Interstitial Lung Disease 1

Disease-characteristics research report

Disease: Interstitial lung disease 1 (ILD1)
MONDO: MONDO:0030608
Defining gene: SFTPA1
OMIM phenotype: 619611
Inheritance: Usually autosomal dominant with incomplete, age-dependent penetrance; one autosomal-recessive family is established
Evidence base reviewed through: 15 October 2026

Scope note. ILD1 is the specific Mendelian surfactant-protein-A1 disorder caused by pathogenic germline variants in SFTPA1. It should not be conflated with the broad clinical category “interstitial lung disease,” with SFTPA2-associated ILD2, or with all familial pulmonary fibrosis.

Executive summary

Interstitial lung disease 1 is an exceptionally rare, predominantly lung-limited surfactant disorder whose clinical spectrum ranges from fatal infantile fibrosing interstitial pneumonia to adult-onset idiopathic interstitial pneumonia, usual interstitial pneumonia/idiopathic pulmonary fibrosis, respiratory failure, and lung adenocarcinoma. The phenotype can be absent in young carriers and is highly variable even within a family. OMIM maps ILD1 to SFTPA1 at 10q22.3 and recognizes both autosomal-dominant and autosomal-recessive inheritance. [1][31]

Disease-associated missense variants cluster in exon 6, which encodes the C-terminal carbohydrate-recognition domain of surfactant protein A1. The best-established variants are p.Val178Met, p.Tyr208His, p.Trp211Arg, and p.Val225Met. Functional studies consistently find preserved intracellular protein production but markedly reduced or absent extracellular secretion. In the recessive p.Tyr208His model, retained mutant protein activates an IRE1α–JNK–RIPK3–MLKL necroptosis pathway in alveolar type II cells, leading to epithelial loss, inflammation, collagen deposition, impaired gas exchange, and progressive fibrosis. Influenza A infection markedly accelerates this process in knock-in mice. [53][78][83]

No therapy is approved specifically for SFTPA1-associated ILD. Current practice extrapolates from IPF and progressive pulmonary fibrosis: avoidance of inhalational injury, vaccination, pulmonary rehabilitation, oxygen when indicated, antifibrotic therapy according to the radiologic/clinical phenotype, early lung-transplant referral, and unusually careful surveillance for lung cancer. In a 2023 transplant cohort, 20 adults with surfactant-gene ILD—including five with SFTPA1 variants—had a median post-transplant survival of 8.6 years, and none of the five SFTPA1 recipients died during reported follow-up. [91][92]

1. Disease information

1.1 Definition

ILD1 is a monogenic disorder caused by germline pathogenic variants in SFTPA1, encoding surfactant protein A1, a collectin produced mainly by alveolar epithelial type II cells. Its defining pathology is progressive remodeling and fibrosis of the distal lung, variably expressed as idiopathic interstitial pneumonia, nonspecific interstitial pneumonia, usual interstitial pneumonia, or clinical IPF. Dyspnea, restrictive physiology, ground-glass or reticular abnormalities, reduced gas transfer, clubbing, respiratory failure, and lung adenocarcinoma may occur. [31]

The original molecular report described phenotypes “ranging from severe respiratory insufficiency occurring early in life to the association of lung fibrosis and cancer in adult patients.” The same study showed that p.Trp211Arg impairs SP-A1 secretion and alters SP-A distribution in alveolar epithelium (Nathan et al., 15 April 2016, PMID 26792177, DOI: 10.1093/hmg/ddw014). [46][47]

1.2 Identifiers and terminology

OMIM explicitly records SFTPA1-associated ILD1 as autosomal dominant or autosomal recessive. Orphanet/ICD/MeSH cross-references generally point to the broader IPF phenotype and therefore have lower specificity than MONDO:0030608 or OMIM:619611. [166][168][173][176]

Common names: ILD1; SFTPA1-associated interstitial lung disease; SP-A1–related interstitial lung disease; SFTPA1-related pulmonary fibrosis; familial idiopathic interstitial pneumonia due to SFTPA1; familial IPF due to SFTPA1.

1.3 Information provenance

The evidence is chiefly aggregated disease-level evidence from:

• multigenerational pedigrees;
• rare-disease sequencing cohorts;
• patient HRCT, pathology and transplant cohorts;
• ClinVar/OMIM/MedGen;
• in-vitro protein-expression studies;
• genetically engineered mice.

