ILD Genomics

Project description

Background

Genetic predisposition is a key driver in the pathogenesis of interstitial lung diseases (ILDs), with the incidence of pulmonary fibrosis (PF) being 100-fold higher in families where a member has a diagnosis of IPF (1) and up to 30% of asymptomatic relatives of sporadic cases of IPF having interstitial lung abnormalities (ILAs) on chest CT. (2)

There is growing recognition of the clinical value of identifying inherited genetic factors, particularly rare genetic variants, with implications for personalised management and early diagnosis of high-risk patients. Pathogenic variants in telomere related genes (TRGs) including TERT, TERC, RTEL1, PARN, DKC1, TINF2, NOP10, NHP2, ACD, NAF1, ZCCHC8, RPA, POT1 as well as in surfactant related genes (SRGs) including SFTPC and ABCA3 have been identified in both familial and sporadic cases of pulmonary fibrosis, with different clinical presentations. (3–6) Telomere attrition is more accelerated in ILD patients compared to age-matched controls and has been associated with faster disease progression and worse clinical outcomes. (7–9)

Despite the obvious clinical value of implementing genetic testing in ILD, a major barrier remains where many of the gene variants identified are of uncertain significance (VUS), meaning that there is not sufficient evidence to classify the variant as disease-causing (pathogenic/likely pathogenic) or benign. VUSs provide no clear answers and therefore are a source of substantial frustration for both the clinicians and patients alike. Variant curation and reclassification of VUSs is painstaking work and despite internationally co-ordinated efforts there remains a large and ever-growing pile of unresolved VUSs that require either clinical evidence such as further reports of the variant in additional patients, in particular segregation with disease in families (increase evidence towards pathogenicity) or unaffected individuals (evidence towards benignity), and/or functional evidence from experimental studies. Functional studies are costly to perform, therefore reducing duplication of this work internationally by having access to a central ILD-specific database would be beneficial.

Aims and scope of the project

ILDGenomics.com is an anonymised ILD-specific international gene variant curation database. It allows clinicians and researchers from around the world to contribute and have access to relevant genetic test results and clinical data reviewed by dedicated variant curators with ILD expertise.

The project aims to significantly accelerate the reclassification of VUSs specifically in ILD patients and relatives as pathogenic or benign, by collecting relevant information in a central database. It also aims to facilitate scientific collaboration between ILD-Genetics clinicians and researchers internationally and contribute to raising awareness and the broader education of health care providers.

The database has been designed to be intuitive and user-friendly, as this will facilitate wider adoption within the ILD community.

The database is stored on secure, encrypted cloud-based servers to ensure stability and good functionality. To protect confidentiality, the database is anonymized and can only be accessed via individual, password-protected, user-created accounts (subject to agreement to the Terms of use) to ensure traceability and compliance to the ethical approval while facilitating collaboration between contributors.

Contributing to the project

By registering an account as a contributor, you will be able to see summaries of ILD gene variants and clinical data for ILD patients and relatives submitted by contributors from around the world. You will also be able to submit your own variants and anonymised clinical data for review by our database curators who have specific expertise in ILD, and who can provide their expert input , to aid variant reclassification. Additionally, we can help you connect with other contributors worldwide (subject to mutual agreement) who have submitted variants of interest, to support scientific collaboration.

The utility of the database relies on contributors submitting anonymized but detailed clinical and genetic test result data. We cannot verify or guarantee that each anonymized record submitted by individual contributors is correct, however we take several steps to ensure that the database is relevant for ILD variant curation.

Entries must be from patients and relatives meeting the following inclusion and exclusion criteria to ensure a minimum relevant clinical information set is available.

Inclusion criteria

  1. Adults > 18 years
  2. Patients with ILD, interstitial lung abnormalities (ILA) or related clinical phenotypes suggestive of telomere biology disorders or other genetic cause for ILD
  3. Relatives of patients who meet criterion 2 (both symptomatic and asymptomatic)
  4. Individuals who have clinical or research genetic test results available (e.g. gene panel, telomere length testing) OR currently awaiting genetic test results (previously requested)

Exclusion criteria

  1. Individuals <18 years of age
  2. Individuals for whom no genetic result is currently available or pending
  3. Individuals for whom insufficient clinical data is available
  4. Individuals for whom there is a risk of breaching the Terms of use.

Contributors must register individual accounts using an institutional email address where possible to submit data, to ensure traceability and legitimate access, and must agree to submit anonymised, but bona fide ILD patient and relatives’ genetic test results and clinical data, and complete data fields as fully as possible. Our dedicated database curators will review entries that appear implausible or contain significant missing data and may reach out to contributors to seek clarification or ask for further data completion where possible.

