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Pilot experience of multidisciplinary team discussion dedicated to inherited pulmonary fibrosis

  • Raphael BorieEmail author
  • Caroline Kannengiesser
  • Laurent Gouya
  • Clairelyne Dupin
  • Serge Amselem
  • Ibrahima Ba
  • Vincent Bunel
  • Philippe Bonniaud
  • Diane Bouvry
  • Aurélie Cazes
  • Annick Clement
  • Marie Pierre Debray
  • Philippe Dieude
  • Ralph Epaud
  • Pascale Fanen
  • Elodie Lainey
  • Marie Legendre
  • Aurélie Plessier
  • Flore Sicre de Fontbrune
  • Lidwine Wemeau-Stervinou
  • Vincent Cottin
  • Nadia Nathan
  • Bruno Crestani
Open Access
Research
Part of the following topical collections:
  1. Rare pulmonary diseases

Abstract

Background

Genetic testing is proposed for suspected cases of monogenic pulmonary fibrosis, but clinicians and patients need specific information and recommendation about the related diagnosis and management issues. Because multidisciplinary discussion (MDD) has been shown to improve accuracy of interstitial lung disease (ILD) diagnosis, we evaluated the feasibility of a genetic MDD (geneMDD) dedicated to the indication for and interpretation of genetic testing. The geneMDD group met monthly and included pediatric and adult lung specialists with ILD expertise, molecular and clinical geneticists, and one radiologist. Hematologists, rheumatologists, dermatologists, hepatologists, and pathologists were also invited to attend.

Results

Since 2016, physicians from 34 different centers in 7 countries have participated in the geneMDD. The medical files of 95 patients (53 males) have been discussed. The median age of patients was 43 years [range 0–77], 10 were ≤ 15 years old, and 6 were deceased at the time of the discussion. Among 85 analyses available, the geneMDD considered the rare gene variants pathogenic for 61: 37 variants in telomere-related genes, 23 variants in surfactant-related genes and 1 variant in MARS. Genetic counseling was offered for relatives of these patients. The geneMDD therapeutic proposals were as follows: antifibrotic drugs (n = 25), steroids or immunomodulatory therapy (n = 18), organ transplantation (n = 21), watch and wait (n = 21), or best supportive care (n = 4).

Conclusion

Our experience shows that a dedicated geneMDD is feasible regardless of a patient’s age and provides a unique opportunity to adapt patient management and therapy in this very rare condition.

Keywords

Interstitial pulmonary fibrosis Telomerase Surfactant TERT Familial; multidisciplinary discussion 

Abbreviations

CT

Computed tomography

DIP

Desquamative interstitial pneumonia

geneMDD

genetic multidisciplinary discussion

HP

Hypersensitivity pneumonitis

ILD

Interstitial lung disease

IPF

Idiopathic pulmonary fibrosis

MDD

Multidisciplinary discussion

NGS

Next-generation sequencing

NSIP

Non-specific interstitial pneumonia

PPFE

Pleuro-parenchymal fibro-elastosis

TRGs

Telomere-related genes

UIP

Usual interstitial pneumonia

VUS

Variants of unknown significance

VUSD

Working diagnosis of damaging variant

WES

Whole-exome sequencing

Introduction

The central role of multidisciplinary discussion (MDD) in the diagnostic algorithm of interstitial lung disease (ILD) was recently highlighted by the 2018 ATS/ERS/JRS/ALAT recommendations for the diagnosis of idiopathic pulmonary fibrosis (IPF) [1]. ILD-specific MDD should include expert respiratory physicians and at least one radiologist and one histopathologist with specific expertise in ILD; experienced rheumatologists and immunologists are of utmost help in difficult cases [2]. MDD is the worldwide standard of care in ILD centers [2, 3, 4, 5].

The field of monogenic pulmonary fibrosis has made great progress in the last 10 years, raising specific issues that should be addressed by a specialized team [6]. Approximately 30% of patients with a familial history of pulmonary fibrosis are carriers of mutations in telomere-related genes (TRGs), surfactant-related genes or other rare genes [6]. Monogenic ILD could also arise in an apparently sporadic context because of incomplete penetrance and variable expressivity or recessive inheritance. For instance, lung fibrosis associated with a mutation in a TRG is frequently associated with specific hematological or hepatic diseases that may be at the forefront [7] and raise specific diagnostic and therapeutic issues [8, 9, 10, 11]. Genetic disorders of surfactant dysfunction have been recognized as underlying causes of respiratory disease in neonates and children as well as adults and requires a close interaction with pediatricians with dedicated expertise [12]. Finally, the genetic diagnosis in this field is particularly difficult and requires a specific expertise that is not available in many ILD centers [3, 6, 13].

To offer the expertise required for the diagnosis, interpretation of genetic data and treatment of patients suspected to have a genetic form of lung fibrosis, we have set up a web-based multicenter genetic MDD (geneMDD) dedicated to all suspected or confirmed cases of inherited lung fibrosis. Here we describe the geneMDD set-up and our retrospective analysis of the impact of the geneMDD in terms of pulmonary and genetic diagnosis, disease management and genetic counseling for cases discussed to date in the geneMDD.

Methods

The geneMDD

The geneMDD was created in September 2016 and has met monthly ever since. It is chaired by a respiratory physician (RB) and includes at least one geneticist (molecular or clinical), one pediatrician with specific expertise in ILD, and one chest radiologist. When needed, a pathologist, rheumatologist, dermatologist, hepatologist, immunologist, hematologist and psychologist could also attend.

Patients with ILD of suspected or known genetic origin are proposed for discussion by their ILD physician. A standardized form, including a pedigree, is filed before the meeting and presented by the referring physician. Chest high-resolution CT images and histology reports are reviewed during the MDD. The referring physician can come to Bichat hospital or connect by visioconference sharing his screen to show the requested images as well as the pedigree.

Inclusion criteria

Patients in this study represent consecutive patients referred to the geneMDD from September 2016 to October 2018. Any patient with suspected inherited pulmonary fibrosis, without age limitation, could be discussed. A genetic testing was not required for the discussion, but most patients had at least TERT or TERC sequencing results available [7]. Our actual proposal for a genetic analysis is the presence of familial pulmonary fibrosis, a specific syndrome suggestive of an heritable pulmonary fibrosis such as telomere syndrome, or cryptogenic pulmonary fibrosis before age 50 [6]. The geneMDD was offered to all patients with a variant of class 3 or more evidenced during that period. Patients could also be discussed on the request of the referring physician in case of negative results in a patient with highly suggestive heritable pulmonary fibrosis (e.g., young age and extra-pulmonary disease and > 2 ILD cases in the family) [7].

