pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1

Summary

pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 (MONDO:0013878) is a disease caused by TERT (GenCC Definitive), with 4 cohort genes. The dominant Reactome pathway is Telomere Extension By Telomerase (3 cohort genes).

At a glance

• Causal gene: TERT (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 188

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1
Mondo ID	MONDO:0013878
EFO	EFO:1001501
OMIM	614742
UMLS	C3553617
MedGen	766531
GARD	0024959
Is cancer (heuristic)	no

Also known as: PFBMFT1 · pulmonary fibrosis and/or bone marrow failure, Telomere-related caused by mutation in TERT · pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 · pulmonary fibrosis and/or bone marrow failure, Telomere-related, type 1 · TERT pulmonary fibrosis and/or bone marrow failure, Telomere-related

Data availability: 188 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › lower respiratory tract disorder › lung disorder › interstitial lung disease › pulmonary fibrosis › pulmonary fibrosis and/or bone marrow failure, telomere-related › pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1

Related subtypes (8): pulmonary fibrosis and/or bone marrow failure, Telomere-related, 2, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3, pulmonary fibrosis and/or bone marrow failure, telomere-related, 6, pulmonary fibrosis and/or bone marrow failure, telomere-related, 5, pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7, pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8, pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 9

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

188 retrieved; paginated sample, class counts are floors:

72 conflicting classifications of pathogenicity, 58 uncertain significance, 12 benign/likely benign, 11 benign, 10 likely pathogenic, 10 pathogenic/likely pathogenic, 8 pathogenic, 7 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
36946	NM_198253.2(TERT):c.[2371G>A;2599G>A]		Pathogenic	no assertion criteria provided
12738	NM_198253.3(TERT):c.219+1G>A	LOC110806263	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36945	NM_198253.3(TERT):c.164T>A (p.Leu55Gln)	LOC110806263	Pathogenic	no assertion criteria provided
12736	NM_198253.3(TERT):c.2594G>A (p.Arg865His)	TERT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12737	NM_198253.3(TERT):c.2240del (p.Val747fs)	TERT	Pathogenic	criteria provided, single submitter
1686800	NM_198253.3(TERT):c.2583-2A>T	TERT	Pathogenic/Likely pathogenic	criteria provided, single submitter
242683	NM_198253.3(TERT):c.2599G>A (p.Val867Met)	TERT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29899	NM_198253.3(TERT):c.1892G>A (p.Arg631Gln)	TERT	Pathogenic	criteria provided, multiple submitters, no conflicts
3237356	NM_198253.3(TERT):c.2053_2055del (p.Asp685del)	TERT	Pathogenic	criteria provided, single submitter
36944	NM_198253.3(TERT):c.2583-2A>C	TERT	Pathogenic	no assertion criteria provided
36948	NM_198253.3(TERT):c.2146G>A (p.Ala716Thr)	TERT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36949	NM_198253.3(TERT):c.2705A>G (p.Lys902Arg)	TERT	Pathogenic	no assertion criteria provided
39108	NM_198253.3(TERT):c.2110C>T (p.Pro704Ser)	TERT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39109	NM_198253.3(TERT):c.2147C>T (p.Ala716Val)	TERT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
410651	NM_198253.3(TERT):c.336dup (p.Glu113fs)	TERT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
436993	NM_198253.3(TERT):c.579_580delinsTT (p.Arg194Ter)	TERT	Pathogenic	criteria provided, single submitter
523957	NM_198253.3(TERT):c.2991del (p.Cys998fs)	TERT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
950401	NM_198253.3(TERT):c.2638G>A (p.Ala880Thr)	TERT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065578	NM_198253.3(TERT):c.3026C>T (p.Ala1009Val)	TERT	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686798	NM_198253.3(TERT):c.2131-2A>G	TERT	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686799	NM_198253.3(TERT):c.2426_2427del (p.Phe809fs)	TERT	Likely pathogenic	criteria provided, single submitter
1686801	NM_198253.3(TERT):c.1601A>G (p.His534Arg)	TERT	Likely pathogenic	criteria provided, single submitter
1695949	NM_198253.3(TERT):c.2521C>T (p.Leu841Phe)	TERT	Likely pathogenic	criteria provided, single submitter
265267	NM_198253.3(TERT):c.1700C>T (p.Thr567Met)	TERT	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3065428	NM_198253.3(TERT):c.2665C>T (p.Arg889Ter)	TERT	Likely pathogenic	criteria provided, single submitter
3377095	NM_198253.3(TERT):c.3033-2A>C	TERT	Likely pathogenic	criteria provided, single submitter
3385331	NM_198253.3(TERT):c.1195_1210dup (p.Pro404fs)	TERT	Likely pathogenic	criteria provided, single submitter
816669	NM_198253.3(TERT):c.345C>G (p.Phe115Leu)	TERT	Likely pathogenic	criteria provided, single submitter
539242	NM_198253.3(TERT):c.189G>A (p.Arg63=)	LOC110806263	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1013653	NM_198253.3(TERT):c.2912G>A (p.Arg971His)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 17 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TERT	Definitive	Autosomal dominant	pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TERT	Orphanet:146	Differentiated thyroid carcinoma
TERT	Orphanet:1501	Adrenocortical carcinoma
TERT	Orphanet:1775	Dyskeratosis congenita
TERT	Orphanet:2032	Idiopathic pulmonary fibrosis
TERT	Orphanet:2495	Meningioma
TERT	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
TERT	Orphanet:457246	Clear cell sarcoma of kidney
TERT	Orphanet:618	Familial melanoma
TERT	Orphanet:88	Idiopathic aplastic anemia
TINF2	Orphanet:1775	Dyskeratosis congenita
TINF2	Orphanet:3088	Revesz syndrome
TINF2	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
TNNI3	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNI3	Orphanet:75249	Familial isolated restrictive cardiomyopathy
RTEL1	Orphanet:1775	Dyskeratosis congenita
RTEL1	Orphanet:2032	Idiopathic pulmonary fibrosis
RTEL1	Orphanet:3322	Hoyeraal-Hreidarsson syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	gencc,clinvar
TINF2	HGNC:11824	ENSG00000092330	Q9BSI4	TERF1-interacting nuclear factor 2	clinvar
TNNI3	HGNC:11947	ENSG00000129991	P19429	Troponin I, cardiac muscle	clinvar
RTEL1	HGNC:15888	ENSG00000258366	Q9NZ71	Regulator of telomere elongation helicase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TERT	Telomerase reverse transcriptase	Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes.
TINF2	TERF1-interacting nuclear factor 2	Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection.
TNNI3	Troponin I, cardiac muscle	Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
RTEL1	Regulator of telomere elongation helicase 1	A probable ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair and the maintenance of genomic stability.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD
TINF2	Other/Unknown	no		TINF2_N, TINF2
TNNI3	Other/Unknown	no		Troponin, Troponin-I_N, Troponin_sf
RTEL1	Other/Unknown	no		Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
olfactory bulb	1
stromal cell of endometrium	1
type B pancreatic cell	1
granulocyte	1
right adrenal gland	1
right adrenal gland cortex	1
apex of heart	1
left ventricle myocardium	1
right atrium auricular region	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TERT	105	broad	yes	stromal cell of endometrium, type B pancreatic cell, olfactory bulb
TINF2	144	ubiquitous	marker	granulocyte, right adrenal gland, right adrenal gland cortex
TNNI3	169	broad	marker	apex of heart, left ventricle myocardium, right atrium auricular region
RTEL1	134	ubiquitous	yes	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TERT	5,717
RTEL1	2,324
TNNI3	1,836
TINF2	1,769

