Myelodysplastic syndrome with ring sideroblasts

Summary

Myelodysplastic syndrome with ring sideroblasts (MONDO:0019157) is a disease with 1 cohort gene and 20 clinical trials. Top therapeutic interventions include fludarabine phosphate, cyclophosphamide anhydrous, and abatacept.

At a glance

• Prevalence: <1 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 2
• Phenotypes (HPO): 28
• Clinical trials: 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.09	Europe	Validated
Point prevalence	1-9 / 100 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0004828	Refractory anemia with ringed sideroblasts	Very frequent (80-99%)
HP:0010972	Anemia of inadequate production	Very frequent (80-99%)
HP:0000980	Pallor	Frequent (30-79%)
HP:0001895	Normochromic anemia	Frequent (30-79%)
HP:0001897	Normocytic anemia	Frequent (30-79%)
HP:0012132	Erythroid hyperplasia	Frequent (30-79%)
HP:0200143	Megaloblastic erythroid hyperplasia	Frequent (30-79%)
HP:0001231	Abnormal fingernail morphology	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0001931	Hypochromic anemia	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002863	Myelodysplasia	Occasional (5-29%)
HP:0011447	Hyposegmentation of neutrophil nuclei	Occasional (5-29%)
HP:0012136	Dysplastic granulopoesis	Occasional (5-29%)
HP:0012137	Abnormal number of granulocyte precursors	Occasional (5-29%)
HP:0012143	Abnormal megakaryocyte morphology	Occasional (5-29%)
HP:0031035	Chronic infection	Occasional (5-29%)
HP:0001635	Congestive heart failure	Very rare (<1-4%)
HP:0001875	Decreased total neutrophil count	Very rare (<1-4%)
HP:0001876	Pancytopenia	Very rare (<1-4%)
HP:0001892	Abnormal bleeding	Very rare (<1-4%)
HP:0001894	Thrombocytosis	Very rare (<1-4%)
HP:0001913	Granulocytopenia	Very rare (<1-4%)
HP:0001974	Leukocytosis	Very rare (<1-4%)
HP:0004808	Acute myeloid leukemia	Very rare (<1-4%)
HP:0005513	Increased megakaryocyte count	Very rare (<1-4%)
HP:0005528	Bone marrow hypocellularity	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	myelodysplastic syndrome with ring sideroblasts
Mondo ID	MONDO:0019157
EFO	EFO:0003812
Orphanet	75564
ICD-10-CM	D46.1
ICD-11	1793160341
NCIT	C4036
SNOMED CT	109998009
UMLS	C4016601
MedGen	865038
GARD	0008249
Is cancer (heuristic)	no

Also known as: acquired idiopathic sideroblastic anaemia · acquired idiopathic sideroblastic anemia · AISA · MDS with ring sideroblasts · MDS-RS · myelodysplastic syndrome with Ring sideroblasts · primary acquired sideroblastic anaemia · primary acquired sideroblastic anemia · Pure sideroblastic Anaemia · Pure sideroblastic Anemia · RARS · refractory Anaemia with Ring sideroblasts · refractory Anaemia with ringed sideroblasts · refractory anaemia with ringed sideroblasts · refractory Anemia with Ring sideroblasts · refractory Anemia with ringed sideroblasts · refractory anemia with ringed sideroblasts

Data availability: 2 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › sideroblastic anemia › myelodysplastic syndrome with ring sideroblasts

Related subtypes (2): pyridoxine-responsive sideroblastic anemia, inherited sideroblastic anemia

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

2 retrieved; paginated sample, class counts are floors:

2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
9664	NC_012920.1(MT-CO1):m.6742T>C	MT-CO1	Uncertain significance	reviewed by expert panel
9665	NC_012920.1(MT-CO1):m.6721T>C	MT-CO1	Uncertain significance	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MT-CO1	Orphanet:104	Leber hereditary optic neuropathy
MT-CO1	Orphanet:254905	Isolated cytochrome C oxidase deficiency
MT-CO1	Orphanet:550	MELAS
MT-CO1	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness
MT-CO1	Orphanet:99845	Genetic recurrent myoglobinuria

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
MT-CO1	HGNC:7419	ENSG00000198804	P00395	Cytochrome c oxidase subunit 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MT-CO1	Cytochrome c oxidase subunit 1	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MT-CO1	Enzyme (other)	yes	7.1.1.9	Cyt_C_Oxase_1, Cyt_c_Oxase_su1_BS, Cyt_c_oxase-like_su1_dom

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
rectum	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MT-CO1	134	ubiquitous	marker	granulocyte, stromal cell of endometrium, rectum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MT-CO1	3,547

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MT-CO1	P00395	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Complex IV assembly	1	228.4×	0.011	MT-CO1
Cytoprotection by HMOX1	1	184.2×	0.011	MT-CO1
TP53 Regulates Metabolic Genes	1	129.8×	0.011	MT-CO1
Mitochondrial protein degradation	1	114.2×	0.011	MT-CO1
Mitochondrial translation termination	1	109.8×	0.011	MT-CO1
Respiratory electron transport	1	95.2×	0.011	MT-CO1

