Poikiloderma with neutropenia

Summary

Poikiloderma with neutropenia (MONDO:0011405) is a disease caused by USB1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: USB1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 52

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	poikiloderma with neutropenia
Mondo ID	MONDO:0011405
OMIM	604173
Orphanet	221046
DOID	DOID:0060551
NCIT	C177535
UMLS	C1858723
MedGen	388129
GARD	0004085
NORD	2022
Is cancer (heuristic)	no

Also known as: Clericuzio type poikiloderma with neutropenia · PN · poikiloderma with neutropenia · poikiloderma with neutropenia Clericuzio type · poikiloderma with neutropenia, Clericuzio type

Data availability: 52 ClinVar variants · 4 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › leukocyte disorder › leukopenia › agranulocytosis › neutropenia › constitutional neutropenia › poikiloderma with neutropenia

Related subtypes (12): cyclic hematopoiesis, Chediak-Higashi syndrome, Cohen syndrome, glycogen storage disease Ib, Lichtenstein syndrome, Barth syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome 2, primary immunodeficiency syndrome due to p14 deficiency, neutropenia-monocytopenia-deafness syndrome, severe congenital neutropenia, WHIM syndrome 1

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

52 retrieved; paginated sample, class counts are floors:

18 uncertain significance, 15 pathogenic, 6 not provided, 3 benign, 3 likely pathogenic, 3 conflicting classifications of pathogenicity, 2 likely benign, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071879	NM_024598.4(USB1):c.63del (p.Met22fs)	USB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1326260	NM_024598.3:c.334dup	USB1	Pathogenic	no assertion criteria provided
156347	NM_024598.4(USB1):c.243G>A (p.Trp81Ter)	USB1	Pathogenic	no assertion criteria provided
18399	NM_024598.4(USB1):c.179del (p.Pro60fs)	USB1	Pathogenic	no assertion criteria provided
201	NM_024598.4(USB1):c.504-2A>C	USB1	Pathogenic	no assertion criteria provided
202	NM_024598.4(USB1):c.683_693+1del	USB1	Pathogenic	no assertion criteria provided
203	NM_024598.4(USB1):c.502A>G (p.Arg168Gly)	USB1	Pathogenic	no assertion criteria provided
496744	NM_024598.4(USB1):c.499del (p.Thr167fs)	USB1	Pathogenic	criteria provided, single submitter
496745	NM_024598.4(USB1):c.531del (p.His179fs)	USB1	Pathogenic	no assertion criteria provided
496746	NM_024598.4(USB1):c.541C>T (p.Gln181Ter)	USB1	Pathogenic	no assertion criteria provided
496748	NM_024598.4(USB1):c.673C>T (p.Gln225Ter)	USB1	Pathogenic	criteria provided, single submitter
496749	NM_024598.4(USB1):c.693+1G>T	USB1	Pathogenic	criteria provided, single submitter
496750	NM_024598.4(USB1):c.176_177del (p.Gly59fs)	USB1	Pathogenic	criteria provided, single submitter
496754	NM_024598.4(USB1):c.266-1G>A	USB1	Pathogenic	criteria provided, multiple submitters, no conflicts
496757	NM_024598.4(USB1):c.415C>T (p.Gln139Ter)	USB1	Pathogenic	criteria provided, single submitter
496761	NM_024598.4(USB1):c.489_492del (p.Asn163fs)	USB1	Pathogenic	criteria provided, single submitter
496747	NM_024598.4(USB1):c.623A>G (p.His208Arg)	USB1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
559873	NM_024598.4(USB1):c.345del (p.Arg115_Met116insTer)	USB1	Likely pathogenic	criteria provided, single submitter
800958	NM_024598.4(USB1):c.370T>C (p.Ser124Pro)	USB1	Likely pathogenic	no assertion criteria provided
496759	NM_024598.4(USB1):c.518T>G (p.Leu173Arg)	USB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626043	NM_024598.4(USB1):c.641G>A (p.Cys214Tyr)	USB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
784580	NM_024598.4(USB1):c.512T>C (p.Ile171Thr)	USB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1444921	NM_024598.4(USB1):c.1A>G (p.Met1Val)	LOC112469011	Uncertain significance	criteria provided, multiple submitters, no conflicts
3581124	NM_024598.4(USB1):c.17del (p.Leu6fs)	LOC112469011	Uncertain significance	criteria provided, single submitter
1409669	NM_024598.4(USB1):c.74G>C (p.Arg25Thr)	LOC130059131	Uncertain significance	criteria provided, multiple submitters, no conflicts
1013673	NM_024598.4(USB1):c.209G>A (p.Arg70Gln)	USB1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028327	NM_024598.4(USB1):c.253G>A (p.Val85Ile)	USB1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032181	NM_024598.4(USB1):c.796T>G (p.Ter266Gly)	USB1	Uncertain significance	criteria provided, single submitter
1051365	NM_024598.4(USB1):c.646G>A (p.Gly216Ser)	USB1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1057267	NM_024598.4(USB1):c.335G>A (p.Arg112Gln)	USB1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
USB1	Definitive	Autosomal recessive	poikiloderma with neutropenia	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
USB1	Orphanet:1775	Dyskeratosis congenita
USB1	Orphanet:221046	Poikiloderma with neutropenia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
USB1	HGNC:25792	ENSG00000103005	Q9BQ65	U6 snRNA phosphodiesterase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
USB1	U6 snRNA phosphodiesterase 1	3’-5’ RNA exonuclease that trims the 3’ end of oligo(U) and oligo(A) tracts of the pre-U6 small nuclear RNA (snRNA) molecule, leading to the formation of a mature U6 snRNA 3’ end-terminated with a 2’,3’-cyclic phosphate.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
USB1	Other/Unknown	no		Usb1

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
USB1	259	ubiquitous	marker	granulocyte, leukocyte, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
USB1	570

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
USB1	Q9BQ65	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
U6 snRNA 3’-end processing	1	8426.0×	4e-04	USB1
snRNA 3’-end processing	1	1296.3×	0.001	USB1
RNA splicing	1	88.2×	0.011	USB1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
USB1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	USB1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
USB1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.