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In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
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Biallelic FGF4 Variants Linked to Thoracic Dystrophy and Respiratory Insufficiency
Laura M Watts1,2, Esther Kinning3, Donald R Latner4
1Oxford NIHR Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, UK.
Clinical Genetics
|April 22, 2025
Summary
Biallelic alterations in the FGF4 gene are newly identified as a cause of thoracic dystrophy, a rare inherited skeletal condition. This finding helps diagnose patients with unexplained respiratory insufficiency and narrow chest deformities.
Area of Science:
- Genetics
- Developmental Biology
- Medical Genetics
Background:
- Thoracic dystrophies are inherited skeletal disorders characterized by a narrow chest and pulmonary hypoplasia, often resulting in severe respiratory insufficiency.
- Most thoracic dystrophies are linked to genetic alterations affecting ciliary function, yet approximately 20% of patients lack a molecular diagnosis.
Purpose of the Study:
- To identify the genetic cause of thoracic dystrophy in two families with unexplained respiratory insufficiency.
- To investigate the role of FGF4 mutations in the pathogenesis of thoracic dystrophy.
Main Methods:
- Whole-exome sequencing was performed on patients from two unrelated families.
- Segregation analysis and in silico prediction tools were used to assess the pathogenicity of identified FGF4 variants.
Main Results:
- Two families presented with thoracic dystrophy, short ribs, narrow chest, and respiratory insufficiency.
- Rare biallelic missense substitutions in FGF4, predicted to be deleterious, were identified in affected individuals from both families.
- The identified FGF4 alterations were associated with the thoracic dystrophy phenotype, while other known genetic causes were excluded.
Conclusions:
- Biallelic alterations in FGF4 represent a novel genetic cause of thoracic dystrophy.
- This discovery expands the genetic landscape of thoracic dystrophies and aids in diagnosing patients with this condition.
- FGF4 plays a crucial role in thoracic skeleton development, and its disruption leads to a specific spectrum of skeletal and respiratory abnormalities.
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