Molecular Investigation in Early-Onset Interstitial Lung Disease: Results From 699 Unrelated Patients

Interstitial lung diseases (ILDs) are rare and severe respiratory conditions that may ultimately result in pulmonary fibrosis (PF). The objective of this study was to present the results of molecular diagnosis of early-onset ILD (from neonates to young adults < 50 years) in a reference genetic diagnostic laboratory.

DNAs from 699 index cases and 190 relatives were studied over 6 years by Sanger and/or targeted next generation sequencing of surfactant-related genes and other genes involved in early-onset ILD.

Pathogenic/likely pathogenic variants were evidenced for 62 patients (8.9%). The genes most frequently involved were SFTPA2 (13/62), followed by ABCA3 (12/62) and SFTPC (10/62). Among index cases for whom precise clinical data were available (n = 542), indications associated with a high molecular diagnostic yield were pulmonary alveolar proteinosis (61.5%, 8/13; p < 0.0007); family history of ILD/PF and lung cancer (36.8%, 7/19; p = 0.0132) and newborns > 32 weeks gestation with neonatal respiratory distress (14.8%, 9/61). The proportion of positive molecular investigations culminated in two age groups over the lifespan: 23.3% (7/30) in children aged 1 to 10 years, and 18.3% (15/82) in adults aged 30 to 40 years. Over the 6-year period, 190 relatives were subjected to testing in order to perform segregation studies (n = 123) and/or predictive testing (n = 79).

This study highlights the specific patient's characteristics associated with a high or low molecular diagnostic yield in clinical practice. Furthermore, it emphasises the importance of establishing a molecular diagnosis in order to provide genetic counselling to the family.