A Newfoundland cohort of familial and sporadic idiopathic pulmonary fibrosis patients: clinical and genetic features

• Published in: Respiratory Research
• Main Authors: Fernandez, Bridget A., Fox, George, Bhatia, Rick, Sala, Eric, Noble, Barbara, Denic, Nash, Fernandez, Dzintra, Duguid, Nigel, Dohey, Amanda, Kamel, Fady, Edwards, Laura, Mahoney, Krista, Stuckless, Susan, Parfrey, Patrick S., Woods, Michael O.
• Format: Article in Journal/Newspaper
• Language: English
• Published: BioMed Central Ltd. 2012
• Subjects: R Medicine (General); Newfoundland
• Online Access: https://research.library.mun.ca/620/; https://research.library.mun.ca/620/1/newfoundland_cohort_familial.pdf; https://research.library.mun.ca/620/3/newfoundland_cohort_familial.pdf; https://doi.org/10.1186/1465-9921-13-64

Background: Idiopathic pulmonary fibrosis (IPF) is an adult-onset Idiopathic Interstitial Pneumonia (IIP) usually diagnosed between age 50 to 70 years. Individuals with Familial Pulmonary Fibrosis (FPF) have at least one affected first or second-degree relative and account for 0.5-20% of cases. Methods: We ascertained and collected DNA samples from a large population-based cohort of IPF patients from Newfoundland, Canada. For each proband, a family history was documented and medical records were reviewed. Each proband was classified as familial (28 patients) or sporadic (50 patients) and all 78 probands were screened for variants in four highly penetrant, adult-onset PF genes (SFTPC, SFTPA2, TERT, TERC). Results: Seventy-eight IPF probands were enrolled of whom 28 (35.9%) had a positive family history. These 28 familial patients led to the recruitment of an additional 49 affected relatives (total of 77 FPF patients). By age 60 years, 42% of the familial cohort had been diagnosed with PF compared with only 16% of the sporadic patient collection (χ2 = 8.77, p = 0.003). Mean age of diagnosis in the familial group was significantly younger than the sporadic group (61.4 years vs. 66.6 yrs, p = 0.012) with a wider age range of diagnosis (19–92 years compared with 47–82 years). Thirty-three of 77 (42.8%) FPF patients had a tissue diagnosis and all but five had usual interstitial pneumonia histology. Compared with other published case series, the familial IIP histologies were more homogeneous. Three of 28 familial probands (10.7%) and none of the 50 sporadic probands had pathogenic variants in the four genes tested. All three familial probands had mutations in TERT. Other phenotypes associated with telomerase deficiency were present in these families including cirrhosis, bone marrow hypoplasia and premature graying. Telomere length assays were performed on mutation carriers from two families and confirmed telomere-related deficiency. Conclusion: The proportion of familial cases in our cohort is higher than any ...