Patients could be deceased at the time of the geneMDD, and those cases were presented to discuss the genetic counseling. In that situation, the age at death was considered for the age at presentation.

geneMDD meeting

During the geneMDD, clinical data, chest CT scan and lung histological pattern were reviewed and classified according to the 2018 ATS/ERS/JRS/ALAT statement for IPF and the 2013 ATS/ERS classification of idiopathic interstitial pneumonias [1, 14]. Chest CT scans were initially classified according to the 2011 ATS/ERS/JRS/ALAT Statement and were reclassified according to the latter classification in light of the geneMDD description [15]. The geneMDD provided a written conclusion, including a diagnosis; a suggestion for further diagnostic procedures, such as a surgical lung biopsy; and a treatment strategy, including evaluation for lung, liver or bone-marrow transplantation, antifibrotic therapy, steroids and immunomodulators, watch and wait, or best supportive care.

Genetic and functional analysis findings, when available, were reviewed, and genetic variants were classified according to the American College of Medical Genetics and Genomics guidelines and the European Society for Human Genetics recommendations [16]. For the variants of unknown significance (VUS), we considered variants with 1 moderate criteria and 3 supporting criteria for pathogenicity as a working diagnosis of damaging VUS (VUSD) [7, 16]. For each case, a genetic conclusion was proposed by the geneticist: pathogenic variant (class 4 or 5), VUSD, VUS (class 3), benign variant (class 2) or no variant identified. Benign variants usually do not appear in the genetic report. Complementary analysis coud be offered: functional analysis (e.g., telomere length, surfactant secretion in transfected cell lines or interferon signature, as described [7, 17, 18]), familial investigation, segregation study or extension of the genetic analysis (e.g., next-generation sequencing [NGS] panel or whole-exome sequencing [WES]). According to the genetic conclusion, genetic counseling could be proposed to the affected patient and relatives [6]. A survey was performed in January 2019 to evaluate the follow-up of the geneMDD proposals.

All patients signed informed consent for genetic analysis, including for research purposes. The clinical charts of the patients were collected on a standardized and anonymous form. This study was approved by the local ethics committee (CPP Ile de France 1, no. 0811760). All data are available on request.

Results

Patient characteristics

From September 2016 to October 2018, the geneMDD was held 18 times, and 34 different ILD centers from 7 different countries participated (France, Algeria, Belgium, Greece, Italy, Ireland and Japan; Table 1, Fig. 1). Overall, 95 patients (53 males) from 83 families were discussed, with a mean of 5.2 patients [range 2–12] discussed per session. The median age of the patients was 43 years [range 0–77]; 6 patients were deceased at the time of the geneMDD.
Table 1

Characteristics of the centers and main characteristics of the patients discussed at the genetic multidisciplinary discussion (geneMDD)

Number of participating centers

34

Number of countries

7

Number of patients discussed

95

Number of families

83

Patient age (years) (median [range])

43 [0–77]

Male

53 (56%)

CT pattern (N = 85)

 UIP or probable UIP

22 (26%)

 Indeterminate for UIP

32 (37%)

 Alternative to UIP

23 (27%)

 No ILD

8 (9%)

Histology (N = 21)

 UIP or probable UIP

8 (38%)

 Alternative diagnosis

9 (43%)

 Unclassifiable

4 (19%)

Pulmonary function tests (median [range])

 FVC (% of predicted value)

68 [24–135]

 DLCO (% of predicted value)

52 [13–108]

Data are n (% of available data) unless indicated. (%). FVC forced vital capacity, DLCO diffusing capacity of lung for CO, UIP usual interstitial pneumonia, ILD interstitial lung disease

Fig. 1

Overall, 34 different interstitial lung disease (ILD) centers from 7 different countries took part in the genetic multidisciplinary discussion (geneMDD) up to October 2018 (empowered by Google map®)

Genetic analysis and counseling

Indications for genetic testing were familial pulmonary fibrosis (n = 53, 55%), specific syndrome (n = 30, 32%, including 27 [28%] with telomere syndrome and 3 [3%] with brain, lung thyroid syndrome), cryptogenic ILD before age 50 (n = 43, 45%), or asymptomatic relative (n = 13, 13%). Some patients had several indications for genetic analysis.

Genetic analyses were not available for 10 patients at the time of the geneMDD (5 ongoing, 5 not yet done). Among the 85 cases with available genetic analyses, 58 had a targeted genetic analysis including TERT or TERC sequencing or only one gene such as NKX2–1 analyzed; 24 had NGS panel testing including TRGs, and 3 had WES results available. TERC and TERT were initially the only genes tested in familial pulmonary fibrosis or telomere syndrome; other TRGs such as RTEL1 or PARN were later included in the NGS panel.

Before the geneMDD genetic analysis, rare monoallelic or biallelic variants were identified in 66 of the 85 (77%) patients analyzed, in accordance with the dominant or recessive inheritance. The variants included 22 VUS (class 3) and 44 pathogenic or likely pathogenic variants (class 4 and 5) (Fig. 2) [3, 5]. A rare variant within one TRG was identified in 39 cases (59%): TERT (n = 25, 37%), TERC (n = 7, 11%), RTEL1 (n = 4, 6%), PARN (n = 2, 3%), and DKC1 (n = 1, 1%). A rare variant within a gene of the surfactant pathway was identified in 26 cases (30%): SFTPC (n = 10, 15%), SFTPA1 or SFTPA2 (n = 7, 11%), ABCA3 (n = 5, 8%), NKX2–1 (n = 4, 6%) (Fig. 2). One patient carried a previously reported MARS mutation [19]. No case of digenic inheritance was considered in this series although we envision that in the era of next generation sequencing, whole exome sequencing and pan genome analyses, the number of patients with more than one rare variant will be growing.
Fig. 2

