This disorder is caused by mutations in genes encoding components of the cohesion complex. Most cases occur sporadically but numerous familial cases suggest autosomal dominant inheritance. However, since at least three genes code for components of the cohesion complex including one located on the X-chromosome (610759), familial cases reported earlier without genotyping have created some confusion. Hence, even autosomal recessive inheritance has been suggested in some families. Genetic counseling should be family-specific based on the genotype and family pattern.
About 50% of cases result from mutations in the NIPBL gene (122470; 5p13.1) but less than 1% have an affected parent and the recurrence risk for sibs is similar. The X-linked form of CDLS (300590; Xp11.22-p11.21) is caused by a mutation in the SMC1A gene, and a mild form (610759) results from mutations in the SMC3 gene (10q25). Mutations in RAD21 (8q24) have been found in patients with milder disease and atypical presentations (614701).
A CDLS phenotype can also result from a specific duplication of a 3q 26-27 band.