pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4

Summary

pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4 (MONDO:0014612) is a disease caused by PARN (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: PARN (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 866

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, 4
Mondo ID	MONDO:0014612
OMIM	616371
UMLS	C4225347
MedGen	903928
GARD	0016097
Is cancer (heuristic)	no

Also known as: PARN pulmonary fibrosis and/or bone marrow failure, Telomere-related · PFBMFT4 · pulmonary fibrosis and/or bone marrow failure, Telomere-related caused by mutation in PARN · pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4 · pulmonary fibrosis and/or bone marrow failure, Telomere-related, type 4

Data availability: 866 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, 4

Related subtypes (8): pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 2, 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

600 retrieved; paginated sample, class counts are floors:

279 uncertain significance, 259 likely benign, 24 pathogenic, 18 likely pathogenic, 12 benign, 5 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1394752	NM_002582.4(PARN):c.1624C>T (p.Gln542Ter)	PARN	Pathogenic	criteria provided, single submitter
1418162	NM_002582.4(PARN):c.417_420del (p.Glu139fs)	PARN	Pathogenic	criteria provided, single submitter
1451667	NM_002582.4(PARN):c.1123C>T (p.Gln375Ter)	PARN	Pathogenic	criteria provided, single submitter
1452326	NM_002582.4(PARN):c.382C>T (p.Arg128Ter)	PARN	Pathogenic	criteria provided, single submitter
1455611	NC_000016.9:g.(?14645858)(14711527_?)del	PARN	Pathogenic	criteria provided, single submitter
1675108	NM_002582.4(PARN):c.758_759del (p.Glu253fs)	PARN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190468	NM_002582.4(PARN):c.246-2A>G	PARN	Pathogenic	criteria provided, single submitter
190469	NM_002582.4(PARN):c.529C>T (p.Gln177Ter)	PARN	Pathogenic	criteria provided, multiple submitters, no conflicts
190470	NM_002582.4(PARN):c.563dup (p.Glu189fs)	PARN	Pathogenic	criteria provided, single submitter
1941438	NM_002582.4(PARN):c.177+1del	PARN	Pathogenic	criteria provided, single submitter
1998806	NM_002582.4(PARN):c.1414C>T (p.Gln472Ter)	PARN	Pathogenic	criteria provided, single submitter
2008012	NM_002582.4(PARN):c.122_123del (p.Ser41fs)	PARN	Pathogenic	criteria provided, single submitter
2029210	NM_002582.4(PARN):c.714del (p.Arg237_Tyr238insTer)	PARN	Pathogenic	criteria provided, single submitter
2424488	NC_000016.9:g.(?14711427)(14711527_?)del	PARN	Pathogenic	criteria provided, single submitter
2424489	NC_000016.9:g.(?14645858)(14724045_?)del	PARN	Pathogenic	criteria provided, single submitter
2936222	NM_002582.4(PARN):c.1645C>T (p.Gln549Ter)	PARN	Pathogenic	criteria provided, single submitter
2942751	NM_002582.4(PARN):c.1481-1G>A	PARN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2949321	NM_002582.4(PARN):c.994C>T (p.Gln332Ter)	PARN	Pathogenic	criteria provided, single submitter
3243537	NC_000016.9:g.(?14530574)(14724045_?)del	PARN	Pathogenic	criteria provided, single submitter
3243539	NC_000016.9:g.(?14704491)(14704676_?)del	PARN	Pathogenic	criteria provided, single submitter
3243540	NC_000016.9:g.(?14711427)(14724045_?)del	PARN	Pathogenic	criteria provided, single submitter
3243541	NC_000016.9:g.(?14693741)(14700403_?)del	PARN	Pathogenic	criteria provided, single submitter
3243542	NC_000016.9:g.(?14720953)(14721203_?)del	PARN	Pathogenic	criteria provided, single submitter
3376859	NM_002582.4(PARN):c.634del (p.Lys211_Leu212insTer)	PARN	Pathogenic	criteria provided, single submitter
3747959	NM_002582.4(PARN):c.24dup (p.Lys9Ter)	PARN	Pathogenic	criteria provided, single submitter
3754250	NM_002582.4(PARN):c.305dup (p.Asp103fs)	PARN	Pathogenic	criteria provided, single submitter
1068174	NC_000016.9:g.(?14645858)(14649586_?)dup	PARN	Likely pathogenic	criteria provided, single submitter
1345454	NM_002582.4(PARN):c.1405+1G>T	PARN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1475274	NM_002582.4(PARN):c.555-2A>G	PARN	Likely pathogenic	criteria provided, single submitter
1482244	NM_002582.4(PARN):c.1263-11_1269del	PARN	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 7 · 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
PARN	Strong	Autosomal dominant	pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PARN	Orphanet:1775	Dyskeratosis congenita
PARN	Orphanet:2032	Idiopathic pulmonary fibrosis
PARN	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
PKD1	Orphanet:730	Autosomal dominant polycystic kidney disease
PKD1	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
PRKD1	Orphanet:276145	Malignant epithelial tumor of salivary glands
PRKD1	Orphanet:708019	Congenital heart defect-ectodermal dysplasia- brachydactyly-telangiectasia syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PARN	HGNC:8609	ENSG00000140694	O95453	Poly(A)-specific ribonuclease PARN	gencc,clinvar
PKD1	HGNC:9008	ENSG00000008710	P98161	Polycystin-1	clinvar
PRKD1	HGNC:9407	ENSG00000184304	Q15139	Serine/threonine-protein kinase D1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PARN	Poly(A)-specific ribonuclease PARN	3’-exoribonuclease that has a preference for poly(A) tails of mRNAs, thereby efficiently degrading poly(A) tails.
PKD1	Polycystin-1	Component of a heteromeric calcium-permeable ion channel formed by PKD1 and PKD2 that is activated by interaction between PKD1 and a Wnt family member, such as WNT3A and WNT9B.
PRKD1	Serine/threonine-protein kinase D1	Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of MAPK8/JNK1 and Ras signaling, Golgi membrane integrity and tr…