It is not primarily an EHR-defined disease. The foundational literature comprises small, deeply phenotyped families rather than population-scale clinical records.

2. Etiology

2.1 Primary causal factor

The primary cause is a germline pathogenic SFTPA1 variant. Most reported disease is associated with a heterozygous missense variant and dominant inheritance; homozygous p.Tyr208His produced severe recessive disease in one consanguineous Japanese family. [16][76]

SFTPA1 encodes a calcium-dependent C-type lectin/collectin involved in:

• pulmonary-surfactant organization and homeostasis;
• binding of phospholipids;
• pathogen recognition and opsonization;
• regulation of alveolar macrophages and pulmonary inflammation.

Expression is strongly enriched in alveolar type II cells. [153][154]

2.2 Genetic risk factors

No reproducible ILD1-specific modifier gene has yet been established.

2.3 Environmental and acquired risk modifiers

Evidence is suggestive rather than sufficient to calculate exposure-specific relative risks.

• Reported carriers had exposures to tobacco, silica, occupational dust, birds, barge work, and cannabis, while other affected carriers had no recognized exposure.
• Cigarette smoke and fibrogenic dust plausibly increase alveolar epithelial stress but are not required for disease.
• Respiratory infection may accelerate disease: influenza A caused striking worsening in Sftpa1^Y208H/Y208H^ mice without increasing viral titers or delaying clearance. [78]
• Aging is a major biological cofactor in the knock-in model; fibrosis, hypoxemia, and death emerged progressively with age.

2.4 Protective factors

No ILD1-specific genetic or environmental protective factor is validated.

Reasonable risk-reduction measures include:

• never smoking and avoiding secondhand smoke;
• respiratory protection against silica, metal, wood and other fibrogenic dusts;
• minimizing avian/mold antigen exposure if sensitization or hypersensitivity is suspected;
• influenza, pneumococcal, COVID-19 and age-appropriate vaccination;
• prompt treatment of respiratory infection;
• avoidance of unnecessary pneumotoxic drugs.

These measures reduce additional lung injury but have not been shown to prevent disease in genetically susceptible carriers.

2.5 Gene–environment interaction

The strongest experimental interaction is:

SFTPA1 p.Tyr208His → latent epithelial vulnerability → influenza A exposure → amplified IRE1α/JNK/RIPK3 signaling → accelerated alveolar type II-cell necroptosis and fibrosis.

In the human p.Trp211Arg family, marked variability among relatives exposed to tobacco or occupational environments led the authors to propose environmental contributions, but causality could not be separated from age-dependent penetrance and other genetic modifiers. [47]

3. Phenotypes

Frequencies below are based on very small ascertainment-biased cohorts. The most detailed mixed SFTPA1/SFTPA2 cohort contained 28 carriers, so these figures are informative but not ILD1 population estimates.

The 2020 SP-A cohort reported the following exact abstract statement:

“Among the 28 SFTPA1 or SFTPA2 mutation carriers, the mean age at ILD onset was 45 years (range 0.6–65 years) and 48% underwent lung transplantation.”

Seven carriers were asymptomatic. Ground-glass opacity and fibrosis were each present in 7/10 centrally reviewed CT scans; UIP, indeterminate-UIP, NSIP, hypersensitivity-pneumonitis-like, and pleuroparenchymal fibroelastosis patterns all occurred. [74][83]

Quality-of-life burden

No disease-specific EQ-5D, SF-36 or PROMIS study has been reported for ILD1. Expected burdens are those of progressive fibrotic ILD:

• exertional limitation and loss of employment capacity;
• oxygen dependence;
• fatigue and cough;
• anxiety related to progression, transplantation and cancer;
• major caregiver burden;
• genetic and reproductive uncertainty.

