# Integrating imaging and genomics in prenatal Treacher Collins syndrome: evidence for practice and policy

## TL;DR

This study explores prenatal diagnosis and management of Treacher Collins syndrome, emphasizing genetic testing and ultrasound findings to guide clinical decisions and counseling.

## Contribution

The study provides new insights into the genetic and clinical variability of Treacher Collins syndrome, highlighting the importance of parental mosaicism in recurrence risk counseling.

## Key findings

- Frameshift variants are the most common TCOF1 mutations in Treacher Collins syndrome.
- Severe phenotypes are associated with truncating mutations in later exons of TCOF1.
- Low-level parental mosaicism affects recurrence risk and should be considered in de novo fetal cases.

## Abstract

To elucidate the prenatal diagnostic challenges, genetic landscape, and clinical outcomes of Treacher Collins syndrome (TCS), focusing on the role of TCOF1 variants, prenatal ultrasound findings, and counselling implications.

A systematic literature review (2000–2025) identified 273 TCS cases, supplemented by two index cases(one from each of two unrelated families) from our centre. Data included genetic testing (whole-exome sequencing, Sanger sequencing), prenatal imaging, and clinical outcomes. Variants in TCOF1 were analyzed alongside genotype-phenotype correlations and mosaicism.

We assembled 275 patients in total, including 273 cases from the literature and two index cases from our centre. We summarized 15 individuals with prenatal ultrasound assessment and/or pregnancy outcomes(2 from our centre and 13 from the literature). Across 303 TCOF1 variant entries extracted from the included reports frameshift changes were most frequent at 66.01%, followed by nonsense variants at 10.56%, with missense, large deletions, and splice variants comprising the remainder. Pathogenic TCOF1 variants were dominated by frameshift and nonsense changes, and truncations in later exons, for example exon 24, were enriched among severe phenotypes; overall, 68 of 275 cases, that is, 24.73%, were categorized as severe. Parental mosaicism was identified or suspected in 6 of the 275 cases (2.18%), including low-level paternal mosaicism confirmed in blood and semen in one family. Termination of pregnancy (ToP) occurred in 6 cases within this prenatal findings dataset, attributable to severe airway risks or parental choice. Postnatal management (airway support, hearing aids, reconstructive surgery) supported survival in 263/275 (95.64%) of all reported cases.

Prenatal diagnosis of TCS relies on ultrasound detection of craniofacial anomalies and gene testing, but severity prediction remains challenging due to mosaicism and variable expressivity. Low-level parental mosaicism materially affects recurrence-risk counselling and should be actively considered when a foetal variant appears de novo. Early genetic diagnosis and personalized counselling are crucial for effective TCS management, helping families navigate medical, ethical, and sociocultural concerns.

The online version contains supplementary material available at 10.1186/s13023-025-04094-4.