We welcome any queries seeking clarification if you are unsure about what data should be submitted.

Connecting with other contributors

To facilitate scientific collaboration regarding specific variants stored in the database, contributor contact details (name and e-mail address) may be shared with other registered contributors on the platform if a legitimate request is received and with the agreement of both parties.

Any communications / data sharing / agreements entered into following connection of the contributors is independent of this platform and is the responsibility of the connected contributors including maintaining patient and relatives’ confidentiality when communicating with other contributors, abiding by your own jurisdictional and institutional ethical requirements. The investigators will not be directly involved or responsible for any data sharing or communication that occurs externally to the platform.

Ethical approval

This research project was approved by the Sydney Local Health District (SLHD) Human Research Ethics Committee (HREC), Australia – Sydney Local Health District (SLHD) Ref. No. 2025/ETH02343.

Queries regarding the ethical approval can be directed to the ILD Genomics Oversight Committee (contact details to be confirmed).

ILD Genomics Oversight Committee

This will comprise of Prof. Joanne Dickinson (University of Tasmania, Australia), Prof. Tamera Corte (Royal Prince Alfred Hospital, Sydney, Australia and University of Sydney, Australia), Dr. Sionne Lucas (University of Tasmania, Australia), Dr. Stefan Cristian Stanel (University of Sydney, Australia and Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK), and Dr John Mackintosh (Prince Charles Hospital, Brisbane, Australia). The Oversight Committee is responsible for governance and ethical compliance and liaising with the database developer to ensure functionality in line with the scope of the project.

The ILD Genomics Oversight Committee together with the database curators will have access to the anonymized database to perform variant curation and data analysis. Over time, the Genomics Oversight Committee may appoint new members as needed who will bring a high level of expertise to the variant curation process and provide appropriate oversight of the database.

We encourage contributors to liaise with the Steering Committee to contribute to ethical and fair use of the platform.

Research Use

The database will be used for research purposes in accordance with the scope of the project (as described on the website) and ethical guidelines and approvals.

Contributors and investigators on the project who undertake research projects or publications using summary data accessed from the platform must reference the ILDgenomics.com platform in any publication / communication that uses its data, to ensure recognition of the platform and the contributions of all its users.

References

  1. Steele MP, Peljto AL, Mathai SK, et al. Incidence and Progression of Fibrotic Lung Disease in an At-Risk Cohort. Am J Respir Crit Care Med. 2023;207(5):587-593. doi:10.1164/rccm.202206-1075OC
  2. Hunninghake GM, Quesada-Arias LD, Carmichael NE, et al. Interstitial Lung Disease in Relatives of Patients with Pulmonary Fibrosis. Am J Respir Crit Care Med. 2020;201(10):1240-1248. doi:10.1164/rccm.201908-1571OC
  3. Borie R, Kannengiesser C, Antoniou K, et al. European Respiratory Society statement on familial pulmonary fibrosis. Eur Respir J. 2023;61(3):2201383. Published 2023 Mar 16. doi:10.1183/13993003.01383-2022
  4. Newton CA, Oldham JM, Applegate C, et al. The Role of Genetic Testing in Pulmonary Fibrosis: A Perspective From the Pulmonary Fibrosis Foundation Genetic Testing Work Group. Chest. 2022;162(2):394-405. doi:10.1016/j.chest.2022.03.023
  5. Klay D, Platenburg MGJP, van Rijswijk RHNAJ, Grutters JC, van Moorsel CHM. ABCA3 mutations in adult pulmonary fibrosis patients: a case series and review of literature. Curr Opin Pulm Med. 2020;26(3):293-301. doi:10.1097/MCP.0000000000000680
  6. van Moorsel CHM, van der Vis JJ, Grutters JC. Genetic disorders of the surfactant system: focus on adult disease. Eur Respir Rev. 2021;30(159):200085. Published 2021 Feb 16. doi:10.1183/16000617.0085-2020
  7. Adegunsoye A, Newton CA, Oldham JM, et al. Telomere length associates with chronological age and mortality across racially diverse pulmonary fibrosis cohorts. Nat Commun. 2023;14(1):1489. Published 2023 Mar 17. doi:10.1038/s41467-023-37193-6
  8. Stuart BD, Lee JS, Kozlitina J, et al. Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis: an observational cohort study with independent validation. Lancet Respir Med. 2014;2(7):557-565. doi:10.1016/S2213-2600(14)70124-9
  9. Newton CA, Batra K, Torrealba J, et al. Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive. Eur Respir J. 2016;48(6):1710-1720. doi:10.1183/13993003.00308-2016