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

Abstract

Twenty-eight families with a clinical diagnosis of Treacher Collins syndrome were screened for mutations in the 25 coding exons of TCOF1 and their adjacent splice junctions through SSCP and direct sequencing. Pathogenic mutations were detected in 26 patients, yielding the highest detection rate reported 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 clustering of pathogenic mutations. Thirteen novel polymorphic alterations were characterized, confirming previous reports that TCOF1 has an unusually high rate of single-nucleotide polymorphisms (SNPs) within its coding region. We suggest a possible different mechanism leading to TCS or genetic heterogeneity for this condition, as we identified two families with no apparent pathogenic mutation in the gene. Furthermore, our data confirm the absence of genotype-phenotype correlation and reinforce that the apparent anticipation often observed in TCS families is due to ascertainment bias.

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

“…We observed in each situation that 20 and 28% of patients needed feeding or respiratory support, respectively, compared with 11% who needed respiratory support in the study by Teber et al 2 ( Table 1). Cleft palate was less frequent in our study (22%) compared with those by Teber et al 2 (33%) and Splendore et al 18 (28%) ( Table 1). Surprisingly, we observed a high rate of congenital cardiac defects in patients with mutations in TCOF1 (8%), which was never described in the literature.…”

“…In this study we identified 47 novel mutations spread throughout the TCOF1 gene and only one clustering located in exons 23 and 24, which contained 27% of the mutations. The common 5-bp deletion in exon 24 (p.Lys1457Glufs) was present in 7% of patients in our series compared with 20% of patients in the study by Splendore et al 18 and none in the study by Teber et al 2 We hypothesize that the distinct geographic origin of the patients between studies explains such difference (Brazilian versus European centers), given that population in our study was quite diverse.…”

“…Despite the high rate of SNPs in the TCOF1 gene, 18 we did not observe any association between these polymorphic variants and the 19 clinical features considered. The functional SNP in the promoter region of TCOF1 16 does not seem to be associated with clinical severity according to the score calculated by Teber et al 2 and our score.…”

“…In the literature, the percentage of patients with mutations in TCOF1 ranged from 53% (97/182) 8 to 93% (26/28). 2,8,18 In the study by Bowman et al, 8 the proportion increased from 53 to 71% if patients with a high clinical suspicion of TCS are considered, and in the study by Teber et al 2 it increased from 61 to 78%.…”

“…Splendore et al 18,19 observed a clustering of pathogenic mutations in exons 10, 15, 16, 23, and 24. In this study we identified 47 novel mutations spread throughout the TCOF1 gene and only one clustering located in exons 23 and 24, which contained 27% of the mutations.…”