Pulmonary rehabilitation is used to improve exercise tolerance, symptoms and emotional well-being, although it does not reverse fibrosis. [129]

4. Genetic and molecular information

4.1 Gene annotation

4.2 Established and reported variants

Nathan et al. identified nine heterozygous p.Trp211Arg carriers in one extended pedigree. Disease onset ranged from 7 months to 69 years, and unaffected carriers demonstrated incomplete penetrance (PMID 26792177). [46][50]

Doubková et al. identified heterozygous c.532G>A, p.Val178Met by WES and Sanger confirmation in a three-generation Czech family (published 5 March 2019, PMID 30854216, DOI: 10.1038/s41439-019-0044-z). Its abstract states: “This variant encodes the substitution p.(Val178Met), localized within the carbohydrate recognition domain.” [61][64]

Takezaki et al. identified homozygous p.Tyr208His in three brothers from a consanguineous family (published 10 October 2019, PMID 31601679, DOI: 10.1084/jem.20182351). [78]

Variant interpretation cautions

• A missense VUS in SFTPA1 is not sufficient for diagnosis.
• Useful pathogenic evidence includes extreme rarity, CRD location, segregation, preserved production with failed secretion, abnormal tissue localization, and phenotype compatibility.
• Testing should report transcript, genome build, read quality, allele balance, zygosity and ACMG/AMP criteria.
• All proven human variants are germline, not somatic driver mutations.

4.3 Molecular consequence and mode of action

For dominant alleles, the precise mechanism may combine:

1. reduced extracellular SP-A1 dosage;
2. intracellular retention/misfolding;
3. ER stress and epithelial toxicity;
4. possible interference with SP-A1/SP-A2 oligomer secretion.

A universal dominant-negative mechanism has not been directly proven. In p.Tyr208His experiments, mutant SP-A1 associated intracellularly with wild-type SP-A1 or SP-A2, but these complexes were scarcely secreted, supporting a potential retention effect. [78]

4.4 Modifier genes, epigenetics and chromosome abnormalities

• Modifier genes: none validated for ILD1.
• Epigenetic signature: no diagnostic ILD1 methylation or chromatin signature is established.
• Structural variants/CNVs: no recurrent ILD1-specific deletion, duplication, inversion or translocation has been demonstrated.
• Somatic changes: lung cancers arising in carriers may acquire conventional somatic cancer alterations, but these do not define ILD1.

5. Environmental information

ILD1 is not infectious and is not transmitted between people. Infection is a potential trigger or accelerator, not the Mendelian cause.

6. Mechanism and pathophysiology

6.1 Ordered causal chain

1. A germline SFTPA1 missense lesion in the carbohydrate-recognition domain leads to structurally or electrostatically abnormal SP-A1.

2. Abnormal SP-A1 leads to failure of secretion from alveolar epithelial type II cells, despite preserved intracellular protein synthesis.

3. Failed secretion leads to reduced/abnormally distributed SP-A at the alveolar surface and intracellular retention in type II pneumocytes.

4. Intracellular retention leads to ER stress and IRE1α phosphorylation; this step is demonstrated for p.Tyr208His in mice and inferred for several dominant variants.

5. Phosphorylated IRE1α leads to JNK activation, which leads to increased RIPK3 expression.

6. RIPK3 activation leads to MLKL phosphorylation and membrane-disruptive necroptosis of alveolar epithelial type II cells.

7. Type II-cell necroptosis leads to loss of epithelial integrity and regenerative capacity, release of inflammatory/damage signals, macrophage recruitment and fibroblast activation.

8. Fibroblast/myofibroblast activation leads to excessive extracellular-matrix and collagen deposition, alveolar-wall thickening, architectural distortion and honeycombing.

9. Fibrotic remodeling leads to restrictive physiology, reduced diffusion capacity, hypoxemia, dyspnea and respiratory failure.

10. Chronic epithelial injury and compensatory proliferation lead—by an incompletely demonstrated branch—to increased lung-adenocarcinoma risk.

11. A respiratory viral insult such as influenza A can branch at steps 4–7 and leads to accelerated ER stress, necroptosis and fibrosis in the p.Tyr208His mouse model.

6.2 Protein and surfactant biology

SP-A is a multimeric collectin. Its carbohydrate-recognition domain binds microbial and lipid ligands in a calcium-dependent manner. SP-A participates in tubular-myelin/surfactant organization and innate immune defense. SFTPA1 is strongly enriched in alveolar type II cells, whereas secreted protein is present at the alveolar air–liquid interface and in alveolar macrophages. [153][154]

Normal pulmonary surfactant is predominantly lipid, with a smaller protein fraction. SP-A is not the principal surface-tension-lowering component—that function depends strongly on phospholipids and hydrophobic surfactant proteins—but it organizes surfactant and regulates host defense.

