High mutation detection rate in TCOF1 among Treacher Collins syndrome patients reveals clustering of mutations and 16 novel pathogenic changes

Twenty-eight families with a clinical diagnosis of Treacher Collins syndrom e were screened for mutations in the 25 coding exons of TCOF1 and their adj acent splice junctions through SSCP and direct sequencing. Pathogenic mutat ions were detected in 26 patients, yielding the highest detection rate repo rted so far for this disease (93%) and bringing the number of known disease -causing mutations from 35 to 51. This is the first report to describe clus tering of pathogenic mutations. Thirteen novel polymorphic alterations were characterized, confirming previous reports that TCOF1 has an unusually hig h rate of single-nucleotide polymorphisms (SNPs) within its coding region. We suggest a possible different mechanism leading to TCS or genetic heterog eneity for this condition, as we identified two families with no apparent p athogenic mutation in the gene. Furthermore, our data confirm the absence o f genotype-phenotype correlation and reinforce that the apparent anticipati on often observed in TCS families is due to ascertainment bias. Hum Mutat 1 6:315-322, 2000. (C) 2000 Wiley-Liss, Inc.