Treacher Collins syndrome (TCS) is a congenital disorder that affects the development of the bones and tissues of the face. This condition is characterized by distinctive features, including downward-slanting eyes, underdeveloped cheekbones, and small or absent ears. The malformations seen in TCS are rooted in a failure of structures derived from the first and second pharyngeal arches, confirming the underlying cause is genetic.
The Specific Genes Involved
The vast majority of Treacher Collins syndrome cases (81 to 93 percent) are caused by a mutation in the TCOF1 gene. This gene provides instructions for creating the Treacle protein, which is active within the cell’s nucleolus. Treacle plays a foundational role in the production of ribosomal RNA (rRNA), a molecule essential for the assembly of all proteins within a cell.
A mutation in TCOF1 reduces functional Treacle, lowering the cell’s ability to produce sufficient rRNA. This deficit is theorized to trigger the premature self-destruction (apoptosis) of neural crest cells, which are the precursors for the bones and cartilage of the face.
A small minority of cases (about 2 percent) are linked to mutations in the POLR1C or POLR1D genes. These genes also code for subunits of RNA polymerases involved in making ribosomal RNA. The shared consequence is a disruption in the cell’s protein-making machinery, leading to the characteristic craniofacial defects.
Patterns of Genetic Transmission
The most common pattern of transmission is autosomal dominant inheritance, associated with the TCOF1 and POLR1D genes. This means a person only needs one copy of the mutated gene to develop the condition. If a parent has the dominant form of TCS, there is a 50 percent chance they will pass the altered gene copy to any child.
However, 55 to 61 percent of dominant cases result from a de novo mutation, meaning the genetic change occurs spontaneously in the affected individual. In these spontaneous cases, the condition is not inherited from the family line.
The less common mutations in the POLR1C gene follow an autosomal recessive pattern. For an individual to develop TCS, they must inherit an altered copy of the gene from both parents, who are typically unaffected carriers.
Genetic Testing and Diagnosis
Genetic testing serves as the definitive tool to confirm a clinical diagnosis of Treacher Collins syndrome. The process involves sequencing the DNA to look for pathogenic variants within the TCOF1, POLR1C, and POLR1D genes. Identifying the precise genetic change allows clinicians to confirm the diagnosis and determine the specific subtype of TCS.
Genetic testing can also be performed for family members to determine their carrier status, particularly if the affected individual has a mutation in the POLR1C gene. This is helpful for unaffected parents planning future pregnancies. Molecular genetic testing can also be used in prenatal diagnosis. The identification of a specific pathogenic variant is crucial for genetic counseling, as it provides the necessary molecular data to accurately estimate future risk.
Prevalence and Recurrence Risk
Treacher Collins syndrome is a rare disorder, affecting an estimated one in 50,000 live births globally. A genetic diagnosis directly informs the recurrence risk for a family, which varies widely depending on the mode of transmission.
If a person has the autosomal dominant form of TCS and inherited the gene from an affected parent, the chance of their children inheriting the condition is 50 percent for each pregnancy. If the affected individual’s case was the result of a de novo mutation, the risk for their future siblings is significantly lower, though not zero. This low risk is due to the small possibility of germline mosaicism, where the mutation is present only in a small proportion of the parents’ reproductive cells.
For the autosomal recessive form of TCS caused by POLR1C mutations, the parents are typically asymptomatic carriers. If they have had one affected child, the chance of recurrence for each subsequent child is 25 percent. Furthermore, there is a 50 percent chance that a future child will be an unaffected carrier.