6.3 Cellular processes

Relevant cell types

6.4 Experimental proof of the necroptosis pathway

The p.Tyr208His study supplied unusually strong causal evidence:

• increased phosphorylated MLKL in an affected human lung;
• increased IRE1α and JNK phosphorylation and Ripk3 expression in mutant mice;
• absence of increased active caspase-3, arguing against apoptosis as the primary death mechanism;
• Ripk3 deletion improved survival, oxygenation and fibrosis;
• Mlkl deletion protected against post-influenza fibrosis;
• JNK inhibitor SP600125 reduced Ripk3 expression and fibrosis;
• IRE1α inhibitor KIRA6 reduced JNK activation and fibrosis;
• forced Ripk3 expression partially reversed JNK-inhibitor benefit.

The authors’ abstract states that p.Tyr208His “promotes necroptosis of AEII cells through JNK-mediated up-regulation of Ripk3.” These are model-system findings, not an established human therapy. [78]

6.5 Immune involvement

SP-A binds carbohydrates on microorganisms and modulates phagocytosis, cytokine production and reactive-oxygen responses. Loss or mislocalization may therefore alter innate immunity. Sftpa1-null mice show reduced resistance to respiratory infection and exaggerated inflammatory responses to lipopolysaccharide. [158]

No evidence supports a primary autoimmune etiology. Rheumatoid arthritis occurred in a minority of the combined SFTPA1/SFTPA2 cohort, but causality is uncertain.

6.6 Molecular profiling and advanced technologies

• Transcriptomics: The p.Tyr208His model demonstrated increased Ripk3 and Col1a1 expression. A disease-specific human ILD1 transcriptomic signature has not been validated.
• Proteomics: No diagnostic plasma or BAL proteomic signature specific to ILD1.
• Metabolomics/lipidomics: No reproducible ILD1-specific signature. Altered surfactant lipid organization is biologically plausible but not adequately quantified.
• Single-cell analysis: SFTPA1 is a canonical alveolar type II-cell marker; general IPF atlases demonstrate epithelial-state heterogeneity, but no sufficiently powered single-cell ILD1 cohort exists.
• Spatial transcriptomics: No ILD1-specific spatial atlas.
• CRISPR: CRISPR-Cas9 insertion of p.Tyr208His reproduced fibrosis in mice, supporting variant causality.
• Organoids/iPSC: Potentially useful for individualized secretion and rescue studies, but not established diagnostic tools.

7. Anatomical structures affected

Disease is normally bilateral, not unilateral. Secondary structures include pulmonary vasculature and the right ventricle if chronic hypoxemia causes pulmonary hypertension/cor pulmonale. Lung cancer represents a secondary but major organ-level complication.

8. Temporal development

8.1 Onset

Onset is exceptionally broad:

• fatal infantile respiratory disease beginning at 7 months;
• young-adult recessive IPF diagnosed at 24 and 27 years;
• dominant disease commonly emerging in the fourth to sixth decades;
• latest reported onset in the original pedigree: 69 years.

The combined SP-A cohort’s mean/median onset was approximately 45 years, range 0.6–65 years. [83]

8.2 Course and stages

The course is generally chronic and progressive but highly variable. Spontaneous durable remission is not documented. Treatment may slow progression but does not reverse established fibrosis.

The recessive family showed severe progression: two brothers diagnosed in their twenties died at 32 and 34, while the third developed dyspnea at 40. [76]

8.3 Critical intervention windows

• Before irreversible FVC/DLCO decline and extensive honeycombing.
• Before severe frailty or pulmonary hypertension limits transplantation.
• At the first evidence of cancer, given the high cancer burden.
• During family-based presymptomatic surveillance, although the ideal CT interval remains unknown.

9. Inheritance, penetrance and population

9.1 Inheritance

• Autosomal dominant: most established families.
• Autosomal recessive: homozygous p.Tyr208His family.
• Penetrance: incomplete and age dependent.
• Expressivity: extremely variable.
• Anticipation: not demonstrated.
• Germline mosaicism: not reported, though theoretically possible.
• Founder effect: none established.
• Consanguinity: relevant to the recessive Japanese family.
• Sex ratio: no clear sex-limited effect; combined SP-A cohort male:female ratio was 0.65.