(a) Genetic variants (variants of unknown significance [VUS] or pathogenic) discussed during the geneMDD, (b) Pulmonary diagnoses proposed by the geneMDD. IPF, idiopathic pulmonary fibrosis; NSIP, non-specific intersititial pneumonia; DIP, desquamative intersitial pneumonia; CIP, cellular interstitial pneumonia; PPFE, pleuro-parenchymal fibroelastosis; HP, hypersensitivity pneumonitis; RA-ILD, rheumatoid arthritis interstitial lung disease; IPAF, interstitial pneumonia with auto-immune features; HPS, hepatopulmonary syndrome; ARDS, Acute respiratory distress syndrome; Unk, unknown

After geneMDD file review, all variants initially considered pathogenic or likely pathogenic were retained as pathogenic (n = 44), 17 of 22 VUS were considered a VUSD [7], and 5 were still considered a VUS (Table 2). Additional evaluation was proposed for 39 patients (45%): WES or targeted NGS (n = 18, 21%); familial screening (n = 14, 15%); functional analysis (n = 16, 17%), including telomere length measurement (n = 7, 7%); surfactant analysis (n = 9, 9%); or interferon signature analysis (n = 3, 3%). The suggested analyses were done for 28 patients so far (72%).
Table 2

Pre- and post-geneMDD diagnosis

 

Pre-geneMDD

Post-geneMDD

Pulmonary diagnosis

 IPF

27 (28%)

25 (26%)

 Unclassifiable

34 (36%)

29 (30%)

 Alternative ILD diagnosis

18 (19%)

22 (23%)

 No ILD

16 (16%)

18 (19%)

Genetic diagnosis

 VUS

22

5

 VUSD or pathogenic

44

61

VUS variant of unknown significance, VUSD working diagnosis of damaging variant

Bold data signifies Data ate N (%)

Additionally, the referring physician informed 61 patients (52 families) with overt disease that a presymptomatic genetic diagnosis for their relatives was recommended by the geneMDD. For 48 patients of childbearing age, a favorable opinion in principle was issued in the event of a request for prenatal diagnosis in a context of particular clinical gravity associated with pathogenic mutations. In January 2019, screening had been performed for 37 families (71%) (Fig. 3).
Fig. 3

Pedigree of a family including 4 siblings with pulmonary fibrosis and heterorozygous carriers of a TERT mutation (c.2516C > T, p.Thr839Met, wild type (wt)/*). Individual II,4 refused the clinical and genetic evaluation. The geneMDD proposed genetic analysis for all children of generation III, which is currently ongoing

Pulmonary diagnosis

A CT scan was available for review in 85 cases (89%). The CT scan did not show any ILD in 8 (9%) patients. In the other cases, the CT pattern observed was definite or probable usual interstitial pneumonia (UIP) in 22 (26%); indeterminate for UIP in 32 (17%, including 5 previously classified as possible UIP and 27 without suggested specific diagnosis); or suggestive of an alternative diagnosis to UIP in 23 (27%). For these 23 patients, the CT pattern suggested a diagnosis of pleuro-parenchymal fibro-elastosis (PPFE, n = 11, 13%), desquamative interstitial pneumonia (DIP, n = 3, 4%), non-specific interstitial pneumonia (NSIP, n = 7, 8%) and hypersensitivity pneumonitis (HP, n = 2, 2%). The pattern was not suggestive of a specific diagnosis for 27 (32%) patients, mainly because of extensive ground-glass opacities and/or cysts (Figs. 4, 5 and 6).
Fig. 4

(a) A 64-year-old non-smoking man with familial pulmonary fibrosis and no extra-pulmonary manifestation. (b, c) The CT scan pattern was considered usual interstitial pneumonia (UIP). Genetic analysis revealed a heterogeneous TERT mutation (c.3216G > A, p.Trp1072*), classified as pathogenic, in both siblings. Genetic counselling was proposed for the relatives. Antifibrosing therapy was offered along with lung transplantation screening for the proband

Fig. 5

(a) A 44-year-old non-smoking woman with rheumatoid arthritis and familial pulmonary fibrosis. (b, c) The CT pattern was considered indeterminate for UIP and not suggestive of a specific diagnosis. Genetic analysis revealed a heterozygous SFTPA2 mutation (c.532G > A, p.Val178Met) classified as pathogenic, and genetic counseling was proposed for the relatives. A double lung transplantation was proposed and performed in April 2017. d Histology of lung transplant tissue was considered indeterminate for UIP: patchy fibrosis with both subpleural and centrilobular fibrosis with dense inflammatory infiltrates (*).b: bronchiole, C: subpleural cyst. Hematoxylin Eosin Saffron stain, bar = 3000 μm

Fig. 6

A 57-year-old patient with macrocytosis and liver steatosis. a, b The CT pattern was considered indeterminate for UIP, not suggestive of a specific diagnosis. Genetic analysis revealed a heterozygous TERC mutation (r.235C > G) classified as pathogenic, and genetic counseling was proposed for the relatives. Lung transplantation was proposed and performed in August 2018. c Histology of the lung transplant tissue was considered indeterminate for UIP: patchy fibrosis with both subpleural and centrilobular fibrosis (*) with dense inflammatory infiltrates and fibroblastic foci (>). (*), b: bronchiole. Hematoxylin Eosin Saffron stain, bar = 3000 μm

Histology was available for 21 patients. UIP was the most frequent pattern (n = 9, 42%), followed by NSIP (n = 2, 10%), PPFE (n = 2, 10%), HP (n = 1, 5%), DIP (n = 1, 5%), and cellular interstitial pneumonia (n = 1, 5%). In five cases, the histological pattern remained unclassifiable (Figs. 5 and 6).

Before the geneMDD, the diagnosis was IPF for 27 patients (28%), and the geneMDD confirmed the diagnosis for 25/27 (93%) (Table 2 and Fig. 2). The pulmonary diagnosis was modified by the geneMDD for only 10 (10%) patients: for 7 patients, a diagnosis of unclassifiable pulmonary fibrosis before the geneMDD was reclassified as PPFE (n = 3), working diagnosis of IPF (n = 2) or no ILD (n = 2); conversely, for 3 patients, a diagnosis of IPF was reclassified as PPFE (n = 2) and unclassifiable pulmonary fibrosis (n = 1). After the geneMDD, the most frequent diagnoses were IPF (n = 25, 26%), unclassifiable pulmonary fibrosis (n = 29, 31%, including 24 patients without available histology − 10 patients having predominant ground glass opacities- and 5 with available histology from surgical lung biopsy), no ILD (n = 18, 19%; including 13 patients without normal CT scan, 1 with emphysema, 1 with hepato-pulmonary syndrome or 3 with bronchiolitis), and PPFE (n = 10, 10%). In addition, a diagnostic surgical lung biopsy was proposed for 4 patients and eventually performed for 3 of them. The histology was probable UIP (n = 1), unclassifiable fibrosis (n = 1) and DIP (n = 1).

