title: 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.
authors.affiliation: Centro de Estudos do Genoma Humano, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: A
authors.initials: A
authors.lastname: Splendore
authors.forename: E O
authors.initials: EO
authors.lastname: Silva
authors.forename: L G
authors.initials: LG
authors.lastname: Alonso
authors.forename: A
authors.initials: A
authors.lastname: Richieri-Costa
authors.forename: N
authors.initials: N
authors.lastname: Alonso
authors.forename: A
authors.initials: A
authors.lastname: Rosa
authors.forename: G
authors.initials: G
authors.lastname: Carakushanky
authors.forename: D P
authors.initials: DP
authors.lastname: Cavalcanti
authors.forename: D
authors.initials: D
authors.lastname: Brunoni
authors.forename: M R
authors.initials: MR
authors.lastname: Passos-Bueno
mesh_terms: D004252:DNA Mutational Analysis; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008342:Mandibulofacial Dysostosis / Q000209:etiology / Q000235:genetics*; D005810:Multigene Family; D009687:Nuclear Proteins / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018807:Polymorphism, Single-Stranded Conformational; D012744:Sex Ratio; D013577:Syndrome
chemical_list: D005819:Genetic Markers; D009687:Nuclear Proteins; D010750:Phosphoproteins; C105442:TCOF1 protein, human