losses from the dynamic mosaicism of RC instability through mitosis. Cytogenomic heterogeneity ranging from simple complete RCs to complex rearranged RCs and variable RC intolerance with different relative frequencies have been observed. Clinical heterogeneity, including chromosome-specific deletion and duplication syndromes, gene-related organ and tissue defects, cancer predisposition to different types of tumors, and reproductive failure, has been reported in the literature. However, the patients with RCs reported in the literature accounted for less than 1% of its occurrence. Current diagnostic practice lacks laboratory standards for analyzing cellular behavior and genomic imbalances of RCs to evaluate the compound effects on patients. Under-representation of clinical cases and lack of comprehensive diagnostic analysis make it a challenge for evidence-based interpretation of clinico-cytogenomic correlations and recommendation of follow-up clinical management. Given recent advancements in genomic technologies and organized efforts by international collaborations and patient advocacy organizations, the prospective of standardized cytogenomic diagnosis and evidence-based clinical management for all patients with RCs could be achieved at an unprecedented global scale.