In total, 41 patients required specific extra-pulmonary evaluation, for hematologic abnormalities (n = 20, 49%), liver abnormalities (n = 13, 32%), or rheumatologic disorders (n = 7, 17%) (Table 3). Hematological diagnoses were dysmyelopoiesis (n = 8), myelodysplasia (n = 4), toxic aplasia (n = 1), aplastic anemia (n = 1), refractory anemia with blast excess (n = 1), acute myeloid leukemia (n = 1), and isolated macrocytosis (n = 2). Two patients were considered free of hematological disease but had a familial history of acute leukemia. Including the results of 6 liver biopsies, the liver diseases were hepatic cytolysis of unknown etiology (n = 2), sinusoidal distension (n = 1), liver cirrhosis (n = 6), venoocclusive disease (n = 1), regenerative nodular hyperplasia (n = 1), and steatosis (n = 1). One patient was considered free of hepatological disease but reported a familial history of liver cirrhosis.
Table 3

Extra-pulmonary manifestations discussed by the geneMDD

Extra-pulmonary manifestations

Total

41 (43%)

Hematological

20 (21%)

Hepatic

13 (14%)

Rheumatological

7 (7%)

Neurologicala

6 (6%)

Immunological

5 (5%)

Dermatologicala

2 (2%)

Ophthalmologicala

2 (2%)

ENTa

2 (2%)

ENT ear nose and throat. a Specialists not attending the GeneMDD

Treatment

A therapeutic strategy was offered to all living patients (n = 89): antifibrotic therapy (n = 25, 28%); watch and wait policy (n = 21, 23%); evaluation for lung transplantation (e.g. for the MARS mutation carrier, n = 20, 22%) and liver transplantation (n = 1); immunomodulatory therapy (n = 18, 20%), including steroids (n = 10), inhaled granulocyte-macrophage colony-stimulating (inhaled GM-CSF, n = 3), macrolides (n = 2), danazol (n = 2), hydroxychloroquine (n = 1), and statins (n = 1); and best supportive care (n = 4, 4%). According to the previous received treatment and the CT pattern the following treatment was offered to all living patients with unclassifiable fibrosis (n = 28): antifibrotic therapy (n = 7); watch and wait policy (n = 4); evaluation for lung transplantation (n = 3); immunomodulatory therapy (n = 9), including steroids (n = 7), inhaled GM-CSF (n = 3), hydroxychloroquine (n = 1), and statins (n = 1); and best supportive care (n = 3). Inhaled GM-CSF was offered to 3 patients with alveolar proteinosis superimposed with unclassifiable pulmonary fibrosis: 1 with MARS mutation and 2 brothers without any identified known mutation. Among all 64 patients for whom the geneMDD proposed medication, 63 (93%) eventually received it.

Discussion

Here we report the results of the first genetic MDD dedicated to patients with ILD of suspected genetic origin. A total of 95 patients from 34 centers in 7 countries were discussed, which highlights the need for such a specific MDD and the unique experience we could acquire. Indeed, the geneMDD determined that 61 patients were carriers of a pathogenic mutation, which allowed for genetic counseling, performed for 71% of them. Moreover, the geneMDD suggested a specific therapy for 64 patients according to the pulmonary and extra-pulmonary diagnoses and the genetic conclusion; in 93% of the cases, the referring physician followed the geneMDD proposals.

With the increasing number of genetic variants identified in ILD patients, genetics expertise seems needed in the daily practice of ILD centers. From a technical viewpoint, genetic analysis methods are rapidly evolving and each technique has its own advantages and pitfalls. Moreover, the analysis of data generated by these techniques can be difficult. For instance, none of the TRG is the site of a recurrent mutation, and new genetic variants are continually being identified [20, 21, 22]. The genetic conclusion can therefore be difficult [10].

TRG mutations were the most frequent category evaluated during the geneMDD (59%). Patient carriers of TRG mutations also frequently present hematological and hepatic disease, so the presence of a hematologist and hepatologist with specific expertise is required for a thorough discussion of these cases [7, 9, 23, 24]. Because of evidence of anticipation in these families, a discussion with pediatricians was the rule when young adults with children were being discussed [17, 25]. The surfactant gene mutations were the second most frequent category of genes identified during the geneMDD supporting the presence of pediatricians.

Moreover, other specialists could participate in and be required by the geneMDD for specific cases. For instance, NKX2–1 mutations are frequently associated with thyroid and neurological disorders, which require specific expertise [26]. Obviously, except for at least a requirement for one ILD specialist and one geneticist, other specialists were not required for the whole duration of the geneMDD. Indeed, the list of patients to discuss was prepared before the meeting to combine specific issues to discuss (pediatric, hematological or hepatic etc.)

Videoconferencing is relevant for an efficient meeting [3]. It allows for discussing at the same time different individuals from a single family living in different geographical areas, comparing the respiratory and extra-respiratory phenotypes, and adopting a coordinated and homogeneous approach for all family members. All ILD meeting will not include genetic evaluation, but videoconferencing allows every center to access genetic expertise for patients with suspected heritable pulmonary fibrosis. Conversely, with new clinical information, the geneticist was able to propose a diagnosis of VUSD after the geneMDD.

The geneMDD report includes the limitations for the diagnosis and therapeutic proposals and references any trial that could be proposed to the patient. Evidence available for these patients are currently limited. From a therapeutic point of view, no therapeutic trial dedicated to patients with genetic lung fibrosis supports any evidence-based therapeutic decisions. Post-hoc analysis of the ASCEND and CAPACITY trials indicated that pirfenidone slows the decline of lung function in patients with a TRG mutation [27]. Danazol has been tested in patients with a TRG mutation and hematological abnormalities, but the data concerning the lung in that study are very limited [8]. A retrospective study of pirfenidone efficacy in patients with a TERT or TERC mutation did not demonstrate a beneficial effect of pirfenidone on lung function decline in these patients [28]. Several retrospective series have reported the outcome of lung transplantation in ILD patients with TRG mutations and noted a specific hematological risk and possible reduced survival [9, 10, 11, 29, 30].

