Thiamine-responsive megaloblastic anemia syndrome

Summary

Thiamine-responsive megaloblastic anemia syndrome (MONDO:0009575) is a disease caused by SLC19A2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC19A2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 160
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		80	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0000819	Diabetes mellitus	Very frequent (80-99%)
HP:0000980	Pallor	Very frequent (80-99%)
HP:0001254	Lethargy	Very frequent (80-99%)
HP:0001889	Megaloblastic anemia	Very frequent (80-99%)
HP:0002014	Diarrhea	Very frequent (80-99%)
HP:0002039	Anorexia	Very frequent (80-99%)
HP:0002315	Headache	Very frequent (80-99%)
HP:0003401	Paresthesia	Very frequent (80-99%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0001873	Thrombocytopenia	Frequent (30-79%)
HP:0000556	Retinal dystrophy	Occasional (5-29%)
HP:0000572	Visual loss	Occasional (5-29%)
HP:0001297	Stroke	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0001631	Atrial septal defect	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0001695	Cardiac arrest	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0006671	Paroxysmal atrial tachycardia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	thiamine-responsive megaloblastic anemia syndrome
Mondo ID	MONDO:0009575
MeSH	C536510
OMIM	249270
Orphanet	49827
DOID	DOID:0090117
SNOMED CT	237617006
UMLS	C0342287
MedGen	83338
GARD	0009210
Is cancer (heuristic)	no

Also known as: megaloblastic anaemia thiamine-responsive with diabetes mellitus and sensorineural deafness · megaloblastic anemia thiamine-responsive with diabetes mellitus and sensorineural deafness · Rogers syndrome · thiamine metabolism dysfunction syndrome 1 · thiamine responsive megaloblastic anaemia syndrome · thiamine responsive megaloblastic anemia syndrome · thiamine-responsive Anaemia syndrome · thiamine-responsive anemia syndrome · thiamine-responsive megaloblastic anemia syndrome · thiamine-responsive megaloblastic anemia with diabetes mellitus and sensorineural deafness · thiamine-responsive myelodysplasia · THMD1 · TRMA

Data availability: 160 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › disorder of metabolite absorption and transport › disorder of vitamin and non-protein cofactor absorption and transport › disorder of thiamine metabolism and transport › thiamine-responsive dysfunction syndrome › thiamine-responsive megaloblastic anemia syndrome

Related subtypes (4): Amish lethal microcephaly, biotin-responsive basal ganglia disease, progressive demyelinating neuropathy with bilateral striatal necrosis, childhood encephalopathy due to thiamine pyrophosphokinase deficiency

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

160 retrieved; paginated sample, class counts are floors:

