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.

Mutational analysis of theTCOF1gene in 11 Japanese patients with Treacher Collins Syndrome and mechanism of mutagenesis

“…The types of mutations were three small deletions, two small insertions, one complex of a small deletion and an insertion, two nonsense and one splicing mutation. Most likely, all of these mutations result in the creation of a premature termination codon and a truncated gene product; the findings were similar to those previously reported [Edwards et al, 1997; Splendore et al, 2000]. It has been suggested that mutations are more frequently observed in exons 10, 15, 16, 23, and 24 of the TCOF1 gene [Splendore et al, 2002], however, no TCS patients in this study had a mutation in these exons.…”

Mutational analysis of theTCOF1gene in 11 Japanese patients with Treacher Collins Syndrome and mechanism of mutagenesis

“…The types of mutations were three small deletions, two small insertions, one complex of a small deletion and an insertion, two nonsense and one splicing mutation. Most likely, all of these mutations result in the creation of a premature termination codon and a truncated gene product; the findings were similar to those previously reported [Edwards et al, 1997; Splendore et al, 2000]. It has been suggested that mutations are more frequently observed in exons 10, 15, 16, 23, and 24 of the TCOF1 gene [Splendore et al, 2002], however, no TCS patients in this study had a mutation in these exons.…”

Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation

“…Interestingly, most family members with TCOF1 mutations have no ear anomalies, even if microtia in index cases is severe. This is in line with Splendore et al, 15 who reported that the frequency of external ear abnormalities in index patients in familial cases is nine times that of their affected relatives. Thus, microtia is not helpful for detecting mildly affected patients.…”

TCOF1mutations excluded from a role in other first and second branchial arch‐related disorders

“…Polymorphic changes in exons 6, 10, 11, 13, 16, 19, 21, and 23 were detected in similar frequencies found in other studies [Splendore et al, 2000]. Two apparently rare changes were identified: patient F369 has a silent mutation (c.1863A → G; E621E) in exon 12, and patient F1250 has a novel silent mutation in exon 2 (c.162A → G; Q54Q).…”

Mutational analysis of theTCOF1gene in 11 Japanese patients with Treacher Collins Syndrome and mechanism of mutagenesis

“…The types of mutations were three small deletions, two small insertions, one complex of a small deletion and an insertion, two nonsense and one splicing mutation. Most likely, all of these mutations result in the creation of a premature termination codon and a truncated gene product; the findings were similar to those previously reported [Edwards et al, 1997; Splendore et al, 2000]. It has been suggested that mutations are more frequently observed in exons 10, 15, 16, 23, and 24 of the TCOF1 gene [Splendore et al, 2002], however, no TCS patients in this study had a mutation in these exons.…”

Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation

“…Interestingly, most family members with TCOF1 mutations have no ear anomalies, even if microtia in index cases is severe. This is in line with Splendore et al, 15 who reported that the frequency of external ear abnormalities in index patients in familial cases is nine times that of their affected relatives. Thus, microtia is not helpful for detecting mildly affected patients.…”

TCOF1mutations excluded from a role in other first and second branchial arch‐related disorders

“…Polymorphic changes in exons 6, 10, 11, 13, 16, 19, 21, and 23 were detected in similar frequencies found in other studies [Splendore et al, 2000]. Two apparently rare changes were identified: patient F369 has a silent mutation (c.1863A → G; E621E) in exon 12, and patient F1250 has a novel silent mutation in exon 2 (c.162A → G; Q54Q).…”

Mutational analysis of theTCOF1gene in 11 Japanese patients with Treacher Collins Syndrome and mechanism of mutagenesis

“…The types of mutations were three small deletions, two small insertions, one complex of a small deletion and an insertion, two nonsense and one splicing mutation. Most likely, all of these mutations result in the creation of a premature termination codon and a truncated gene product; the findings were similar to those previously reported [Edwards et al, 1997; Splendore et al, 2000]. It has been suggested that mutations are more frequently observed in exons 10, 15, 16, 23, and 24 of the TCOF1 gene [Splendore et al, 2002], however, no TCS patients in this study had a mutation in these exons.…”

Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation

“…Interestingly, most family members with TCOF1 mutations have no ear anomalies, even if microtia in index cases is severe. This is in line with Splendore et al, 15 who reported that the frequency of external ear abnormalities in index patients in familial cases is nine times that of their affected relatives. Thus, microtia is not helpful for detecting mildly affected patients.…”

TCOF1mutations excluded from a role in other first and second branchial arch‐related disorders

“…Polymorphic changes in exons 6, 10, 11, 13, 16, 19, 21, and 23 were detected in similar frequencies found in other studies [Splendore et al, 2000]. Two apparently rare changes were identified: patient F369 has a silent mutation (c.1863A → G; E621E) in exon 12, and patient F1250 has a novel silent mutation in exon 2 (c.162A → G; Q54Q).…”