The geneMDD has several limitations because it actually relies on the referring physicians to volunteer to discuss their patient, inducing a selection bias. We now systematically offer for discussion the files of patients for whom a genetic variant is identified in our lab, though some centers did not discussed their cases in geneMDD and some cases were not proposed to the geneMDD during the first 2 years of operation. This approach is of particular importance when the variant is classified as a VUS. In such cases, only additional non-routine analyses such as telomere length, telomerase activity, or other functional studies could decipher their pathogenicity [16]. Moreover, the geneMDD insists on better characterizing all members of a family because the segregation study is an important point for a genetic conclusion [16]. Lastly it was not required to send the CT scan and the pathogical samples before the geneMDD. The radiologist (MPD) and the pathologist (AC) analyzed some of the CT scan and histological samples only during the geneMDD. Indeed, we have to assume that a double reading could reclassify some patients.

Conclusion

We suggest that a valuable geneMDD should include at least an ILD specialist, a geneticist, a pediatrician, and one chest radiologist, and a web-based conference system with excellent imaging transmission. A specific report need to be given after the MDD. A dedicated secretary is important to collect the forms, data, and CT scan before the meeting, to send weblink, codes and solve technical issues during the meeting, and to complete, send and safely store the report for each patient after the meeting. However, our experience demonstrates that the geneMDD is feasible and offers the expertise for adequate management of genetic forms of pulmonary fibrosis. We believe that the geneMDD should be the standard of care for patients with suspected or confirmed genetic ILD, although it may be limited to an expertise center.

Notes

Acknowledgements

Collaborators:

Claire Andrejak, Eline Magois, (CHU d’Amiens, Amiens), Efrosyni Manali (Athènes, Grece); Manuela Funke-Chambour, Thomas Geiser (Berne, Suisse); Anne Gondouin (CHU Besancon, Besancon), Marianne Kambouchner; Hilario Nunes, Dominique Valeyre, Yurdagul Uzunhan (Hopital Avicenne, Bobigny), Elodie Blanchard (CHU Bordeaux, Bordeaux), Severine Audebert Cecile Tromeur (CHU Brest, Brest), Benjamin Bondue, Antoine Froidure (Bruxelles, Belgique), Emmanuel Bergot, Lucie Reviron-Rabec (CHU Caen, Caen), Frédéric Schlemmer (Hopital Mondor, Créteil); Guillaume Beltramo (CHU Dijon, Dijon), Aurelie Fabre, Oisin O Connell (Dublin, Ireland), Anas Mehdaoui (Hopital Eure Seine, Evreux), Filomena Pierri (Genoa, Italy), Sebastien Quetant, Sophie Park (Centre Hospitalier Universitaire Grenoble Alpes, Grenoble), Reza Azarian (Hopital André Mignot, Le Chesnay), David Montani, Barbara Girerd (Hopital de Bicetre, Le Kremlin Bicetre); Nicolas Pottier, Benoit Wallaert (CHU de Lille, Lille), Caroline Dahlqvist (Louvain, Belgique); Julie Traclet, Kaïs Ahmad, M Nasser (Hôpital Louis Pradel, Lyon), Martine Louise Reynaud-Gaubert (CHU Marseille, Marseille); Anne Sophie Gamez, Arnaud Bourdin, (CHRU de Montpellier, Montpellier), Francois Chabot (CHU Nancy, Nancy); Anne Laure Chene (CHU Nantes, Nantes), Hiroyuki Ito (Nagasaki, Japan); Lisa Giovannini-Chami (CHU Nice, Nice); Farida Skander, Faiza Serradj (Centre Hospitalier Universitaire, Oran, Algéria), Ibrahima Ba, Olivier Brugière, Claire Danel, Gaelle Dauriat, Marie Christine Dombret, Mada Ghanem; Pierre-Antoine Juge, Aurelien Justet, Albane Lassus, Pierre Le Guen, Hervé Mal, Christelle Menard, Camille Taillé (Hopital Bichat, Paris), Christine Lorut, Marie Wislez (Hopital Cochin, Paris), Élodie Lainey (Hopital Debre, Paris); Dominique Israel-Biet (HEGP, Paris); David Drummond, Alice Hadchouel (Hopital Necker, Paris); Anne Bergeron, David Boutboul, Tiphaine Goletto, Abdellatif Tazi (Hopital St Louis, Paris), Jacques Cadranel, Jean-Marc Naccache (Hopital Tenon, Paris), Annick Clement (Hopital Trousseau, Paris), Stephane JOUNEAU (CHU Rennes, Rennes); Stephane Dominique, Elodie Lhuillier (Hopital Universitaire de Rouen, Rouen); Leticia Kawano-Dourado (Sao Paulo, Brazil); Tristan Degot, Sandrine Hirschi, Armelle Schuller, Elise Schaeffer (Hôpitaux Universitaires de Strasbourg, Strasbourg), Mathilde Phillips, Antoine Roux (Hopital Foch, Suresnes), Nathalie Allou, Vincent Boulay (St Denis de la Réunion, France); Gregoire Prevot (Hopital Larrey, Toulouse), Sylvain Marchand-Adam (Chu Tours, Tours).

Authors’ contributions

RB, CK, LG, CD, SA, IB, VB, PB, DB, ACa, ACl, ML, MPD, PD, RE, PF, EL, ML, AP, FSF, LWS, VC, NN, BC. RB and CK collected the data. RB, CK, LG, CD, SA, IB, VB, PB, DB, ACa, ACl, ML, MPD, PD, RE, PF, EL, ML, AP, FSF, LWS, VC, NN, BC contributed data. CK, ML, SA, IB, EL performed the genetic and functional analysis. RB, CK, NN and BC wrote the paper and all authors reviewed the paper. All authors read and approved the final manuscript.

Funding

This work was supported by le Fond de Recherche en Santé Respiratoire-Fondation du Souffle.

Ethics approval and consent to participate

All patients signed informed consent for genetic analysis, including for research purposes. The clinical charts of the patients were collected on a standardized and anonymous form. This study was approved by the local ethics committee (CPP Ile de France 1, no. 0811760).

Consent for publication

All patients signed informed consent for publication.

