Complete Tracheal Ring Deformity: A Translational Genomics Approach to Pathogenesis.

Complete tracheal ring deformity (CTRD) is a rare congenital abnormality of unknown etiology characterized by circumferentially continuous or nearly-continuous cartilaginous tracheal rings, variable degrees of tracheal stenosis and/or shortening, and/or pulmonary arterial sling anomaly. We hypothesized CTRD is caused by inherited or de novo mutations in genes required for normal tracheal development.CTRD and normal tracheal tissues were examined microscopically to define the tracheal abnormalities present in CTRD. Whole-exome sequencing was performed on children with CTRD and their biological parents (Trio analysis) to identify gene variants in CTRD patients. Mutations were confirmed by Sanger sequencing and their potential impact on structure and/or function of encoded proteins was examined using human gene mutation databases. Relevance was further examined by comparison to the effects of targeted deletion of murine homologues important to tracheal development in mice.The trachealis muscle was absent in all of five patients with CTRD. Exome analysis identified six de novo, three recessive, and multiple compound-heterozygous or rare hemizygous variants in children with CTRD. De novo variants were identified in Sonic hedgehog (SHH) and inherited variants were identified in Perlecan (HSPG2), receptor tyrosine kinase like orphan receptor 2 (ROR2), and Wntless (WLS), genes involved in morphogenetic pathways known to mediate trachea-esophageal development in mice.Results demonstrate that absence of the trachealis muscle is associated with CTRD. Variants predicted to cause disease were identified in genes encoding Hedgehog and WNT signaling pathway molecules, which are critical to cartilage formation and normal upper airway development in mice.