Figures
- FIGURE 1
a) Main genes and b) corresponding pathways identified in 2016 as a Mendelian cause of suspected monogenic pulmonary fibrosis in adults.
- FIGURE 2
Typical pedigree of a family suggestive of a TERC mutation with autosomal dominant transmission and anticipation. Ages are those reported at diagnosis. ILD: interstitial lung disease. The arrow indicates the proband.
- FIGURE 3
Representative computed tomography scans of carriers of a) RTEL1 and b) TERC mutations. Usual interstitial pneumonia is the most frequent pattern seen (a), but a pattern suggestive of pleuro-parenchymal fibroelastosis diagnosis seems unexpectedly frequent (b).
- FIGURE 4
Representative computed tomography scans of carriers of a) SFTPC, b) SFTPA1, c) ABCA3, d) NFKX2-1 and e) NF1 pathogenic mutations, all inconsistent with usual interstitial pneumonia.
- FIGURE 5
Significance of the principal genetic variants associated with familial pulmonary fibrosis by their strength and frequency. For example, TERT mutations are rare but have a powerful effect with great penetrance, whereas polymorphism of the MUC5B promoter is frequent but with a weaker effect. Modified from [117, 118, 119].
- FIGURE 6
Simplified diagram of the multidisciplinary process to diagnose interstitial lung disease, including a clinician, radiologist, pathologist and also a geneticist: a first path to personalised medicine. CT: computed tomography.
- FIGURE 7
Diagram of genetic and somatic evaluation offered for asymptomatic relatives. Somatic evaluation includes chest computed tomography scan, pulmonary function test, complete blood count and liver blood test.
Tables
- TABLE 1
Main genes with rare variants associated with pulmonary fibrosis
Function Gene Transmission Age of onset of pulmonary manifestation Associated signs Telomerase TERT-TERC AD Adults, average 55 years Telomeropathy;
combined pulmonary fibrosis and emphysemaTINF2 AD Children, rare adults <50 years Telomeropathy [31] DKC1 X Children, rare adults <50 years Telomeropathy [120] Helicase RTEL1 AD Adults 35–60 years Telomeropathy RNA regulation PARN AD Adults 47–81 years Pulmonary granulomatosis;
telomeropathy [33]NAF1 AD Adults 45–60 years Telomeropathy [5] Surfactant SFTPA1-SFTPA2 AD From newborn to 72 years Lung cancer [90, 121] SFTPB AR Newborn [122] SFTPC AD Children, rare adults <50 years Combined pulmonary fibrosis and emphysema [123] ABCA3 AR Children, rare adults <50 years Combined pulmonary fibrosis and emphysema [83] NFKX2-1 (TITF1) AD Children, rare adults <50 years Chorea, hypothyroidism [93] Tumour suppressor NF1 AD Adults Type 1 neurofibromatosis [124] Lysosome HPS-1 to HPS-8/AP-3B1 AR Adults Hermansky–Pudlak syndrome [125] Stimulation of interferon synthesis TMEM173 AD Children, rare adults <50 years Recurrent fever;
alopecia; skin rash;
antinuclear antibodies;
vasculitis [95, 100]Endoplasmic reticulum stress COPA AD Children, rare adults <25 years Arthritis, antinuclear antibodies and ANCA [8] Unknown FAM111B AD 7–30 years Myopathy, poikiloderma [6] Mitochondria NDUFAF6 AR 19–50 years Acadian variant of Fanconi syndrome [126] Zinc finger transcription factors GATA2 AD 4–76 years Alveolar proteinosis;
myeloid disease;
monoMAC syndrome [10]AD: autosomal dominant; X: X-linked; AR: autosomal recessive; ANCA: anti-neutrophil cytoplasmic antibodies.
- TABLE 2
Patients with interstitial lung disease (ILD) for whom we propose genetic testing
Idiopathic or non-idiopathic ILD with at least one of the following: Familial ILD Cryptogenic pulmonary fibrosis <50 years old Rare syndrome (table 1) or telomeropathy assessed as personal, or familial history of: Bone-marrow failure, thrombocytopenia or myelodysplasia Dyskeratosis congenita Cryptogenic cirrhosis
