Collagen XI sequence variations in nonsyndromic cleft palate, Robin sequence and micrognathia

Abstract

Cleft palate is a common birth defect, but its etiopathogenesis is mostly unknown. Several studies have shown that cleft palate has a strong genetic component. Robin sequence consists of three of the following four findings: micrognathia, glossoptosis, obstructive apnea, and cleft palate. While cleft palate is mainly nonsyndromic, about 80 percent of Robin sequence cases are associated with syndromes. Mutations in genes coding for cartilage collagens II and XI, COL2A1, COL11A1 and COL11A2, have been shown to cause chondrodysplasias that are commonly associated with Robin sequence, micrognathia or cleft palate. We therefore analyzed a cohort of 24 patients with nonsyndromic Robin sequence, 17 with nonsyndromic cleft palate and 21 with nonsyndromic micrognathia for mutations in COL11A2. A total of 23 Robin sequence patients were also analyzed for mutations in COL2A1 and COL11A1. We detected two disease-associated mutations in patients with Robin sequence, an Arg to stop codon mutation in COL11A2 and a splicing mutation in COL11A1. Two putatively disease-associated sequence variations were found in COL11A1 in Robin sequence patients, one in COL11A2 in a patient with micrognathia and one in COL2A1 in two patients with Robin sequence. The results showed that sequence variations in these genes can play a role in the etiology of Robin sequence, cleft palate and micrognathia but are not common causes of these phenotypes.