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
response to copper ion	1	1532.0×	0.003	MT-CO1
respiratory electron transport chain	1	842.6×	0.003	MT-CO1
mitochondrial electron transport, cytochrome c to oxygen	1	766.0×	0.003	MT-CO1
response to electrical stimulus	1	648.1×	0.003	MT-CO1
cellular respiration	1	432.1×	0.004	MT-CO1
cerebellum development	1	358.6×	0.004	MT-CO1
aerobic respiration	1	247.8×	0.005	MT-CO1
response to oxidative stress	1	130.6×	0.009	MT-CO1
response to hypoxia	1	95.8×	0.010	MT-CO1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MT-CO1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MT-CO1	19	Binding:12, Functional:4, ADMET:2, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MT-CO1	7.1.1.9	cytochrome-c oxidase

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	MT-CO1
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)
MT-CO1	19	—

Clinical trials & evidence

Clinical trials

Clinical trials: 20.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	8
PHASE1	5
PHASE1/PHASE2	4
Not specified	2
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00002798	PHASE3	COMPLETED	Combination Chemotherapy With or Without Bone Marrow Transplantation in Treating Children With Acute Myelogenous Leukemia or Myelodysplastic Syndrome
NCT00392353	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Vorinostat and Azacitidine in Treating Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia
NCT00015990	PHASE2	COMPLETED	Thalidomide in Treating Patients With Myelodysplastic Syndrome
NCT00027820	PHASE1/PHASE2	COMPLETED	Total-Body Irradiation and Fludarabine Phosphate Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies or Kidney Cancer
NCT00078858	PHASE1/PHASE2	COMPLETED	Mycophenolate Mofetil and Cyclosporine in Reducing Graft-Versus-Host Disease in Patients With Hematologic Malignancies or Metastatic Kidney Cancer Undergoing Donor Stem Cell Transplant
NCT00119366	PHASE2	TERMINATED	Iodine I 131 Monoclonal Antibody BC8, Fludarabine Phosphate, Total Body Irradiation, and Donor Stem Cell Transplant Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients With Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome
NCT00397813	PHASE2	COMPLETED	Fludarabine Phosphate and Total Body Irradiation Followed by a Donor Peripheral Stem Cell Transplant in Treating Patients With Myelodysplastic Syndromes or Myeloproliferative Disorders
NCT00462605	PHASE2	COMPLETED	MS-275 and GM-CSF in Treating Patients With Myelodysplastic Syndrome and/or Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphocytic Leukemia
NCT01012492	PHASE2	COMPLETED	Pilot of Abatacept-based Immunosuppression for Prevention of Acute GvHD During Unrelated Donor HCT
NCT01165996	PHASE1/PHASE2	COMPLETED	Differentiation Therapy With Decitabine in Treating Patients With Myelodysplastic Syndrome
NCT01384513	PHASE2	COMPLETED	A Two-Step Approach to Reduced Intensity Bone Marrow Transplant for Patients With Hematological Malignancies
NCT01789255	PHASE2	COMPLETED	Vorinostat, Tacrolimus, and Methotrexate in Preventing GVHD After Stem Cell Transplant in Patients With Hematological Malignancies
NCT02566304	PHASE2	COMPLETED	Reduced Intensity Chemotherapy and Radiation Therapy Before Donor Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT00005845	PHASE1	COMPLETED	Tipifarnib in Treating Patients With Myelodysplastic Syndromes
NCT00008177	PHASE1	COMPLETED	Radiolabeled Monoclonal Antibody Therapy, Fludarabine Phosphate, and Low-Dose Total-Body Irradiation Followed by Donor Stem Cell Transplant and Immunosuppression Therapy in Treating Older Patients With Advanced Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes
NCT00012376	PHASE1	COMPLETED	Chemotherapy Plus Sargramostim in Treating Patients With Refractory Myeloid Cancer
NCT00104962	PHASE1	COMPLETED	Lenalidomide in Treating Young Patients With Relapsed or Refractory Solid Tumors or Myelodysplastic Syndromes
NCT00589316	PHASE1	TERMINATED	Iodine I 131 Monoclonal Antibody BC8, Fludarabine Phosphate, Cyclophosphamide, Total-Body Irradiation and Donor Bone Marrow Transplant in Treating Patients With Advanced Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or High-Risk Myelodysplastic Syndrome
NCT04869683	Not specified	RECRUITING	Biocollection in MyeloDysplastic Syndrome (P-MDS)
NCT01146210	Not specified	COMPLETED	Identification of de Novo Fanconi Anemia in Younger Patients With Newly Diagnosed Acute Myeloid Leukemia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLUDARABINE PHOSPHATE	4	9
CYCLOPHOSPHAMIDE ANHYDROUS	4	3
ABATACEPT	4	1
ALDESLEUKIN	4	1
ASPARAGINASE	4	1
AZACITIDINE	4	1
BUSULFAN	4	1
CYTARABINE	4	1
DAUNORUBICIN HYDROCHLORIDE	4	1
DECITABINE	4	1
ETOPOSIDE	4	1
FILGRASTIM	4	1
HYDROCORTISONE	4	1
IDARUBICIN	4	1
THIOGUANINE	4	1
VORINOSTAT	4	1
ENTINOSTAT	3	1
TIPIFARNIB	3	1
BRYOSTATIN 1	2	1
ZEBULARINE	0	1