A high-throughput single-cell imaging-based framework to help diagnose Chromosomal Instability aiding Variants (CIVa) in humans

Abstract number
Presentation Form
Contributed Talk
Corresponding Email
[email protected]
Clinical Diagnostic Imaging
Prof Viji Draviam (1), Dr Asifa Islam (1), Ms Catalina Manjarrez (1), Ms Xinhong Song (1)
1. Queen Mary University of London

Chromosome Segregation, Deconvolution microscopy, SIM

Abstract text

The vast majority of Chromosomal Instability (CIN) promoting mutations remain unknown, although several naturally occurring Loss-of-Function (LoF) variants have been identified in chromosome segregation genes. Here we assess the prevalence of Chromosomal Instability aiding Variants (CIVa) by collating LoF variants in 135 chromosome segregation genes from over 150,000 humans, including consanguineous individuals. Surprisingly, we observe heterozygous and homozygous CIVa in Astrin, SKA3 and Ndc80 genes that encode evolutionarily conserved microtubule-associated kinetochore proteins essential for chromosome segregation. By establishing a high-resolution microscopy framework, we show the naturally occurring Astrin variant as potentially harmful because it fails to localise normally, delays anaphase onset, induces chromosome misalignment and promotes chromosome missegregation. We show that N-terminal frameshift variants in Astrin, Ndc80 and SKA3 are likely to generate shorter isoforms that do not compromise chromosome segregation revealing resilient mechanisms to cope with harmful variants. By combining deconvolution and super-resolution live-imaging techniques, this study provides a framework to predict and stratify naturally occurring CIVa, an important step towards precision medicine for CIN syndromes.