ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 5q32-q33.1
  • GRCh37/hg19 chr5: 149,737,202-149,779,871
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr5: 150,357,697-150,400,306
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000005.9) (NC_000005.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
9042910 Edwards et al (1997) catalogued 25 TCOF1 variants, all but one resulting in the introduction of a premature-termination codon.
12114482 Splendore et al (2002) observed that the majority of pathogenic variants are small deletions and insertions causing frameshifts that are predicted to result in a truncated protein and that more than 50% of all described pathogenic variants known at the time were clustered in five exons (10, 15, 16, 23, and 24).
15340364 Teber et al (2004) assessed 36 patients with a clinically unequivocal diagnosis of Treacher-Collins syndrome (TCS), and detected 28 pathogenic variants, including 25 novel alterations. Most of the variants were predicted to lead to premature termination codons because of frameshift length alterations (variants in 14 patients) or nonsense substitutions (variants in six patients). Variants identified in five patients affected invariable bases at splice donor (n=2) or acceptor (n=3) sites. No variant 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.
8875242 Dixon et al (1996) catalogued 20 variants all resulting in the introduction of a premature stop codon in patients with a clinical diagnosis of Treacher Collins syndrome, supporting a mechanism of haploinsufficiency.
22317976 Bowman et al (2012) assessed 182 patients with clinical features consistent with TCS, and identified 92 pathogenic sequence level variants (57% frameshift, 23% nonsense, 16% splicing, 4% missense), as well as 5 partial gene deletions. Many of the sequence variants arose de novo.

Haploinsufficiency phenotype comments:

Phenotype (from GeneReviews): "Treacher Collins syndrome (TCS) is characterized by bilateral and symmetric downslanting palpebral fissures, malar hypoplasia, micrognathia, and external ear abnormalities. Hypoplasia of the zygomatic bones and mandible can cause significant feeding and respiratory difficulties. About 40%-50% of individuals have conductive hearing loss attributed most commonly to malformation of the ossicles and hypoplasia of the middle ear cavities. Inner ear structures tend to be normal. Other, less common abnormalities include cleft palate and unilateral or bilateral choanal stenosis or atresia. Typically intellect is normal." TSC is associated with extreme clinical variability, between families and within families. Some cases are subclinical and go undiagnosed, while others result in severe facial manifestations and airway compromise. There is no apparent genotype-phenotype correlation. It is estimated that 50-60% of TCOF1 variants occur de novo. Individuals with a TCOF1 variant have a 50% chance of passing it to their offspring. No isolated whole gene TCOF1 deletions have been reported at the time of this review. Contiguous gene deletions are reported in association with TCS phenotype plus intellectual disability. Many intragenic TCOF1 deletion and insertions have been reported.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

No isolated whole gene TCOF1 duplications reported. No evidence for TCOF1 triplosensitivity.