Intra-cohort edges

A	B	Sources
RTEL1	TERT	string_interaction
RTEL1	TINF2	string_interaction
TERT	TINF2	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNNI3	P19429	39
TERT	O14746	23
TINF2	Q9BSI4	3
RTEL1	Q9NZ71	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 37. Enrichment computed across 4 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Telomere Extension By Telomerase	3	342.6×	1e-06	TERT, TINF2, RTEL1
Extension of Telomeres	2	300.5×	3e-04	TERT, RTEL1
Telomere Maintenance	2	184.2×	5e-04	TERT, RTEL1
Chromosome Maintenance	2	105.7×	0.001	TERT, RTEL1
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	407.9×	0.018	TERT
Telomere C-strand synthesis initiation	1	203.9×	0.019	TINF2
Processive synthesis on the C-strand of the telomere	1	190.3×	0.019	TINF2
Telomere C-strand (Lagging Strand) Synthesis	1	190.3×	0.019	TINF2
Cytosolic iron-sulfur cluster assembly	1	190.3×	0.019	RTEL1
Removal of the Flap Intermediate from the C-strand	1	158.6×	0.019	TINF2
Resolution of D-Loop Structures	1	158.6×	0.019	RTEL1
Cell Cycle	2	18.0×	0.019	TERT, RTEL1
Polymerase switching on the C-strand of the telomere	1	105.7×	0.027	TINF2
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	98.5×	0.027	RTEL1
Striated Muscle Contraction	1	77.2×	0.028	TNNI3
Homology Directed Repair	1	77.2×	0.028	RTEL1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	77.2×	0.028	RTEL1
DNA Double-Strand Break Repair	1	62.1×	0.031	RTEL1
Packaging Of Telomere Ends	1	54.9×	0.031	TINF2
Recognition and association of DNA glycosylase with site containing an affected purine	1	51.0×	0.031	TINF2
Cleavage of the damaged purine	1	51.0×	0.031	TINF2
Ion homeostasis	1	51.0×	0.031	TNNI3
HDR through Homologous Recombination (HRR)	1	47.6×	0.031	RTEL1
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	1	46.0×	0.031	TINF2
Cleavage of the damaged pyrimidine	1	46.0×	0.031	TINF2
MITF-M-dependent gene expression	1	45.3×	0.031	TERT
Inhibition of DNA recombination at telomere	1	42.0×	0.032	TINF2
DNA Damage/Telomere Stress Induced Senescence	1	40.8×	0.032	TINF2
Meiotic synapsis	1	35.2×	0.036	TINF2
Formation of the beta-catenin:TCF transactivating complex	1	30.1×	0.040	TERT

