First Report of a Single Exon Deletion in TCOF1 Causing Treacher Collins Syndrome

Area of Science:

• Genetics
• Molecular Biology
• Medical Genetics

Background:

• Treacher Collins syndrome (TCS) is a rare craniofacial disorder with significant phenotypic variability.
• Mutations in TCOF1, POLR1D, and POLR1C genes are known causes, but some patients remain genetically undiagnosed.
• TCOF1 mutations often result in premature termination codons, but larger deletions are less understood.

Purpose of the Study:

• To investigate potential large deletions in TCOF1 in TCS patients negative for point mutations or small indels in TCOF1, POLR1D, and POLR1C.
• To identify novel genetic causes of TCS beyond previously known mutation types.

Main Methods:

• Multiplex ligation-dependent probe amplification (MLPA) was used to screen 112 TCS patients for large deletions.
• Patients were pre-screened for mutations in TCOF1, POLR1D, and POLR1C.
• RNA analysis was performed to confirm exon loss.

Main Results:

• A 3.367 kb deletion encompassing exon 3 of the TCOF1 gene was identified in one patient.
• This represents the first described single exon deletion within TCOF1.
• RNA analysis confirmed the loss of exon 3, leading to haploinsufficiency of the TREACLE protein.

Conclusions:

• This study identifies a novel type of TCOF1 mutation (single exon deletion) in Treacher Collins syndrome.
• The findings expand the spectrum of genetic defects underlying TCS.
• This discovery may aid in diagnosing previously unexplained TCS cases and understanding genotype-phenotype correlations.