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

To define the range of phenotypic expression in Treacher Collins syndrome (TCS; Franceschetti–Klein syndrome), we performed mutation analysis in the TCOF1 gene in 46 patients with tentative diagnosis of TCS and evaluated the clinical data, including a scoring system. A total of 27 coding exons of TCOF1 and adjacent splice junctions were analysed by direct sequencing. In 36 patients with a clinically unequivocal diagnosis of TCS, we detected 28 pathogenic mutations, including 25 novel alterations. No mutation was identified in the remaining eight patients with unequivocal diagnosis of TCS and 10 further patients, in whom the referring diagnosis of TCS was clinically doubtful. There is no overt genotype–phenotype correlation except that conductive deafness is significantly less frequent in patients with mutations in the 3′ part of the open reading frame. Inter- and intrafamilial variation is wide. Some mutation carriers, parents of typically affected patients, are so mildly affected that the diagnosis might be overlooked clinically. This suggests that modifying factors are important for phenotypic expression. Based on these findings, minimal diagnostic criteria were defined: downward slanting palpebral fissures and hypoplasia of the zygomatic arch. The difficulties in genetic counselling, especially diagnosis of family members with a mild phenotype, are described.

[1]  M. Dixon,et al.  Increased levels of apoptosis in the prefusion neural folds underlie the craniofacial disorder, Treacher Collins syndrome. , 2000, Human molecular genetics.

[2]  J. Wasmuth,et al.  Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome , 1996, Nature Genetics.

[3]  A. Thomson.  Notice of Several Cases of Malformation of the External Ear, Together with Experiments on the State of Hearing in Such Persons , 1846, Monthly Journal of Medical Science.

[4]  M. Dixon,et al.  Another face of the Treacher Collins syndrome (TCOF1) gene: identification of additional exons. , 2004, Gene.

[5]  A. Verloes,et al.  Feingold syndrome: report of a new family and review. , 1997, American journal of medical genetics.

[6]  Yusuke Nakamura,et al.  Gene-based SNP discovery as part of the Japanese Millennium Genome Project: identification of 190 562 genetic variations in the human genome , 2002, Journal of Human Genetics.

[7]  W. Hauck,et al.  Oculoauriculovertebral dysplasia and variants: phenotypic characteristics of 294 patients. , 1987, American journal of medical genetics.

[8]  J. Hall,et al.  Review and hypotheses: somatic mosaicism: observations related to clinical genetics. , 1988, American journal of human genetics.

[9]  S. Rovin,et al.  MANDIBULOFACIAL DYSOSTOSIS, A FAMILIAL STUDY OF FIVE GENERATIONS. , 1964, The Journal of pediatrics.

[10]  M. Lovett,et al.  TCOF1 gene encodes a putative nucleolar phosphoprotein that exhibits mutations in Treacher Collins Syndrome throughout its coding region. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[11]  J. Autissier,et al.  [Treacher-Collins syndrome]. , 1954, Revue de stomatologie.

[12]  C. Cremers,et al.  The Treacher Collins syndrome. A clinical, radiological, and genetic linkage study on two pedigrees. , 1995, Archives of otolaryngology--head & neck surgery.

[13]  E. Jabs,et al.  Screening of TCOF1 in patients from different populations: confirmation of mutational hot spots and identification of a novel missense mutation that suggests an important functional domain in the protein treacle , 2002, Journal of medical genetics.

[14]  J. Burn,et al.  New dysmorphic syndrome with choanal atresia in siblings. , 1992, Clinical dysmorphology.

[15]  R. Shiang,et al.  Sequence analysis, identification of evolutionary conserved motifs and expression analysis of murine tcof1 provide further evidence for a potential function for the gene and its human homologue, TCOF1. , 1997, Human molecular genetics.

[16]  A. Franceschetti,et al.  Un syndrome nouveau: La dysostose mandibulo-faciale. , 1944 .

[17]  D. Klein,et al.  The mandibulofacial dysostosis; a new hereditary syndrome. , 1949, Acta ophthalmologica.

[18]  M. Ferguson-Smith,et al.  Essential medical genetics , 1987 .

[19]  D. Wieczorek,et al.  Two brothers with Burn‐McKeown syndrome , 2003, Clinical dysmorphology.

[20]  Y. Yamauchi,et al.  Proteomic Analysis of Human Nop56p-associated Pre-ribosomal Ribonucleoprotein Complexes , 2003, Journal of Biological Chemistry.

[21]  B. Hall.  Choanal atresia and associated multiple anomalies. , 1979, The Journal of pediatrics.

[22]  A. Meloni,et al.  A novel β‐thalassemia mutation (G→A) at the initiation codon of the β‐globin gene , 1992 .

[23]  V. McKusick,et al.  Conductive hearing loss and malformed low-set ears, as a possible recessive syndrome. , 1969, Journal of medical genetics.

[24]  M. Dixon,et al.  Mutation Testing in Treacher Collins Syndrome , 2002 .

[25]  M. Passos-Bueno,et al.  High mutation detection rate in TCOF1 among Treacher Collins syndrome patients reveals clustering of mutations and 16 novel pathogenic changes , 2000, Human mutation.

[26]  D. Poswillo.  The pathogenesis of the treacher Collins syndrome (Mandibulofacial dysostosis) , 1975 .

[27]  M. Dixon,et al.  The mutational spectrum in Treacher Collins syndrome reveals a predominance of mutations that create a premature-termination codon. , 1997, American journal of human genetics.

[28]  G. Zampino,et al.  Growth and developmental retardation, ocular ptosis, cardiac defect, and anal atresia: confirmation of the ROCA-Wiedemann syndrome. , 2000, American journal of medical genetics.

[29]  H. Nadler,et al.  Mandibulo-facial dysostosis. (Treacher-Collins syndrome). , 1967, American journal of diseases of children.

[30]  M. Breen,et al.  Canine TCOF1; cloning, chromosome assignment and genetic analysis in dogs with different head types , 2001, Mammalian Genome.

[31]  R. Hennekam,et al.  Treacher Collins syndrome may result from insertions, deletions or splicing mutations, which introduce a termination codon into the gene. , 1996, Human molecular genetics.

[32]  P. Wójcicki,et al.  Novel mutation in the 5′ splice site of exon 4 of the TCOF1 gene in the patient with Treacher Collins syndrome , 2003, American journal of medical genetics. Part A.

[33]  E. Jabs,et al.  TCOF1 mutations excluded from a role in other first and second branchial arch-related disorders. , 2002, American journal of medical genetics.