Suspected Pathophysiologic Mechanism
TCOF1 encodes for the nucleolar phosphoprotein Treacle which is involved in ribosomal biogenesis. It is thought, that likewise in the mouse model, haploinsufficiency for Treacle led to a reduced production of mature ribosomes in cranial neural crest cells. Facial bones and cartilages are derived from these cranial neural crest cells and a reduction in the number at a critical time early in embryogenesis leads to the craniofacial malformations.
Type of Mutations
The spectrum of mutations within the TCOF1 gene that causes TCS is very heterogenous. Hundreds of pathogenic variants in TCOF1 have already been reported and novel variants are described in a great proportion of families. Pathogenic variants have been scattered throughout the gene. And more recently large deletions have also been identified.
Diagnostic Testing
Since the majority of individuals with TCS are heterozygous for a pathogenic sequence-variation in TCOF1, sequence analysis seems to be the appropriated first step diagnostic testing. Possibly in a multigene panel with POLR1B, POLR1C and POLR1D.
In a second step gene-targeted deletion/duplication analysis could be considered.
If autosomal recessive inheritance is suggested the focus should be put on POLR1C and POLR1D.
TCOF1