Reticular dysgenesis

Summary

Reticular dysgenesis (MONDO:0009973) is a disease caused by AK2 (GenCC Definitive), with 1 cohort gene and 3 clinical trials. Top therapeutic interventions include fludarabine phosphate.

At a glance

• Prevalence: <1 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: AK2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 194
• Phenotypes (HPO): 20
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.03	Europe	Validated
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000389	Chronic otitis media	Very frequent (80-99%)
HP:0001874	Abnormality of neutrophils	Very frequent (80-99%)
HP:0001882	Leukopenia	Very frequent (80-99%)
HP:0001903	Anemia	Very frequent (80-99%)
HP:0002014	Diarrhea	Very frequent (80-99%)
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0003287	Abnormality of mitochondrial metabolism	Very frequent (80-99%)
HP:0004313	Decreased circulating antibody level	Very frequent (80-99%)
HP:0004430	Severe combined immunodeficiency	Very frequent (80-99%)
HP:0005374	Cellular immunodeficiency	Very frequent (80-99%)
HP:0010515	Aplasia/Hypoplasia of the thymus	Very frequent (80-99%)
HP:0100806	Sepsis	Very frequent (80-99%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0001945	Fever	Frequent (30-79%)
HP:0002024	Malabsorption	Frequent (30-79%)
HP:0000988	Skin rash	Occasional (5-29%)
HP:0001944	Dehydration	Occasional (5-29%)
HP:0200042	Skin ulcer	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	reticular dysgenesis
Mondo ID	MONDO:0009973
MeSH	C538361
OMIM	267500
Orphanet	33355
DOID	DOID:0060020
NCIT	C27070
SNOMED CT	111584000
UMLS	C0272167
MedGen	124417
GARD	0008625
Is cancer (heuristic)	no

Also known as: AK2 deficiency · congenital aleukocytosis · De Vaal disease · DeVaal disease · generalised haematopoietic hypoplasia · generalized hematopoietic hypoplasia · haematopoietic hypoplasia, generalised · RD · reticular dysgenesis · SCID with leukopenia · severe combined immunodeficiency with leukopenia

Data availability: 194 ClinVar variants · 6 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › combined immunodeficiency › severe combined immunodeficiency › T-B- severe combined immunodeficiency › reticular dysgenesis

Related subtypes (15): severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, short-limb skeletal dysplasia with severe combined immunodeficiency, combined immunodeficiency with skin granulomas, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, severe combined immunodeficiency due to DCLRE1C deficiency, Omenn syndrome, DNA ligase IV deficiency, neutrophil immunodeficiency syndrome, combined immunodeficiency due to partial RAG1 deficiency, Cernunnos-XLF deficiency, severe combined immunodeficiency due to LCK deficiency, severe combined immunodeficiency due to DNA-PKcs deficiency, immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia, immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia, reticular dysgenesis-like severe combined immunodeficiency

Subtypes (1): Immunoerythromyeloid hypoplasia

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

194 retrieved; paginated sample, class counts are floors:

74 uncertain significance, 72 likely benign, 20 pathogenic, 8 likely pathogenic, 7 benign, 6 benign/likely benign, 4 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1379433	NM_001625.4(AK2):c.597_599dup (p.Tyr200Ter)	AK2	Pathogenic	criteria provided, single submitter
1436300	NM_001625.4(AK2):c.409C>T (p.Arg137Ter)	AK2	Pathogenic	criteria provided, single submitter
1453536	NM_001625.4(AK2):c.84dup (p.Gly29fs)	AK2	Pathogenic	criteria provided, multiple submitters, no conflicts
1455489	NC_000001.10:g.(?33490023)(33502429_?)del	AK2	Pathogenic	criteria provided, single submitter
1457960	NC_000001.10:g.(?33473829)(33478866_?)del	AK2	Pathogenic	criteria provided, single submitter
18250	NM_001625.4(AK2):c.636_*4953del (p.Ser213fs)	AK2	Pathogenic	no assertion criteria provided
18251	NM_001625.4(AK2):c.118del (p.Cys40fs)	AK2	Pathogenic	no assertion criteria provided
18252	NM_001625.4(AK2):c.1A>G (p.Met1Val)	AK2	Pathogenic	criteria provided, multiple submitters, no conflicts
18253	NM_001625.4(AK2):c.331-1G>A	AK2	Pathogenic	no assertion criteria provided
18254	NM_001625.4(AK2):c.453del (p.Tyr152fs)	AK2	Pathogenic	criteria provided, single submitter
18255	NM_001625.4(AK2):c.498+1G>A	AK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18256	NM_001625.4(AK2):c.494A>G (p.Asp165Gly)	AK2	Pathogenic	criteria provided, single submitter
18259	NG_016269.1:g.(5157_17324)_(17451_20188)del	AK2	Pathogenic	no assertion criteria provided
18260	NM_001625.4(AK2):c.307C>T (p.Arg103Trp)	AK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18261	NM_001625.4(AK2):c.697A>T (p.Lys233Ter)	AK2	Pathogenic	no assertion criteria provided
18262	NM_001625.4(AK2):c.25G>T (p.Glu9Ter)	AK2	Pathogenic	no assertion criteria provided
190980	NM_001625.4(AK2):c.545C>A (p.Ala182Asp)	AK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2124398	NM_001625.4(AK2):c.374_375del (p.Val125fs)	AK2	Pathogenic	criteria provided, single submitter
3247681	NC_000001.10:g.(?33480103)(33480215_?)del	AK2	Pathogenic	criteria provided, single submitter
3583653	NM_001625.4(AK2):c.3G>A (p.Met1Ile)	AK2	Pathogenic	criteria provided, single submitter
446366	NM_001625.4(AK2):c.523del (p.Arg175fs)	AK2	Pathogenic	no assertion criteria provided
661953	NM_001625.4(AK2):c.330+5G>A	AK2	Pathogenic	criteria provided, multiple submitters, no conflicts
4772296	NM_001625.4(AK2):c.66del (p.Pro23fs)	LOC129930068	Pathogenic	criteria provided, single submitter
1067803	NM_001625.4(AK2):c.614_615del (p.Gly205fs)	AK2	Likely pathogenic	criteria provided, single submitter
18258	NM_001625.4(AK2):c.556C>T (p.Arg186Cys)	AK2	Likely pathogenic	criteria provided, single submitter
3583643	NM_001625.4(AK2):c.400_401del (p.Leu134fs)	AK2	Likely pathogenic	criteria provided, single submitter
3724971	NM_001625.4(AK2):c.425+1G>T	AK2	Likely pathogenic	criteria provided, single submitter
4292743	NM_001625.4(AK2):c.523C>T (p.Arg175Ter)	AK2	Likely pathogenic	criteria provided, single submitter
4735984	NM_001625.4(AK2):c.219+1G>A	AK2	Likely pathogenic	criteria provided, single submitter
657641	NM_001625.4(AK2):c.636_*791del (p.Ala212_Ter240delinsXaa)	AK2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
AK2	Definitive	Autosomal recessive	reticular dysgenesis	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AK2	Orphanet:33355	Reticular dysgenesis

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
AK2	HGNC:362	ENSG00000004455	P54819	Adenylate kinase 2, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AK2	Adenylate kinase 2, mitochondrial	Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP.

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AK2	Kinase	yes	2.7.4.3	Adenylat/UMP-CMP_kin, Adenyl_kin_sub, Adenylate_kinase_lid-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
metanephros cortex	1
mucosa of transverse colon	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AK2	270	ubiquitous	marker	rectum, mucosa of transverse colon, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AK2	4,022

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AK2	P54819	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Interconversion of nucleotide di- and triphosphates	1	356.9×	0.005	AK2
Metabolism of nucleotides	1	300.5×	0.005	AK2
Metabolism	1	11.6×	0.086	AK2

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
ADP biosynthetic process	1	2407.4×	8e-04	AK2
AMP metabolic process	1	1872.4×	8e-04	AK2
nucleobase-containing small molecule interconversion	1	1685.2×	8e-04	AK2
ATP metabolic process	1	468.1×	0.002	AK2

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
AK2	1	1

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CUDC-101	1	AK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
AK2	6	Binding:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AK2	2.7.4.3	adenylate kinase

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)
CUDC-101	1	AK2

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	AK2
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: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01186913	Not specified	ENROLLING_BY_INVITATION	Natural History Study of SCID Disorders
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT01346150	Not specified	UNKNOWN	Patients Treated for SCID (1968-Present)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLUDARABINE PHOSPHATE	4	1