Competing interests

Dr. Borie reports personal fees and non-financial support from Roche, personal fees and non-financial support from Boerhinger Ingelheim, outside the submitted work. Dr. Debray reports personal fees and non-financial support from Boehringer-Ingelheim, personal fees and non-financial support from Roche, outside the submitted work. Dr. Bonniaud reports personal fees and other fees from Roche, personal fees and other fees from Boehringer, personal fees and other fees from Novartis, personal fees from TEVA, other fees from Chiesi, personal fees from AstraZeneca, other fees from Stallergene, outside the submitted work. Dr. Dupin reports personal fees, non-financial support and other fees from Astra-Zeneca; personal fees, non-financial support and other fees from Boehringer; personal fees, non-financial support and other fees from GSK; personal fees and other fees from Chiesi; personal fees from Sanofi; personal fees, non-financial support and other fees from Novartis; non-financial support and other fees from Roche, outside the submitted work. Dr. Cottin reports personal fees and non-financial support from Actelion; grants, personal fees and non-financial support from Boehringer Ingelheim; personal fees from Bayer/MSD; personal fees from Gilead; personal fees from Novartis; grants, personal fees and non-financial support from Roche; personal fees from Sanofi; personal fees from Promedior; personal fees from Celgene; personal fees from Galapagos; personal fees from Galecto, outside the submitted work. Dr. Crestani reports personal fees from Astra Zeneca; grants, personal fees and non-financial support from Boehringer Ingelheim; grants, personal fees and non-financial support from Roche; personal fees and non-financial support from Sanofi; and grants from Novartis, outside the submitted work.

