congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome

Summary

congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome (MONDO:0033683) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 38

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

38 HPO clinical features (Orphanet curated; top 38 by frequency):

HPO ID	Term	Frequency
HP:0001903	Anemia	Very frequent (80-99%)
HP:0005528	Bone marrow hypocellularity	Very frequent (80-99%)
HP:0000280	Coarse facial features	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001635	Congestive heart failure	Frequent (30-79%)
HP:0001873	Thrombocytopenia	Frequent (30-79%)
HP:0001875	Decreased total neutrophil count	Frequent (30-79%)
HP:0001882	Leukopenia	Frequent (30-79%)
HP:0001888	Lymphopenia	Frequent (30-79%)
HP:0001896	Reticulocytopenia	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002788	Recurrent upper respiratory tract infections	Frequent (30-79%)
HP:0002863	Myelodysplasia	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0006872	Cerebral hypoplasia	Frequent (30-79%)
HP:0010976	Decreased total B cell count	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0031688	Erythroid dysplasia	Frequent (30-79%)
HP:0031689	Megakaryocyte dysplasia	Frequent (30-79%)
HP:0000212	Gingival overgrowth	Occasional (5-29%)
HP:0000243	Trigonocephaly	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000684	Delayed eruption of teeth	Occasional (5-29%)
HP:0000765	Abnormal thorax morphology	Occasional (5-29%)
HP:0000916	Broad clavicles	Occasional (5-29%)
HP:0000958	Dry skin	Occasional (5-29%)
HP:0000964	Eczematoid dermatitis	Occasional (5-29%)
HP:0001156	Brachydactyly	Occasional (5-29%)
HP:0001482	Subcutaneous nodule	Occasional (5-29%)
HP:0002783	Recurrent lower respiratory tract infections	Occasional (5-29%)
HP:0004991	Rhizomelic arm shortening	Occasional (5-29%)
HP:0005180	Tricuspid regurgitation	Occasional (5-29%)
HP:0005792	Short humerus	Occasional (5-29%)
HP:0010049	Short metacarpal	Occasional (5-29%)
HP:0011800	Midface retrusion	Occasional (5-29%)
HP:0012490	Panniculitis	Occasional (5-29%)
HP:0012817	Noncompaction cardiomyopathy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome
Mondo ID	MONDO:0033683
Orphanet	508542
UMLS	C5567897
MedGen	1799320
GARD	0022071
Is cancer (heuristic)	no

Also known as: MYSM1 deficiency

Data availability: 1 ClinVar variant.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › congenital hematological disorder › congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome

Related subtypes (20): congenital anemia, congenital agammaglobulinemia, sulfhemoglobinemia, congenital, congenital factor XII deficiency, leukocyte adhesion deficiency type II, thrombocytopenia-absent radius syndrome, congenital thrombotic thrombocytopenic purpura, radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome, GNE myopathy, hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency, congenital factor XI deficiency, congenital plasminogen activator inhibitor type 1 deficiency, congenital analbuminemia, macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome, constitutional neutropenia, congenital vitamin K-dependent coagulation factors deficiency, congenital secondary polycythemia, hereditary thrombocytosis with transverse limb defect, congenital factor XIII deficiency, congenital amegakaryocytic thrombocytopenia 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

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1959262	NM_001085487.3(MYSM1):c.2278C>T (p.Pro760Ser)	MYSM1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYSM1	Orphanet:508542	Congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome

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
MYSM1	HGNC:29401	ENSG00000162601	Q5VVJ2	Deubiquitinase MYSM1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYSM1	Deubiquitinase MYSM1	Metalloprotease with deubiquitinase activity that plays important regulator roles in hematopoietic stem cell function, blood cell production and immune response.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYSM1	Protease	yes		JAMM/MPN+_dom, SANT/Myb, SWIRM

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
calcaneal tendon	1
cardiac muscle of right atrium	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYSM1	252	ubiquitous	marker	calcaneal tendon, cardiac muscle of right atrium, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYSM1	6,171

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYSM1	Q5VVJ2	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 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
Metalloprotease DUBs	1	300.5×	0.013	MYSM1
Deubiquitination	1	124.1×	0.016	MYSM1
Post-translational protein modification	1	19.2×	0.069	MYSM1
Metabolism of proteins	1	12.4×	0.081	MYSM1

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
regulation of hair follicle development	1	4213.0×	0.002	MYSM1
regulation of hemopoiesis	1	1532.0×	0.003	MYSM1
pigmentation	1	702.2×	0.004	MYSM1
immune system process	1	391.9×	0.005	MYSM1
regulation of cell migration	1	157.5×	0.010	MYSM1
chromatin remodeling	1	73.0×	0.018	MYSM1
proteolysis	1	34.2×	0.033	MYSM1
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	MYSM1

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
MYSM1	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	1	MYSM1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
MYSM1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.