Complete Tracheal Ring Deformity. A Translational Genomics Approach to Pathogenesis

Area of Science:

• Genetics
• Developmental Biology
• Pediatric Medicine

Background:

• Complete tracheal ring deformity (CTRD) is a rare congenital condition with unknown causes.
• CTRD involves continuous cartilaginous tracheal rings, potential airway stenosis, and pulmonary arterial sling.
• The underlying genetic basis of CTRD requires further investigation.

Purpose of the Study:

• To investigate the hypothesis that CTRD results from inherited or de novo mutations in genes vital for tracheal development.
• To identify genetic variants associated with CTRD through whole-exome sequencing.

Main Methods:

• Microscopic examination of tracheal tissues from CTRD patients and controls.
• Whole-exome sequencing (trio analysis) in children with CTRD and their parents.
• Confirmation of mutations via Sanger sequencing and bioinformatic analysis.
• Comparison with murine models of tracheal development.

Main Results:

• Absence of the trachealis muscle was observed in all five CTRD patients.
• Exome analysis revealed de novo, recessive, and compound-heterozygous variants in CTRD patients.
• Disease-associated variants were identified in SHH (Hedgehog pathway) and HSPG2, ROR2, WLS (involved in Wnt signaling).

Conclusions:

• Absence of the trachealis muscle is associated with CTRD.
• Genetic variants in Hedgehog and Wnt signaling pathways are implicated in CTRD.
• These pathways are critical for cartilage formation and upper airway development.