References

  1. 1.
    Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, Behr J, Cottin V, Danoff SK, Morell F, Flaherty KR, Wells A, Martinez FJ, Azuma A, Bice TJ, Bouros D, Brown KK, Collard HR, Duggal A, Galvin L, Inoue Y, Jenkins RG, Johkoh T, Kazerooni EA, Kitaichi M, Knight SL, Mansour G, Nicholson AG, Pipavath SNJ, Buendía-Roldán I, et al. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am. J. Respir. Crit. Care Med. 2018;198:e44–68.Google Scholar
  2. 2.
    Jo HE, Glaspole IN, Levin KC, McCormack SR, Mahar AM, Cooper WA, Cameron R, Ellis SJ, Cottee AM, Webster SE, Troy LK, Torzillo PJ, Corte P, Symons KM, Taylor N, Corte TJ. Clinical impact of the interstitial lung disease multidisciplinary service. Respirology. 2016;21:1438–44.CrossRefGoogle Scholar
  3. 3.
    Fujisawa T, Mori K, Mikamo M, Ohno T, Kataoka K, Sugimoto C, Kitamura H, Enomoto N, Egashira R, Sumikawa H, Iwasawa T, Matsushita S, Sugiura H, Hashisako M, Tanaka T, Terasaki Y, Kunugi S, Kitani M, Okuda R, Horiike Y, Enomoto Y, Yasui H, Hozumi H, Suzuki Y, Nakamura Y, Fukuoka J, Johkoh T, Kondoh Y, Ogura T, Inoue Y, et al. Nationwide cloud-based integrated database of idiopathic interstitial pneumonias for multidisciplinary discussion. Eur Respir J. 2019;53:1802243.CrossRefGoogle Scholar
  4. 4.
    Singh S, Collins BF, Sharma BB, Joshi JM, Talwar D, Katiyar S, Singh N, Ho L, Samaria JK, Bhattacharya P, Gupta R, Chaudhari S, Singh T, Moond V, Pipavath S, Ahuja J, Chetambath R, Ghoshal AG, Jain NK, Devi HJG, Kant S, Koul P, Dhar R, Swarnakar R, Sharma SK, Roy DJ, Sarmah KR, Jankharia B, Schmidt R, Katiyar SK, et al. Interstitial lung disease in India. Results of a prospective registry. Am J Respir Crit Care Med. 2016;195:801–13.CrossRefGoogle Scholar
  5. 5.
    Thomeer M, Demedts M, Behr J, Buhl R, Costabel U, Flower CDR, Verschakelen J, Laurent F, Nicholson AG, Verbeken EK, Capron F, Sardina M, Corvasce G, Lankhorst I, Idiopathic pulmonary fibrosis international group exploring N-Acetylcysteine I annual (IFIGENIA) study group. Multidisciplinary interobserver agreement in the diagnosis of idiopathic pulmonary fibrosis. Eur Respir J. 2008;31:585–91.CrossRefGoogle Scholar
  6. 6.
    Borie R, Kannengiesser C, Sicre de Fontbrune F, Gouya L, Nathan N, Crestani B. Management of suspected monogenic lung fibrosis in a specialised centre. Eur Respir Rev. 2017;26:28446600.CrossRefGoogle Scholar
  7. 7.
    Borie R, Tabeze L, Thabut G, Nunes H, Cottin V, Marchand-Adam S, Prevot G, Tazi A, Cadranel J, Mal H, Wemeau-Stervinou L, Bergeron Lafaurie A, Israel-Biet D, Picard C, Reynaud Gaubert M, Jouneau S, Naccache JM, Mankikian J, Menard C, Cordier JF, Valeyre D, Reocreux M, Grandchamp B, Revy P, Kannengiesser C, Crestani B. Prevalence and characteristics of TERT and TERC mutations in suspected genetic pulmonary fibrosis. Eur Respir J. 2016;48:1721–31.CrossRefGoogle Scholar
  8. 8.
    Townsley DM, Dumitriu B, Liu D, Biancotto A, Weinstein B, Chen C, Hardy N, Mihalek AD, Lingala S, Kim YJ, Yao J, Jones E, Gochuico BR, Heller T, Wu CO, Calado RT, Scheinberg P, Young NS. Danazol treatment for telomere diseases. N Engl J Med. 2016;374:1922–31.CrossRefGoogle Scholar
  9. 9.
    Borie R, Kannengiesser C, Hirschi S, Le Pavec J, Mal H, Bergot E, Jouneau S, Naccache JM, Revy P, Boutboul D, Peffault de la Tour R, Wemeau-Stervinou L, Philit F, Cordier JF, Thabut G, Crestani B, Cottin V, Groupe d’Etudes et de Recherche sur les Maladies "Orphelines P. Severe hematologic complications after lung transplantation in patients with telomerase complex mutations. J Heart Lung Transplant. 2015;34:538–46.CrossRefGoogle Scholar
  10. 10.
    Popescu I, Mannem H, Winters SA, Hoji A, Silveira F, McNally E, Pipeling MR, Lendermon EA, Morrell MR, Pilewski JM, Hanumanthu VS, Zhang Y, Gulati S, Shah PD, Iasella CJ, Ensor CR, Armanios M, McDyer JF. Impaired CMV immunity in idiopathic pulmonary fibrosis lung transplant recipients with short telomeres. Am J Respir Crit Care Med. 2018;199:362–76.CrossRefGoogle Scholar
  11. 11.
    Silhan LL, Shah PD, Chambers DC, Snyder LD, Riise GC, Wagner CL, Hellstrom-Lindberg E, Orens JB, Mewton JF, Danoff SK, Arcasoy MO, Armanios M. Lung transplantation in telomerase mutation carriers with pulmonary fibrosis. Eur Respir J. 2014;44:178–87.CrossRefGoogle Scholar
  12. 12.
    Kroner C, Wittmann T, Reu S, Teusch V, Klemme M, Rauch D, Hengst M, Kappler M, Cobanoglu N, Sismanlar T, Aslan AT, Campo I, Proesmans M, Schaible T, Terheggen-Lagro S, Regamey N, Eber E, Seidenberg J, Schwerk N, Aslanidis C, Lohse P, Brasch F, Zarbock R, Griese M. Lung disease caused by ABCA3 mutations. Thorax. 2016;72:213–20.CrossRefGoogle Scholar
  13. 13.
    Lethimonnier F, Levy Y. Genomic medicine France 2025. Ann Oncol. 2018;29:783–4.CrossRefGoogle Scholar
  14. 14.
    Travis WD, Costabel U, Hansell DM, King TE Jr, Lynch DA, Nicholson AG, Ryerson CJ, Ryu JH, Selman M, Wells AU, Behr J, Bouros D, Brown KK, Colby TV, Collard HR, Cordeiro CR, Cottin V, Crestani B, Drent M, Dudden RF, Egan J, Flaherty K, Hogaboam C, Inoue Y, Johkoh T, Kim DS, Kitaichi M, Loyd J, Martinez FJ, Myers J, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188:733–48.CrossRefGoogle Scholar
  15. 15.
    Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King TE Jr, Kondoh Y, Myers J, Muller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183:788–824.CrossRefGoogle Scholar
  16. 16.
    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Committee ALQA. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.CrossRefGoogle Scholar
  17. 17.
    Nathan N, Giraud V, Picard C, Nunes H, Dastot-Le Moal F, Copin B, Galeron L, De Ligniville A, Kuziner N, Reynaud-Gaubert M, Valeyre D, Couderc LJ, Chinet T, Borie R, Crestani B, Simansour M, Nau V, Tissier S, Duquesnoy P, Mansour-Hendili L, Legendre M, Kannengiesser C, Coulomb-L’Hermine A, Gouya L, Amselem S, Clement A. Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer. Hum Mol Genet. 2016;25:1457–67.CrossRefGoogle Scholar
  18. 18.
    Frémond M-L, Rodero MP, Jeremiah N, Belot A, Jeziorski E, Duffy D, Bessis D, Cros G, Rice GI, Charbit B, Hulin A, Khoudour N, Caballero CM, Bodemer C, Fabre M, Berteloot L, Le Bourgeois M, Reix P, Walzer T, Moshous D, Blanche S, Fischer A, Bader-Meunier B, Rieux-Laucat F, Crow YJ, Neven B. Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children. J Allergy Clin Immunol. 2016;138:1752–5.CrossRefGoogle Scholar
  19. 19.
    Hadchouel A, Wieland T, Griese M, Baruffini E, Lorenz-Depiereux B, Enaud L, Graf E, Dubus JC, Halioui-Louhaichi S, Coulomb A, Delacourt C, Eckstein G, Zarbock R, Schwarzmayr T, Cartault F, Meitinger T, Lodi T, de Blic J, Strom TM. Biallelic mutations of Methionyl-tRNA Synthetase cause a specific type of pulmonary alveolar Proteinosis prevalent on Reunion Island. Am J Hum Genet. 2015;96:826–31.CrossRefGoogle Scholar
  20. 20.
    Cogan JD, Kropski JA, Zhao M, Mitchell DB, Rives L, Markin C, Garnett ET, Montgomery KH, Mason WR, McKean DF, Powers J, Murphy E, Olson LM, Choi L, Cheng DS, Blue EM, Young LR, Lancaster LH, Steele MP, Brown KK, Schwarz MI, Fingerlin TE, Schwartz DA, Lawson WE, Loyd JE, Zhao Z, Phillips JA 3rd, Blackwell TS. Rare variants in RTEL1 are associated with familial interstitial pneumonia. Am J Respir Crit Care Med. 2015;191:646–55.CrossRefGoogle Scholar
  21. 21.
    Borie R, Bouvry D, Cottin V, Gauvain C, Cazes A, Debray M-P, Cadranel J, Dieude P, Degot T, Dominique S, Gamez AS, Jaillet M, Juge P-A, Londono-Vallejo A, Mailleux A, Mal H, Boileau C, Menard C, Nunes H, Prevot G, Quetant S, Revy P, Traclet J, Wemeau-Stervinou L, Wislez M, Kannengiesser C, Crestani B. Regulator of telomere length 1 (RTEL1) mutations are associated with heterogeneous pulmonary and extra-pulmonary phenotypes. Eur Respir J. 2018;53:1800508.CrossRefGoogle Scholar
  22. 22.
    Stuart BD, Choi J, Zaidi S, Xing C, Holohan B, Chen R, Choi M, Dharwadkar P, Torres F, Girod CE, Weissler J, Fitzgerald J, Kershaw C, Klesney-Tait J, Mageto Y, Shay JW, Ji W, Bilguvar K, Mane S, Lifton RP, Garcia CK. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. Nat Genet. 2015;47:512–7.CrossRefGoogle Scholar
  23. 23.
    Chiu V, Hogen R, Sher L, Wadé N, Conti D, Martynova A, Li H, Liang G, O’Connell C. Telomerase Variants in Patients with Cirrhosis Awaiting Liver Transplantation. Hepatology. 2019;69:2652–63.Google Scholar
  24. 24.
    Calado RT, Brudno J, Mehta P, Kovacs JJ, Wu C, Zago MA, Chanock SJ, Boyer TD, Young NS. Constitutional telomerase mutations are genetic risk factors for cirrhosis. Hepatology. 2011;53:1600–7.CrossRefGoogle Scholar
  25. 25.
    van Moorsel CH, Ten Klooster L, van Oosterhout MF, de Jong PA, Adams H, Wouter van Es H, Ruven HJ, van der Vis JJ, Grutters JC. SFTPA2 mutations in familial and sporadic idiopathic interstitial pneumonia. Am J Respir Crit Care Med. 2015;192:1249–52.CrossRefGoogle Scholar
  26. 26.
    Nattes E, Lejeune S, Carsin A, Borie R, Gibertini I, Balinotti J, Nathan N, Marchand-Adam S, Thumerelle C, Fauroux B, Bosdure E, Houdouin V, Delestrain C, Louha M, Couderc R, De Becdelievre A, Fanen P, Funalot B, Crestani B, Deschildre A, Dubus J-C, Epaud R. Heterogeneity of lung disease associated with NK2 homeobox 1 mutations. Respir Med. 2017;129:16–23.CrossRefGoogle Scholar
  27. 27.
    Dressen A, Abbas AR, Cabanski C, Reeder J, Ramalingam TR, Neighbors M, Bhangale TR, Brauer MJ, Hunkapiller J, Reeder J, Mukhyala K, Cuenco K, Tom J, Cowgill A, Vogel J, Forrest WF, Collard HR, Wolters PJ, Kropski JA, Lancaster LH, Blackwell TS, Arron JR, Yaspan BL. Analysis of protein-altering variants in telomerase genes and their association with MUC5B common variant status in patients with idiopathic pulmonary fibrosis: a candidate gene sequencing study. Lancet Respir Med. 2018;6:603–14.CrossRefGoogle Scholar
  28. 28.
    Justet A, Thabut G, Manali E, Molina Molina M, Kannengiesser C, Cadranel J, Cottin V, Gondouin A, Nunes H, Magois E, Tromeur C, Prevot G, Papiris S, Marchand-Adam S, Gamez AS, Reynaud-Gaubert M, Wemeau L, Crestani B, Borie R. Safety and efficacy of pirfenidone in patients carrying telomerase complex mutation. Eur Respir J. 2018;51:1701875.CrossRefGoogle Scholar
  29. 29.
    Tokman S, Singer JP, Devine MS, Westall GP, Aubert JD, Tamm M, Snell GI, Lee JS, Goldberg HJ, Kukreja J, Golden JA, Leard LE, Garcia CK, Hays SR. Clinical outcomes of lung transplant recipients with telomerase mutations. J Heart Lung Transplant. 2015;34:1318–24.CrossRefGoogle Scholar
  30. 30.
    Swaminathan AC, Neely ML, Frankel CW, Kelly FL, Petrovski S, Durheim MT, Bush E, Snyder L, Goldstein DB, Todd JL, Palmer SM. Lung Transplant Outcomes in Pulmonary Fibrosis Patients with Telomere-Related Gene Variants. Chest. 2019;156:477–85.CrossRefGoogle Scholar

