Molecular diagnosis and novel genes and phenotypes in a pediatric thoracic insufficiency cohort

Area of Science:

• Genetics
• Pediatrics
• Respiratory Medicine

Background:

• Thoracic insufficiency syndromes (TIS) are complex genetic disorders causing chest wall deformities and restrictive lung disease.
• Understanding the molecular basis of TIS is crucial for diagnosis, predicting disease progression, and identifying extra-skeletal manifestations.

Purpose of the Study:

• To elucidate the genetic underpinnings of syndromic and non-syndromic TIS in a pediatric cohort.
• To identify novel genetic variants associated with TIS and predict clinical outcomes.

Main Methods:

• Whole exome sequencing was performed on 42 children diagnosed with thoracic insufficiency.
• Genetic variants were analyzed to establish molecular diagnoses and identify potential candidate genes.

Main Results:

• A molecular diagnosis was achieved in 57% (24/42) of probands, with 75% of those having definitive diagnoses.
• Commonly implicated genes encoded primary cilium, connective tissue, and extracellular matrix components.
• A novel association between KIF7 and USP9X variants and thoracic insufficiency was identified.

Conclusions:

• Genetic factors play a significant role in the etiology of thoracic insufficiency syndromes.
• The study expands the known genetic and phenotypic spectrum of TIS, including novel associations with KIF7 and USP9X.
• Extra-skeletal manifestations are prevalent in TIS, highlighting the systemic nature of these disorders.