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

Abstract

BackgroundIdiopathic 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.MethodsWe 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).ResultsSeventy-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.ConclusionThe proportion of familial cases in our cohort is higher than any previously reported estimate and we suggest that this is due to the fact that Newfoundland cohort is ethnically homogeneous and drawn from a founder population. In our patient collection, diagnosis with IPF prior to age 45 years predicted familial disease. In two of the three TERT mutation families, the pedigree appearance is consistent with genetic anticipation. In the other 25 FPF families negative for mutations in known PF genes, we did not identify other telomerase associated medical problems (bone marrow dysfunction, cirrhosis) and we hypothesize that there are novel PF genes segregating in our population.

Telomerase and Telomere Length in Pulmonary Fibrosis

“…A recent study reported that 3 of 38 familial probands and none of 50 sporadic cases studied manifested TERT/TR mutations. The three familial TERT mutation carriers exhibited shortened telomeres, but telomere lengths in all other samples from subjects without mutations were not measured (36). These reports indicate that a minority of cases with IPF exhibit telomere shortening, most of which is not associated with TERT or TR mutations.…”

“…The incidence of shortening in the samples reported here was less than 6%, which may reflect the different population samples studied. The present study investigated the telomere lengths in a Mexican cohort, whereas other studies reported on samples collected in the United States or Canada (12,36). The patients with IPF in this study were of the sporadic type, with no genetic information available.…”

Management of suspected monogenic lung fibrosis in a specialised centre

“…In most series, the evolution of FPF was comparable to that of IPF sporadic forms and the causes of death were similar to those observed with IPF sporadic forms [22][23][24]. As observed in sporadic pulmonary fibrosis, a definite radiological or histological UIP pattern is associated with poor prognosis in FPF [16,21].…”

“…Mutations in DKC1, NAF1 and TINF2 are much rarer (figure 1) [9,23,[28][29][30][31][32][33][34][35]. TERT or TERC mutations may be found in about 1-3% of sporadic IPF cases [28].…”

“…SFTPD mutations have not been associated with lung disease. Among surfactant genes, SFTPC mutations are most described in adult familial ILD, but their frequency is usually <5% [23]. Transmission is autosomal dominant.…”