A 2025 penetrance analysis of combined SFTPA1/SFTPA2 pathogenic-variant carriers estimated 89.3% penetrance by age 80 for either ILD or lung cancer. This is not a pure ILD1 estimate and should not be applied uncritically to every SFTPA1 variant. [84]

9.2 Epidemiology

No reliable prevalence, incidence or carrier-frequency estimate exists specifically for ILD1.

• It is likely far below 1 per 100,000 and is represented by a small number of reported families.
• Surfactant-gene variants collectively account for approximately 1–3% of familial pulmonary-fibrosis families, but this includes SFTPA1, SFTPA2, SFTPC, ABCA3 and NKX2-1. [115][117]
• No ethnicity is known to have consistently elevated ILD1 prevalence.
• Published pedigrees include European/French, Czech, Japanese and North African ancestry, indicating worldwide potential distribution.
• Reported variants are generally ultra-rare rather than common founder alleles.

10. Diagnostics

10.1 Clinical diagnostic approach

A diagnosis requires integration of:

1. phenotype compatible with fibrotic ILD;
2. detailed three-generation family history of ILD and lung cancer;
3. HRCT;
4. pulmonary function and oxygenation assessment;
5. exclusion of autoimmune, exposure-related, drug-induced and infectious ILD;
6. identification and classification of a germline SFTPA1 variant;
7. segregation/functional evidence where necessary.

Recommended clinical tests

Routine serum SP-A, SP-D, KL-6 or MMP-7 may reflect epithelial injury in some jurisdictions but are not validated as specific ILD1 diagnostics.

10.2 Genetic testing strategy

The 2023 ERS familial pulmonary fibrosis statement recommends offering sequencing to patients with fibrotic ILD plus an affected first- or second-degree relative, a relative with a known pathogenic variant, suspected short-telomere syndrome, or idiopathic fibrosing ILD before age 50 (published 16 March 2023, PMID 36549714). Telomere- and surfactant-related genes should generally be included. [109][113]

Preferred workflow:

1. Pre-test genetic counseling.
2. Test an affected proband first.
3. Use a comprehensive familial pulmonary-fibrosis/childhood-ILD panel including at least:
4. SFTPA1, SFTPA2, SFTPB, SFTPC, ABCA3, NKX2-1;
5. TERT, TERC, RTEL1, PARN, DKC1, TINF2, NAF1, POT1 and other validated telomere genes;
6. additional syndromic ILD genes according to age/phenotype.
7. Include CNV analysis.
8. If panel testing is negative, consider WES or WGS, preferably family-based.
9. Confirm clinically important variants by an orthogonal method where appropriate.
10. Offer targeted cascade testing only after a familial pathogenic/likely pathogenic variant is identified.

Utility by test type

10.3 Differential diagnosis

10.4 Screening of relatives

• A known familial pathogenic variant permits predictive testing in competent adults after counseling.
• Baseline history, examination, PFT/DLCO and HRCT should be considered for adult carriers.
• The ERS statement supports CT and PFT screening particularly for symptomatic first-degree relatives; evidence for intervals in asymptomatic relatives remains limited. [118]
• Testing minors for an adult-onset disorder is generally deferred, but pediatric testing may be justified when the family includes childhood disease or a biallelic risk.

11. Outcome and prognosis

11.1 Prognostic variability

Prognosis ranges from lifelong asymptomatic carriage to fatal infantile disease or rapidly progressive adult IPF. Poor prognostic factors likely include:

• biallelic pathogenic variants;
• early onset;
• rapid FVC/DLCO decline;
• UIP/honeycombing;
• oxygen requirement;
• acute exacerbation;
• pulmonary hypertension;
• lung cancer;
• inability to undergo transplantation.

No validated SFTPA1-specific prognostic calculator or biomarker exists.

11.2 Mortality and transplantation

In the combined 2020 SFTPA1/SFTPA2 cohort:

• 11/23 symptomatic patients (48%) underwent lung transplantation;
• median transplant age was 51 years;
• median diagnosis-to-transplant interval was 5 years;
• 9/28 carriers (32%) died;
• median death age was 51 years.

These results are affected by referral and severity ascertainment. [83]

The 2023 French transplant study included 20 surfactant-gene patients—SFTPA1 n=5, SFTPA2 n=7, SFTPC n=8:

• diagnosis age: median 45 years;
• transplant age: median 51 years;
• median post-transplant survival: 8.6 years;
• eight patients died overall;
• none of the five SFTPA1 recipients died during follow-up.

