High mutation detection rate inTCOF1 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. Hum Mutat 16:315–322, 2000. © 2000 Wiley‐Liss, Inc.

Reduced transcription of TCOF1 in adult cells of Treacher Collins syndrome patients

“…Seven of the 23 patients included in the present report were previously studied by our group [3,9,21]. Pathogenic mutations were identified in six of these seven individuals (Table 1).…”

“…No genotype-phenotype correlation has been observed in TCS and there is also no evidence of association between the disease severity and parental origin or type of the pathogenic mutation, male or female sex, sporadic or familial cases [5-9]. …”

The Treacher Collins syndrome ( TCOF1 ) gene product is involved in ribosomal DNA gene transcription by interacting with upstream binding factor

“…It was hypothesized that mutations in the TCOF1 gene (7,(14)(15)(16)(17) could result in mislocalization of truncated proteins and, consequently, loss of treacle functions, suggesting that TCS results from treacle haploinsufficiency. No genotype-phenotype correlation has been observed, which might explain the wide clinical variability observed among TCS patients.…”

Novel mutations of TCOF1 gene in European patients with treacher Collins syndrome

“…Both the mutations identified fall within the TCOF1 mutation hot spot rich in 18 Lysine residues. Other microdeletions have already been described in this region [8,11,16-18]. …”

“…Two additional exons have been reported: exon 6A, included in the most common isoform, and exon 16A, included in a minor isoform [9]. The mutations observed in TCS are predominantly sporadic, and the vast majority results in the introduction of a premature termination codon that can lead to the truncation of protein or to nonsense-mediated mRNA decay [10,11]. This suggests in the developmental anomalies result from haploinsufficiency of TCOF1 .…”