Clinical Domain Working Groups

The focus of the Interstitial Lung Disease (ILD) group is on curation of genes causing lung fibrosis across the age spectrum. The pediatric manifestations include the rare set of childhood ILDs (chILD) characterized by remodeling of lung parenchyma leading to abnormal gas exchange. These have been classified broadly into those that occur during infancy (<2 years of age) and those that are not specific to infancy (>2 years of age). The childhood presentations are generally distinct from the presentations of ILD in older adults. Idiopathic Pulmonary Fibrosis (IPF) is the prototypic disease characterized by progressive lung fibrosis disease affecting adults. Overall, it is considered a rare disease, affecting about 5-20 per 100,000 individuals. However, in populations older than 65 years of age, there is a much higher prevalence, up to 0.5%. Progression of lung fibrosis is a defining characteristic of IPF, even though the inter-individual rate of progression is variable. Genetic pulmonary fibrosis is most often diagnosed as IPF, but other forms of progressive pulmonary fibrosis are also common.

There are difficulties in the field, regarding phenotypic variability, tenuous gene-disease links, and questionable pathogenicity of genetic variants. Hence, there is a need for ClinGen-based gene curation. As for many lung presentations of genetic disease, ILD manifests as a disease with variable penetrance, often associated with non-pulmonary phenotypes. Disease characteristics rely upon qualitative assessment of chest radiographs. There may be an increasing reliance on genetic testing and interpretation. It is currently accepted that there are about 35 ILD-causing genes. Current NGS methods can diagnose around 10-25% of cases with causal mutations, hence we expect more genes to emerge. New publications have reported increasingly smaller patient numbers and harder to interpret gene variants. The expert team we have gathered has extensive knowledge about this variable penetrance, multisystem disease. Much remains unknown about genotype-phenotype relationships.