Our analysis of 6 CdLS-associated mutations in conserved amino acids of SMC1 reveals that all but one (smc1-K801Q) exhibit quantifiable deficiencies in 1 or more processes associated with cohesin function, many of which rely at least in part on trans-cohesion (DNA repair, sister chromatid cohesion, metaphase progression, and chromosome segregation), although K801Q had a subtle checkpoint-mediated mitotic delay. Here, SMC1A is linked to Cornelia de Lange syndrome.