103 uncertain significance, 18 pathogenic, 16 conflicting classifications of pathogenicity, 8 benign/likely benign, 5 benign, 5 pathogenic/likely pathogenic, 3 likely pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1178328	NM_006996.3(SLC19A2):c.697C>T (p.Gln233Ter)	SLC19A2	Pathogenic	criteria provided, multiple submitters, no conflicts
2023498	NM_006996.3(SLC19A2):c.749G>A (p.Trp250Ter)	SLC19A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2202878	NM_006996.3(SLC19A2):c.1223+1G>A	SLC19A2	Pathogenic	criteria provided, multiple submitters, no conflicts
2585580	NM_006996.3(SLC19A2):c.314G>A (p.Gly105Glu)	SLC19A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734016	NM_006996.3(SLC19A2):c.1189A>T (p.Arg397Ter)	SLC19A2	Pathogenic	criteria provided, multiple submitters, no conflicts
2734017	NM_006996.3(SLC19A2):c.759dup (p.Glu254Ter)	SLC19A2	Pathogenic	criteria provided, multiple submitters, no conflicts
2993622	NM_006996.3(SLC19A2):c.429_432del (p.Tyr144fs)	SLC19A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3255578	NM_006996.3(SLC19A2):c.566_567delinsTCT (p.Ser189fs)	SLC19A2	Pathogenic	criteria provided, single submitter
3893192	NM_006996.3(SLC19A2):c.405dup (p.Ala136fs)	SLC19A2	Pathogenic	criteria provided, single submitter
492806	NM_006996.3(SLC19A2):c.428C>T (p.Ser143Phe)	SLC19A2	Pathogenic	criteria provided, multiple submitters, no conflicts
492807	NM_006996.3(SLC19A2):c.1082G>A (p.Trp361Ter)	SLC19A2	Pathogenic	no assertion criteria provided
546109	NM_006996.3(SLC19A2):c.1001G>A (p.Gly334Asp)	SLC19A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5955	NM_006996.3(SLC19A2):c.484C>T (p.Arg162Ter)	SLC19A2	Pathogenic	criteria provided, multiple submitters, no conflicts
5956	NM_006996.3(SLC19A2):c.725del (p.Pro242fs)	SLC19A2	Pathogenic	criteria provided, single submitter
5957	NM_006996.3(SLC19A2):c.515G>A (p.Gly172Asp)	SLC19A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5958	NM_006996.3(SLC19A2):c.750G>A (p.Trp250Ter)	SLC19A2	Pathogenic	criteria provided, single submitter
5959	NM_006996.3(SLC19A2):c.885del (p.Leu296fs)	SLC19A2	Pathogenic	no assertion criteria provided
5960	NM_006996.3(SLC19A2):c.1148_1149del (p.Val383fs)	SLC19A2	Pathogenic	no assertion criteria provided
5961	NM_006996.3(SLC19A2):c.242dup (p.Tyr81Ter)	SLC19A2	Pathogenic	criteria provided, multiple submitters, no conflicts
5962	NM_006996.3(SLC19A2):c.429_430del (p.Ile145fs)	SLC19A2	Pathogenic	no assertion criteria provided
5963	NM_006996.3(SLC19A2):c.1074G>A (p.Trp358Ter)	SLC19A2	Pathogenic	no assertion criteria provided
599229	NM_006996.3(SLC19A2):c.584_585del (p.Leu195fs)	SLC19A2	Pathogenic	no assertion criteria provided
599230	NM_006996.3(SLC19A2):c.64_70del (p.Thr22fs)	SLC19A2	Pathogenic	no assertion criteria provided
3599867	NM_006996.3(SLC19A2):c.1365+1G>A	SLC19A2	Likely pathogenic	criteria provided, single submitter
3600013	NM_006996.3(SLC19A2):c.910del (p.Leu304fs)	SLC19A2	Likely pathogenic	criteria provided, single submitter
432105	NM_006996.3(SLC19A2):c.807+2T>G	SLC19A2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1526293	NM_006996.3(SLC19A2):c.104C>T (p.Ala35Val)	LOC129931894	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
876997	NM_006996.3(SLC19A2):c.42G>T (p.Ala14=)	LOC129931894	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
876998	NM_006996.3(SLC19A2):c.30G>A (p.Arg10=)	LOC129931894	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2180929	NM_006996.3(SLC19A2):c.200G>A (p.Arg67Lys)	SLC19A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
SLC19A2	Definitive	Autosomal recessive	thiamine-responsive megaloblastic anemia syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC19A2	Orphanet:49827	Thiamine-responsive megaloblastic anemia 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
SLC19A2	HGNC:10938	ENSG00000117479	O60779	Thiamine transporter 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC19A2	Thiamine transporter 1	High-affinity transporter for the intake of thiamine.

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
Transporter	1	77.8×	0.013

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC19A2	Transporter	yes		Folate_carrier, ThTr-1, MFS_trans_sf

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
gastrocnemius	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC19A2	282	ubiquitous	marker	secondary oocyte, oocyte, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC19A2	1,454

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC19A2	O60779	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
Vitamin B1 (thiamin) metabolism	1	2284.0×	0.002	SLC19A2
Metabolism of water-soluble vitamins and cofactors	1	181.3×	0.011	SLC19A2
Metabolism of vitamins and cofactors	1	116.5×	0.011	SLC19A2
Metabolism	1	11.6×	0.086	SLC19A2

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
pyridoxine transport	1	5617.3×	4e-04	SLC19A2
thiamine-containing compound metabolic process	1	5617.3×	4e-04	SLC19A2
thiamine transport	1	4213.0×	4e-04	SLC19A2
thiamine transmembrane transport	1	4213.0×	4e-04	SLC19A2
thiamine diphosphate biosynthetic process	1	3370.4×	4e-04	SLC19A2
spermatogenesis	1	35.2×	0.028	SLC19A2

Therapeutics

Drug target analysis

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

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
SLC19A2	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMPROLIUM	2	SLC19A2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC19A2	2	Functional:1, Binding:1

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

1 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)
AMPROLIUM	2	SLC19A2

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	1	SLC19A2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.