# Identification of novel TCOF1 mutations in Treacher Collins syndrome and their functional characterization

## TL;DR

This study identifies two new mutations in the TCOF1 gene linked to Treacher Collins syndrome and explains how these mutations affect protein function and disease development.

## Contribution

The study reports two novel TCOF1 mutations and provides the first documented case of intron retention in TCS patients.

## Key findings

- The novel mutations c.2115dupG and c.2142+23_2142+52 del produce truncated proteins lacking nuclear location signals, impairing nuclear entry.
- The mutation c.2142+23_2142+52 del is the first known case of intron retention in TCS patients, disrupting RNA splicing.
- Previously reported mutations c.136C>G and c.1719del also affect nuclear localization and mRNA levels, confirming their pathogenic roles.

## Abstract

Treacher Collins syndrome (TCS) is a congenital disorder primarily caused by the mutation in the Treacle Ribosome Biogenesis Factor 1 (TCOF1) gene. However, the significance of many TCOF1 mutations remains uncertain.

We report two novel mutations identified in two TCS families and assess their pathogenicity alongside two previously reported mutations. Both novel mutations, c.2115dupG (p.T706DfsTer52) and c.2142+23_2142+52 del (p.A715VfsTer31), result in truncated proteins lacking nuclear location signals (NLSs), which impedes their entry into the nucleus and reduces mRNA expression level. Notably, the mutation c.2142+23_2142+52 del, leading to the retention of a 62 bp intron and disrupting RNA splicing, represents the first documented case of intron retention in TCS patients. Additionally, the previously reported mutation c.136 C> G (p.L46V) hinders protein nuclear location, while mutation c.1719del (p.N574TfsTer22) significantly decreases mRNA levels.

Our research expands the spectrum of TCOF1 mutations and provides evidence clarifying their pathogenic nature. These findings are crucial for genetic counseling and prenatal diagnosis for TCS patients.

The online version contains supplementary material available at 10.1186/s13023-025-03667-7.