The investigators concluded that transplantation “may be a valid therapeutic option” and emphasized cancer screening before and after transplant (PMID 38020562, published 20 November 2023). [91][92]

11.3 Lung-cancer risk

The latest major 2024 cohort of 99 carriers of surfactant-related variants found:

• 82/99 (82.8%) had ILD at diagnosis;
• 13 had lung cancer;
• 27 (32.9%) underwent transplantation;
• 15-year cancer-free survival was 0.43 for SFTPA1/SFTPA2 carriers versus 0.85 for non-SFTPA surfactant-gene carriers;
• 28 (28.3%) died during follow-up.

The authors called for specific ILD and lung-cancer surveillance in this relatively young population (published 2 May 2024). [97][100]

12. Treatment

There is no genotype-specific approved treatment and no randomized trial confined to ILD1. Management should occur in a multidisciplinary ILD/genetics center.

12.1 Clinical treatment framework

The 2022 ATS/ERS/JRS/ALAT guideline conditionally recommends nintedanib for non-IPF progressive pulmonary fibrosis after failure of standard management and calls for further pirfenidone research in non-IPF PPF. Both pirfenidone and nintedanib remain appropriate for a patient meeting standard IPF indications, irrespective of SFTPA1 status, absent contraindication. [121][122]

In the 2020 SP-A cohort, some SFTPA1 patients received pirfenidone, nintedanib or unspecified antifibrotic therapy, but the sample was too small for a genotype-specific response rate. [83]

Adverse effects and monitoring

• Nintedanib: diarrhea, nausea, weight loss, elevated liver enzymes, bleeding risk; monitor liver function and interactions.
• Pirfenidone: nausea, anorexia, photosensitivity, rash and hepatotoxicity; monitor liver function and counsel regarding sun protection.
• Oxygen: fire risk and mobility burden.
• Transplantation: rejection, infection, malignancy, renal/metabolic toxicity and chronic allograft dysfunction.

12.2 Experimental and advanced therapeutics

No approved gene, cell, RNA or CRISPR therapy exists for ILD1.

Potential research strategies include:

• correcting SFTPA1 variants by genome/base editing;
• allele-specific suppression of toxic dominant transcripts;
• mRNA or protein replacement;
• pharmacologic enhancement of folding and secretion;
• IRE1α, JNK, RIPK3 or MLKL inhibition;
• alveolar type II-cell regenerative therapy.

IRE1α/JNK/necroptosis interventions are supported only by the p.Tyr208His mouse model. They should not currently be used clinically outside a properly regulated trial. [78]

A 2023 review of personalized therapies for surfactant disorders emphasized gene-, RNA-, protein- and cell-based possibilities but did not identify an approved SFTPA1-directed therapy. [104]

12.3 Treatment algorithm

1. Confirm ILD pattern and SFTPA1 pathogenicity.
2. Eliminate smoking and relevant inhalational exposures.
3. Vaccinate and treat infection promptly.
4. Monitor symptoms, FVC, DLCO, exercise oxygenation and HRCT.
5. If IPF criteria are met, offer approved antifibrotic therapy.
6. If non-IPF fibrotic ILD becomes progressive, consider nintedanib under PPF guidance.
7. Add pulmonary rehabilitation, oxygen and symptom-directed care.
8. Intensify lung-cancer surveillance.
9. Refer early for transplant evaluation when decline is evident.
10. Offer clinical-trial participation and family genetic counseling.

No clinically actionable pharmacogenomic variant is established for antifibrotic choice in ILD1.

13. Prevention

13.1 Primary prevention

The inherited variant cannot currently be prevented after conception. Risk-reduction includes:

• smoking avoidance/cessation;
• dust and aerosol controls;
• respiratory protection at work;
• vaccination;
• minimizing avoidable pneumotoxic exposures;
• reproductive counseling.

13.2 Secondary prevention

• cascade genetic testing after a familial variant is established;
• baseline and longitudinal PFT/DLCO;
• low-threshold HRCT for symptoms or physiologic changes;
• careful review of CT for nodules and early cancer;
• early antifibrotic and transplant assessment where indicated.

There is no proven population-wide screening program because ILD1 is ultra-rare.