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Antibody/Immunoglobulin	1	9.7×	0.157
Kinase	1	9.2×	0.157
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PARN	Other/Unknown	no		R3H_dom, RNase_CAF1, RNaseH-like_sf
PKD1	Antibody/Immunoglobulin	yes		GPS, LRRNT, PC1
PRKD1	Kinase	yes	2.7.11.13	Prot_kinase_dom, PH_domain, PKC_DAG/PE

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
corpus callosum	1
male germ line stem cell (sensu Vertebrata) in testis	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
seminal vesicle	1
thoracic aorta	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PARN	134	ubiquitous	marker	calcaneal tendon, corpus callosum, male germ line stem cell (sensu Vertebrata) in testis
PKD1	290		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PRKD1	239	ubiquitous	marker	ventricular zone, seminal vesicle, thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKD1	2,131
PARN	1,532
PKD1	1,370

Intra-cohort edges

A	B	Sources
PKD1	PRKD1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PKD1	P98161	13
PARN	O95453	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRKD1	Q15139	68.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
KSRP (KHSRP) binds and destabilizes mRNA	1	211.5×	0.015	PARN
VxPx cargo-targeting to cilium	1	173.0×	0.015	PKD1
Deadenylation of mRNA	1	146.4×	0.015	PARN
ATF4 activates genes in response to endoplasmic reticulum stress	1	135.9×	0.015	PARN
Sphingolipid de novo biosynthesis	1	95.2×	0.017	PRKD1
Sphingolipid metabolism	1	56.0×	0.024	PRKD1
Metabolism of lipids	1	10.5×	0.105	PRKD1
Metabolism	1	3.9×	0.237	PRKD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
metanephric distal tubule morphogenesis	1	5617.3×	0.004	PKD1
box H/ACA sno(s)RNA 3’-end processing	1	2808.7×	0.004	PARN
RNA modification	1	2808.7×	0.004	PARN
regulation of skeletal muscle contraction by modulation of calcium ion sensitivity of myofibril	1	2808.7×	0.004	PRKD1
nitrogen cycle metabolic process	1	2808.7×	0.004	PKD1
mesonephric tubule development	1	2808.7×	0.004	PKD1
lncRNA processing	1	2808.7×	0.004	PARN
priRNA 3’-end processing	1	2808.7×	0.004	PARN
siRNA 3’-end processing	1	2808.7×	0.004	PARN
lymph vessel morphogenesis	1	1872.4×	0.005	PKD1
metanephric proximal tubule development	1	1872.4×	0.005	PKD1
calcium-independent cell-matrix adhesion	1	1404.3×	0.005	PKD1
cellular response to norepinephrine stimulus	1	1404.3×	0.005	PRKD1
metanephric ascending thin limb development	1	1404.3×	0.005	PKD1
telomerase RNA stabilization	1	1404.3×	0.005	PARN
regulation of telomerase RNA localization to Cajal body	1	1404.3×	0.005	PARN
mesonephric duct development	1	1123.5×	0.006	PKD1
