Dyskeratosis congenita, autosomal recessive 6

Summary

Dyskeratosis congenita, autosomal recessive 6 (MONDO:0014600) is a disease caused by PARN (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: PARN (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 864

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dyskeratosis congenita, autosomal recessive 6
Mondo ID	MONDO:0014600
OMIM	616353
DOID	DOID:0070024
NCIT	C176929
UMLS	C4225356
MedGen	905452
GARD	0016095
Is cancer (heuristic)	no

Also known as: DKCB6 · dyskeratosis congenita caused by mutation in PARN · dyskeratosis congenita, autosomal recessive 6 · dyskeratosis congenita, autosomal recessive type 6 · PARN dyskeratosis congenita

Data availability: 864 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › dyskeratosis congenita › dyskeratosis congenita, autosomal recessive 6

Related subtypes (15): dyskeratosis congenita, autosomal dominant 1, dyskeratosis congenita, autosomal recessive 1, Revesz syndrome, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, dyskeratosis congenita, autosomal dominant 6, autosomal recessive dyskeratosis congenita 4, dyskeratosis congenita, digenic, DKC1-related disorder, dyskeratosis congenita, autosomal dominant 4, dyskeratosis congenita, autosomal recessive 7, dyskeratosis congenita and related telomere biology disorder, dyskeratosis congenita, autosomal recessive 8

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:

277 uncertain significance, 259 likely benign, 24 pathogenic, 19 likely pathogenic, 12 benign, 5 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 1 benign/likely benign, 1 not provided

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
180661	NM_002582.4(PARN):c.1148C>T (p.Ala383Val)	PARN	Pathogenic	no assertion criteria provided
190290	NM_002582.4(PARN):c.863dup (p.Asn288fs)	PARN	Pathogenic	no assertion criteria provided
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
219121	NM_002582.3(PARN):c.962+295_1263-8706del	PARN	Pathogenic	no assertion criteria provided
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
3747959	NM_002582.4(PARN):c.24dup (p.Lys9Ter)	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: 3 · 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	Definitive	Autosomal recessive	dyskeratosis congenita, autosomal recessive 6	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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PARN	HGNC:8609	ENSG00000140694	O95453	Poly(A)-specific ribonuclease PARN	gencc,clinvar
BFAR	HGNC:17613	ENSG00000103429	Q9NZS9	Bifunctional apoptosis regulator	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.
BFAR	Bifunctional apoptosis regulator	Membrane-bound E3 ubiquitin ligase that plays a role in several processes including apoptosis regulation or reticulum endoplasmic stress.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PARN	Other/Unknown	no		R3H_dom, RNase_CAF1, RNaseH-like_sf
BFAR	Transcription factor	no		SAM, Znf_RING, Znf_RING/FYVE/PHD

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)	2
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
islet of Langerhans	1
pancreas	1
right lung	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
BFAR	139	ubiquitous	marker	islet of Langerhans, right lung, pancreas

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PARN	1,532
BFAR	688

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PARN	O95453	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BFAR	Q9NZS9	82.40

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (1 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 1 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	634.4×	0.002	PARN
Deadenylation of mRNA	1	439.2×	0.002	PARN
ATF4 activates genes in response to endoplasmic reticulum stress	1	407.9×	0.002	PARN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
box H/ACA sno(s)RNA 3’-end processing	1	4213.0×	0.001	PARN
RNA modification	1	4213.0×	0.001	PARN
lncRNA processing	1	4213.0×	0.001	PARN
priRNA 3’-end processing	1	4213.0×	0.001	PARN
siRNA 3’-end processing	1	4213.0×	0.001	PARN
telomerase RNA stabilization	1	2106.5×	0.001	PARN
regulation of telomerase RNA localization to Cajal body	1	2106.5×	0.001	PARN
negative regulation of IRE1-mediated unfolded protein response	1	1404.3×	0.002	BFAR
poly(A)-dependent snoRNA 3’-end processing	1	1053.2×	0.002	PARN
miRNA catabolic process	1	936.2×	0.002	PARN
nuclear-transcribed mRNA poly(A) tail shortening	1	401.2×	0.005	PARN
female gamete generation	1	401.2×	0.005	PARN
positive regulation of telomere maintenance via telomerase	1	366.4×	0.005	PARN
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	1	234.1×	0.007	PARN
protein K63-linked ubiquitination	1	133.8×	0.011	BFAR
protein autoubiquitination	1	117.0×	0.012	BFAR
protein K48-linked ubiquitination	1	84.3×	0.015	BFAR
protein polyubiquitination	1	57.7×	0.021	BFAR
ubiquitin-dependent protein catabolic process	1	37.1×	0.031	BFAR
proteasome-mediated ubiquitin-dependent protein catabolic process	1	26.1×	0.042	BFAR
negative regulation of apoptotic process	1	17.4×	0.059	BFAR
apoptotic process	1	14.3×	0.068	BFAR

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PARN	0	0
BFAR	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PARN	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	2	PARN, BFAR

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)
PARN	1	—
BFAR	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.