Congenital dyserythropoietic anemia type 4

Summary

Congenital dyserythropoietic anemia type 4 (MONDO:0013355) is a disease caused by KLF1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KLF1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 43

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital dyserythropoietic anemia type 4
Mondo ID	MONDO:0013355
OMIM	613673
Orphanet	293825
DOID	DOID:0111400
SNOMED CT	719453009
UMLS	C3150926
MedGen	462276
GARD	0017344
Is cancer (heuristic)	no

Also known as: anemia, congenital dyserythropoietic, type IV · CDA due to KLF1 mutation · CDA IV · CDA type 4 · CDA type IV · CDAN4 · congenital dyserythropoietic anemia due to KLF1 mutation · congenital dyserythropoietic anemia type 4 · dyserythropoietic anemia, congenital, type IV

Data availability: 43 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › congenital anemia › congenital dyserythropoietic anemia type 4

Related subtypes (7): myopathy, lactic acidosis, and sideroblastic anemia, congenital nonspherocytic hemolytic anemia, congenital dyserythropoietic anemia type 3, congenital dyserythropoietic anemia type 2, severe congenital hypochromic anemia with ringed sideroblasts, Fanconi anemia, congenital dyserythropoietic anemia type 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

43 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 8 conflicting classifications of pathogenicity, 8 benign, 6 benign/likely benign, 4 pathogenic, 2 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2087	NM_000159.4(GCDH):c.91+5G>T	GCDH	Pathogenic	criteria provided, multiple submitters, no conflicts
56891	NM_006563.5(KLF1):c.892G>C (p.Ala298Pro)	KLF1	Pathogenic	criteria provided, multiple submitters, no conflicts
56892	NM_006563.5(KLF1):c.1012C>T (p.Pro338Ser)	KLF1	Pathogenic	no assertion criteria provided
18447	NM_006563.5(KLF1):c.973G>A (p.Glu325Lys)	LOC117125591	Pathogenic	criteria provided, multiple submitters, no conflicts
100801	NM_006563.5(KLF1):c.913+1G>A	KLF1	Likely pathogenic	criteria provided, single submitter
3765538	NM_006563.5(KLF1):c.858C>A (p.Cys286Ter)	KLF1	Likely pathogenic	criteria provided, single submitter
1693737	NM_006563.5(KLF1):c.649C>T (p.Gln217Ter)	KLF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328313	NM_006563.5(KLF1):c.690C>T (p.Ala230=)	KLF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328315	NM_006563.5(KLF1):c.606G>A (p.Gly202=)	KLF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328321	NM_006563.5(KLF1):c.311C>T (p.Ala104Val)	KLF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328323	NM_006563.5(KLF1):c.259C>G (p.Pro87Ala)	KLF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
891355	NM_006563.5(KLF1):c.803G>T (p.Arg268Leu)	KLF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
891356	NM_006563.5(KLF1):c.757G>A (p.Glu253Lys)	KLF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
892550	NM_006563.5(KLF1):c.541T>A (p.Tyr181Asn)	LOC130063673	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
328304	NM_006563.5(KLF1):c.*367C>G	KLF1	Uncertain significance	criteria provided, single submitter
328305	NM_006563.5(KLF1):c.*311A>G	KLF1	Uncertain significance	criteria provided, single submitter
328309	NM_006563.5(KLF1):c.*263C>T	KLF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
328318	NM_006563.5(KLF1):c.478G>A (p.Glu160Lys)	KLF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
328319	NM_006563.5(KLF1):c.353G>A (p.Gly118Asp)	KLF1	Uncertain significance	criteria provided, single submitter
328324	NM_006563.5(KLF1):c.255G>A (p.Pro85=)	KLF1	Uncertain significance	criteria provided, single submitter
889116	NM_006563.5(KLF1):c.*312G>C	KLF1	Uncertain significance	criteria provided, single submitter
889805	NM_006563.5(KLF1):c.*2C>T	KLF1	Uncertain significance	criteria provided, single submitter
891357	NM_006563.5(KLF1):c.676G>A (p.Ala226Thr)	KLF1	Uncertain significance	criteria provided, single submitter
892551	NM_006563.5(KLF1):c.409C>T (p.Arg137Cys)	KLF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
931601	NM_006563.5(KLF1):c.1079G>A (p.Arg360His)	KLF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
891353	NM_006563.5(KLF1):c.1036C>T (p.Arg346Cys)	LOC117125591	Uncertain significance	criteria provided, single submitter
891354	NM_006563.5(KLF1):c.1016T>C (p.Phe339Ser)	LOC117125591	Uncertain significance	criteria provided, single submitter
3242138	NM_006563.5(KLF1):c.587C>T (p.Pro196Leu)	LOC130063673	Uncertain significance	criteria provided, single submitter
260001	NM_006563.5(KLF1):c.304T>C (p.Ser102Pro)	KLF1	Benign	criteria provided, multiple submitters, no conflicts
328303	NM_006563.5(KLF1):c.*454C>G	KLF1	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 4 · 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
KLF1	Definitive	Autosomal dominant	congenital dyserythropoietic anemia type 4	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KLF1	Orphanet:251380	Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
KLF1	Orphanet:293825	Congenital dyserythropoietic anemia type IV
KLF1	Orphanet:46532	Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
GCDH	Orphanet:25	Glutaryl-CoA dehydrogenase deficiency