13.3 Tertiary prevention

• oxygen and rehabilitation to limit disability;
• infection prevention;
• management of reflux, sleep-disordered breathing and cardiovascular comorbidity;
• surveillance for pulmonary hypertension and malignancy;
• early transplant referral;
• palliative-care integration.

13.4 Reproductive options

After identification of a familial pathogenic variant:

• natural conception with prenatal diagnosis;
• preimplantation genetic testing for monogenic disease;
• donor gametes;
• adoption;
• conception without testing.

For dominant disease, each child of a heterozygous carrier generally has a 50% transmission probability, but disease severity cannot be predicted reliably. For two heterozygous carriers of a recessive pathogenic allele, the classic per-pregnancy risks are 25% affected, 50% carrier and 25% non-carrier.

14. Other species and natural disease

14.1 Comparative biology

MGI reports that homozygous Sftpa1-null mice have impaired responses to lung stress, reduced resistance to pulmonary infection and enhanced LPS-induced inflammation. [158]

14.2 Naturally occurring veterinary disease

Idiopathic pulmonary fibrosis occurs naturally in animals—most notably West Highland White Terriers—but a direct causal SFTPA1 ortholog variant equivalent to human ILD1 has not been established. Consequently:

• no VBO breed term should be assigned specifically to SFTPA1-related ILD1;
• natural canine/feline fibrosis is comparative pathology, not a confirmed orthologous Mendelian disease;
• ILD1 has no zoonotic potential and no cross-species transmission.

15. Model organisms and experimental systems

The central model paper’s abstract directly reports:

“Sftpa1 knock-in (Sftpa1-KI) mice that harbored the same mutation as patients spontaneously developed pulmonary fibrosis that was accelerated by influenza virus infection.”

It further reports that JNK inhibition ameliorated fibrosis and that RIPK3 overexpression worsened it (Takezaki et al., PMID 31601679). [78]

Useful model resources are MGI, IMSR/MMRRC, IMPC, GEO/SRA for expression datasets, and patient-derived repositories maintained by ILD reference centers.

Recent developments, 2023–2024

Knowledge-base conclusions

1. ILD1 is a specific SFTPA1-related Mendelian disorder, not a generic synonym for all interstitial lung disease.
2. The most defensible core annotation is:
   germline SFTPA1 CRD missense variant → deficient SP-A1 secretion/retention in alveolar type II cells → epithelial stress and death → progressive fibrosis ± lung adenocarcinoma.
3. Autosomal dominant, incompletely penetrant disease is usual, but severe autosomal-recessive disease is proven.
4. Phenotypic onset extends from infancy to late adulthood, with marked intrafamilial variability.
5. Lung-cancer surveillance is a central management issue, particularly for SFTPA1/SFTPA2 carriers.
6. No ILD1-specific drug exists; management uses standard IPF/PPF pathways, supportive care and timely lung transplantation.
7. The p.Tyr208His knock-in mouse is the strongest mechanistic model, but its necroptosis pathway should not automatically be generalized to every dominant SFTPA1 allele.
8. Disease-specific prevalence, variant-specific penetrance, treatment-response rates, validated biomarkers, epigenetic signatures and human single-cell datasets remain major evidence gaps.

Reference Validation

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All extracted references resolved successfully.

Term Validation

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Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• DOID:0060941 (1 mention) - the report calls it "DOID"; DOID calls it interstitial lung disease 1
• CL:0002063 (2 mentions) - the report calls it "Primary SFTPA1-producing and injured cell", "Alveolar epithelial type II cell"; CL calls it pulmonary alveolar type 2 cell
• CL:0002062 (1 mention) - the report calls it "Secondary impairment through architectural destruction"; CL calls it pulmonary alveolar type 1 cell
• CL:0000583 (1 mention) - the report calls it "Surfactant clearance, innate immunity and inflammation"; CL calls it alveolar macrophage
• CL:0000186 (1 mention) - the report calls it "Contractile collagen-producing effector"; CL calls it myofibroblast cell

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

• GO:0045045 (obsolete secretory pathway) (1 mention) - replaced by GO:0032940

Terms named inconsistently

The report gives these identifiers more than one name of its own:

• CL:0002063 - called "Primary SFTPA1-producing and injured cell", "Alveolar epithelial type II cell"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, OMIM, MGI.