Treacher Collins syndrome: a clinical and molecular study based on a large series of patients

Purpose: Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:, TCOF1 , POLR1D , and POLR1C . Methods: We report a clinical and extensive molecular study, including TCOF1 , POLR1D , POLR1C , and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype–genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D , and the type of mutation or its localization in the TCOF1 gene. Results: We identified 92/146 patients (63%) with a molecular anomaly within TCOF1 , 9/146 (6%) within POLR1D , and none within POLR1C . Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature. Conclusion: Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype–genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect. Genet Med 18 1, 49–56.