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of telomere maintenance	2	255.3×	0.001	TINF2, RTEL1
DNA strand displacement	1	4213.0×	0.001	RTEL1
RNA-templated transcription	1	4213.0×	0.001	TERT
DNA strand elongation	1	4213.0×	0.001	TERT
siRNA transcription	1	4213.0×	0.001	TERT
positive regulation of transdifferentiation	1	4213.0×	0.001	TERT
regulation of telomere maintenance via telomere lengthening	1	4213.0×	0.001	TINF2
negative regulation of telomere maintenance in response to DNA damage	1	4213.0×	0.001	RTEL1
positive regulation of telomeric loop disassembly	1	4213.0×	0.001	RTEL1
telomere maintenance	2	133.8×	0.001	TERT, RTEL1
regulation of systemic arterial blood pressure by ischemic conditions	1	2106.5×	0.002	TNNI3
RNA-templated DNA biosynthetic process	1	2106.5×	0.002	TERT
positive regulation of hair cycle	1	2106.5×	0.002	TERT
telomeric loop disassembly	1	2106.5×	0.002	RTEL1
mitotic telomere maintenance via semi-conservative replication	1	1404.3×	0.003	RTEL1
negative regulation of t-circle formation	1	1404.3×	0.003	RTEL1
telomere assembly	1	1053.2×	0.003	TINF2
heart development	2	39.4×	0.003	TERT, TNNI3
positive regulation of telomere capping	1	842.6×	0.004	RTEL1
positive regulation of telomere maintenance via telomere lengthening	1	702.2×	0.004	RTEL1
positive regulation of protein localization to nucleolus	1	702.2×	0.004	TERT
establishment of protein localization to telomere	1	526.6×	0.005	TERT
siRNA processing	1	468.1×	0.006	TERT
telomere maintenance in response to DNA damage	1	468.1×	0.006	RTEL1
negative regulation of ATP-dependent activity	1	421.3×	0.006	TNNI3
telomere maintenance via recombination	1	383.0×	0.006	TERT
protein localization to chromosome, telomeric region	1	383.0×	0.006	TINF2
regulation of cardiac muscle contraction by calcium ion signaling	1	324.1×	0.007	TNNI3
telomere capping	1	324.1×	0.007	TINF2
regulation of smooth muscle contraction	1	300.9×	0.007	TNNI3

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 3

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TERT	BERBERINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TERT	10	4
TINF2	0	0
TNNI3	0	0
RTEL1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
RESVERATROL	3	TERT
EPIGALOCATECHIN GALLATE	3	TERT
PERIFOSINE	3	TERT
ISOMETAMIDIUM	2	TERT
HOMIDIUM BROMIDE	2	TERT
ALLICIN	2	TERT
OLEIC ACID	2	TERT
ETHACRIDINE	2	TERT

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TERT	391	Binding:389, Functional:2
TNNI3	2	Binding:2

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TERT	391

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

10 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
RESVERATROL	3	TERT
EPIGALOCATECHIN GALLATE	3	TERT
PERIFOSINE	3	TERT
ISOMETAMIDIUM	2	TERT
HOMIDIUM BROMIDE	2	TERT
ALLICIN	2	TERT
OLEIC ACID	2	TERT
ETHACRIDINE	2	TERT

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TERT
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	TINF2, TNNI3, RTEL1

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TINF2	0	—
TNNI3	2	—
RTEL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.