positive regulation of sarcomere organization	1	936.2×	0.006	PRKD1
mitocytosis	1	936.2×	0.006	PKD1
lung epithelium development	1	702.2×	0.007	PKD1
poly(A)-dependent snoRNA 3’-end processing	1	702.2×	0.007	PARN
cellular response to hydroperoxide	1	702.2×	0.007	PRKD1
regulation of integrin-mediated signaling pathway	1	702.2×	0.007	PRKD1
miRNA catabolic process	1	624.1×	0.007	PARN
response to fluid shear stress	1	624.1×	0.007	PKD1
genitalia development	1	561.7×	0.007	PKD1
metanephric collecting duct development	1	561.7×	0.007	PKD1
regulation of keratinocyte proliferation	1	510.7×	0.007	PRKD1
Golgi vesicle transport	1	510.7×	0.007	PRKD1
positive regulation of peptide hormone secretion	1	510.7×	0.007	PRKD1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 3 of 3 evidence-associated genes (100%) 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
PRKD1	INGENOL MEBUTATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKD1	26	4
PARN	0	0
PKD1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
INGENOL MEBUTATE	4	PRKD1
MIDOSTAURIN	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
BRIGATINIB	4	PRKD1
NINTEDANIB	4	PRKD1
SUNITINIB	4	PRKD1
CRIZOTINIB	4	PRKD1
GEFITINIB	4	PRKD1
SURAMIN	3	PRKD1
FASUDIL	3	PRKD1
ALVOCIDIB	3	PRKD1
LESTAURTINIB	3	PRKD1
PHORBOL MYRISTATE ACETATE	2	PRKD1
EDELFOSINE	2	PRKD1
UPROSERTIB	2	PRKD1
UCN-01	2	PRKD1
SU-014813	2	PRKD1
AT-9283	2	PRKD1
BI-2536	2	PRKD1
KW-2449	1	PRKD1
BMS-387032	1	PRKD1
PF-03758309	1	PRKD1
SRA-737	1	PRKD1
GSK-690693	1	PRKD1
AST-487	1	PRKD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PRKD1	660	Binding:650, Functional:10
PKD1	27	Binding:27
PARN	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRKD1	2.7.11.13	protein kinase C

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PRKD1	660

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

26 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)
INGENOL MEBUTATE	4	PRKD1
MIDOSTAURIN	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
BRIGATINIB	4	PRKD1
NINTEDANIB	4	PRKD1
SUNITINIB	4	PRKD1
CRIZOTINIB	4	PRKD1
GEFITINIB	4	PRKD1
SURAMIN	3	PRKD1
FASUDIL	3	PRKD1
ALVOCIDIB	3	PRKD1
LESTAURTINIB	3	PRKD1
PHORBOL MYRISTATE ACETATE	2	PRKD1
EDELFOSINE	2	PRKD1
UPROSERTIB	2	PRKD1
UCN-01	2	PRKD1
SU-014813	2	PRKD1
AT-9283	2	PRKD1
BI-2536	2	PRKD1
KW-2449	1	PRKD1
BMS-387032	1	PRKD1
PF-03758309	1	PRKD1
SRA-737	1	PRKD1
GSK-690693	1	PRKD1
AST-487	1	PRKD1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PRKD1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PKD1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PARN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PKD1	27	PRKD1
PARN	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.