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
KLF1	HGNC:6345	ENSG00000105610	Q13351	Krueppel-like factor 1	gencc,clinvar
GCDH	HGNC:4189	ENSG00000105607	Q92947	Glutaryl-CoA dehydrogenase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KLF1	Krueppel-like factor 1	Transcription regulator of erythrocyte development that probably serves as a general switch factor during erythropoiesis.
GCDH	Glutaryl-CoA dehydrogenase, mitochondrial	Catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KLF1	Transcription factor	no		Znf_C2H2_type, EKLF_TAD2, EKLF_TAD1
GCDH	Enzyme (other)	yes	1.3.8.6	Acyl-CoA_DH_CS, AcylCoA_DH/ox_M, AcylCo_DH/oxidase_C

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
blood	1
bone marrow	1
trabecular bone tissue	1
apex of heart	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KLF1	86	tissue_specific	marker	trabecular bone tissue, bone marrow, blood
GCDH	259	ubiquitous	marker	right lobe of liver, liver, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GCDH	2,573
KLF1	1,682

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GCDH	Q92947	4
KLF1	Q13351	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Lysine catabolism	1	1142.0×	9e-04	GCDH

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
obsolete L-tryptophan metabolic process	1	2808.7×	0.004	GCDH
fatty-acyl-CoA biosynthetic process	1	936.2×	0.004	GCDH
fatty acid beta-oxidation using acyl-CoA dehydrogenase	1	702.2×	0.004	GCDH
cellular response to endothelin	1	702.2×	0.004	KLF1
maternal process involved in female pregnancy	1	468.1×	0.005	KLF1
protein destabilization	1	145.3×	0.012	KLF1
erythrocyte differentiation	1	133.8×	0.012	KLF1
ubiquitin-dependent protein catabolic process	1	37.1×	0.037	KLF1
regulation of DNA-templated transcription	1	15.8×	0.076	KLF1
positive regulation of DNA-templated transcription	1	14.0×	0.077	KLF1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	KLF1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GCDH	BALSALAZIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GCDH	1	4
KLF1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BALSALAZIDE	4	GCDH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GCDH	15	Binding:14, ADMET:1
KLF1	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GCDH	1.3.8.6	glutaryl-CoA dehydrogenase (ETF)

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

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)
BALSALAZIDE	4	GCDH

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GCDH
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	KLF1

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)
KLF1	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.