Copyright information

© The Author(s). 2019

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  • Raphael Borie
    • 1
    • 2
    Email author
  • Caroline Kannengiesser
    • 2
    • 3
    • 4
  • Laurent Gouya
    • 2
  • Clairelyne Dupin
    • 1
    • 2
  • Serge Amselem
    • 5
  • Ibrahima Ba
    • 2
    • 3
    • 4
  • Vincent Bunel
    • 6
  • Philippe Bonniaud
    • 7
  • Diane Bouvry
    • 8
  • Aurélie Cazes
    • 9
  • Annick Clement
    • 10
  • Marie Pierre Debray
    • 11
  • Philippe Dieude
    • 12
  • Ralph Epaud
    • 13
  • Pascale Fanen
    • 14
  • Elodie Lainey
    • 15
  • Marie Legendre
    • 5
  • Aurélie Plessier
    • 16
  • Flore Sicre de Fontbrune
    • 17
  • Lidwine Wemeau-Stervinou
    • 18
  • Vincent Cottin
    • 19
  • Nadia Nathan
    • 10
  • Bruno Crestani
    • 1
    • 2
  1. 1.Service de Pneumologie A, DHU FIRE, Centre de Référence (Site Constitutif) Maladies Pulmonaires RaresAPHP, Hôpital BichatParisFrance
  2. 2.INSERM, Unité 1152Université Paris DiderotParisFrance
  3. 3.Laboratoire de Génétique, APHP, Hôpital BichatParisFrance
  4. 4.Université Paris DiderotParisFrance
  5. 5.Département de Génétique, U.F. de Génétique moléculaireAPHP, Sorbonne Université, Inserm U933, Hôpital TrousseauParisFrance
  6. 6.APHP, Hôpital Bichat, Service de Pneumologie B, DHU FIREParisFrance
  7. 7.Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence (Site Constitutif) Maladies Pulmonaires RaresCHU Dijon-BourgogneDijonFrance
  8. 8.Service de Pneumologie, Hôpital Avicenne, Centre de Référence (Site Constitutif) Maladies Pulmonaires RaresAPHPBobignyFrance
  9. 9.APHP, Hôpital Bichat, Service d’AnatomopathologieParisFrance
  10. 10.Service de Pneumologie PediatriqueHôpital Trousseau, Filière RespiFil, APHPParisFrance
  11. 11.APHP, Hôpital Bichat, Service de Radiologie ParisParisFrance
  12. 12.APHP, Hôpital Bichat, Service de RhumatologieParisFrance
  13. 13.Centre des Maladies Respiratoires Rare, Respirare® Centre Hospitalier Intercommunal de CréteilInserm, Unité 955, Equipe 5, Université Paris-Est, Faculté de MédecineCreteilFrance
  14. 14.Laboratoire de Génétique, APHP, Hôpital Henri MondorParisFrance
  15. 15.Laboratoire d’hématologie, APHP, Hôpital Robert DebréParisFrance
  16. 16.APHP, Service d’hépatologie, Hôpital BeaujonClichyFrance
  17. 17.APHP, Service d’hématologie, Hôpital St LouisParisFrance
  18. 18.Service de Pneumologie, Centre de Référence (Site Constitutif) Maladies Pulmonaires RaresCHU de LilleLilleFrance
  19. 19.Coordonnateur, OrphaLung, Centre national de référence des maladies pulmonaires rares, Service de PneumologieHôpital Louis Pradel, UMR754, Université Claude Bernard Lyon 1LyonFrance

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