A Test to Comprehensively Capture the Known Genetic Component of Familial Pulmonary Fibrosis.

The recent European Respiratory Society statement on familial pulmonary fibrosis (FPF) supports the need of genetic testing in the care of patients and their relatives. However, no solution (i.e., a concrete test) was provided to implemented genetic testing in daily practice. Herein, we tabulated and standardized the nomenclature of 128 genetic variants in 20 genes implicated in adult-onset pulmonary fibrosis. The objective was to develop a laboratory developed test (LDT) based on standard Sanger sequencing in order to capture all known FPF-associated variants. Targeted DNA fragments were amplified with harmonized PCR conditions to perform the LDT in a single 96-well plate. The new genetic test was evaluated in 62 sporadic cases of idiopathic pulmonary fibrosis (IPF). As expected in this population, we observed a low yield of disease-causing mutations. More importantly, 100% of targeted variants by the LDT were successfully evaluated. Furthermore, four variants of uncertain significance with in silico -predicted deleterious scores were identified in three patients, suggesting novel pathogenic variants in genes known to cause IPF. Finally, the MUC5B promoter variant rs35705950 was strongly enriched in these patients with a minor allele frequency of 41.1% compared to 10.6% in a matched population-based cohort (n=29,060), leading to an estimation that this variant may explain up to 35% of the population-attributable risk. This LDT provides a solution for rapid clinical translation. Technical laboratory details are provided so that specialised pulmonary centers can implement the LDT in-house in order to expedite the clinical recommendations of experts' panel.