Recent research has unexpectedly showed that mutated genes along the cohesin pathway also cause specific abnormalities during human development. "In these cohesin complex proteins, the strongest effect seems to be in brain development," said Dr. Krantz.
Drs. Krantz and Jackson together maintain the world's largest database of patients with CdLS. The current study screened 115 patients who did not have mutations in the NIPBL gene, but who were judged to have CdLS or a milder variant of the disease, based on evaluations by clinical geneticists.
Of the 115 patients, 11 had mutations in the SMC1A or SMC3 gene. All had some degree of mental retardation, but none had limb abnormalities. Five of the 11 patients had normal height, whereas only 5 percent of patients with classic CdLS achieve normal height. The patients with the SMCIA and SMC3 mutations had milder versions of the distinctive facial features found in classical CdLS, such as thin eyebrows that join together, long eyelashes, thin lips and excessive body hair.
"In many of these patients, an experienced clinician might recognize their more subtle facial features as suggestive of CdLS, but for the most part, they would only come to clinical attention for having mild to moderate mental retardation," said Matthew A. Deardorff, M.D., the first author of the study and a fellow in genetics at Children's Hospital. "This study suggests there may be other, undiscovered mutations along the cohesin pathway among patients thought to have isolated mental retardation."
"This discovery will improve the diagnosis of Cornelia deLange syndrome," added Dr. Krantz, "and also opens an avenue for investigating genetic mechanisms in broader populations of patients with abnormal brain development, in mental retardation and possibly autism as well."