Sengers syndrome

Summary

Sengers syndrome (MONDO:0008922) is a disease caused by AGK (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: AGK (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 303
• Phenotypes (HPO): 10

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		40	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0000486	Strabismus	Very frequent (80-99%)
HP:0000518	Cataract	Very frequent (80-99%)
HP:0000639	Nystagmus	Very frequent (80-99%)
HP:0001639	Hypertrophic cardiomyopathy	Very frequent (80-99%)
HP:0003128	Lactic acidosis	Very frequent (80-99%)
HP:0003198	Myopathy	Very frequent (80-99%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0000501	Glaucoma	Occasional (5-29%)
HP:0000512	Abnormal electroretinogram	Occasional (5-29%)
HP:0001131	Corneal dystrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Sengers syndrome
Mondo ID	MONDO:0008922
MeSH	C538280
OMIM	212350
Orphanet	1369
DOID	DOID:0080132
ICD-11	22670425
SNOMED CT	717812000
UMLS	C1859317
MedGen	395228
GARD	0001142
Is cancer (heuristic)	no

Also known as: cardiomyopathic mitochondrial DNA depletion syndrome 10 · cataract and cardiomyopathy · mitochondrial DNA depletion syndrome 10 · Sengers syndrome

Data availability: 303 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial membrane transport disorder › mitochondrial substrate carrier disorder › Sengers syndrome

Related subtypes (4): cardiomyopathy-hypotonia-lactic acidosis syndrome, developmental and epileptic encephalopathy, 39, combined oxidative phosphorylation deficiency 28, sideroblastic anemia 3

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

303 retrieved; paginated sample, class counts are floors:

117 likely benign, 92 uncertain significance, 34 pathogenic, 24 conflicting classifications of pathogenicity, 13 likely pathogenic, 10 benign/likely benign, 9 benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033892	NM_018238.4(AGK):c.1039_1042dup (p.Ile348fs)	AGK	Pathogenic	criteria provided, single submitter
1070308	NM_018238.4(AGK):c.1035dup (p.Ile346fs)	AGK	Pathogenic	criteria provided, single submitter
1351396	NM_018238.4(AGK):c.412C>T (p.Arg138Ter)	AGK	Pathogenic	criteria provided, multiple submitters, no conflicts
1415657	NM_018238.4(AGK):c.632G>A (p.Trp211Ter)	AGK	Pathogenic	criteria provided, single submitter
1456624	NC_000007.13:g.(?141255267)(141301100_?)del	AGK	Pathogenic	criteria provided, single submitter
1705023	NM_018238.4(AGK):c.518+1G>A	AGK	Pathogenic	criteria provided, multiple submitters, no conflicts
2021455	NM_018238.4(AGK):c.1166_1167dup (p.Tyr390fs)	AGK	Pathogenic	criteria provided, single submitter
209129	NM_018238.4(AGK):c.424-3C>G	AGK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
209130	NM_018238.4(AGK):c.409C>T (p.Arg137Ter)	AGK	Pathogenic	criteria provided, multiple submitters, no conflicts
2120043	NM_018238.4(AGK):c.860G>A (p.Trp287Ter)	AGK	Pathogenic	criteria provided, single submitter
214076	NM_018238.4(AGK):c.3G>C (p.Met1Ile)	AGK	Pathogenic	criteria provided, single submitter
2426458	NC_000007.13:g.(?141292926)(141293005_?)del	AGK	Pathogenic	criteria provided, single submitter
2580922	NM_018238.4(AGK):c.628C>T (p.Arg210Ter)	AGK	Pathogenic	criteria provided, single submitter
280255	NM_018238.4(AGK):c.1047-2A>T	AGK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2921399	NM_018238.4(AGK):c.356dup (p.Ile120fs)	AGK	Pathogenic	criteria provided, single submitter
2931348	NM_018238.4(AGK):c.25C>T (p.Arg9Ter)	AGK	Pathogenic	criteria provided, single submitter
2947480	NM_018238.4(AGK):c.388G>T (p.Glu130Ter)	AGK	Pathogenic	criteria provided, single submitter
2952828	NM_018238.4(AGK):c.409del (p.Arg137fs)	AGK	Pathogenic	criteria provided, single submitter
30823	NM_018238.4(AGK):c.141+2T>C	AGK	Pathogenic	no assertion criteria provided
30824	NM_018238.4(AGK):c.1170T>G (p.Tyr390Ter)	AGK	Pathogenic	no assertion criteria provided
30825	NM_018238.4(AGK):c.975+1G>T	AGK	Pathogenic	no assertion criteria provided
30827	NM_018238.4(AGK):c.517C>T (p.Gln173Ter)	AGK	Pathogenic	no assertion criteria provided
30828	NM_018238.4(AGK):c.306T>G (p.Tyr102Ter)	AGK	Pathogenic	no assertion criteria provided
30829	NM_018238.4(AGK):c.841C>T (p.Arg281Ter)	AGK	Pathogenic	criteria provided, multiple submitters, no conflicts
30830	NM_018238.4(AGK):c.672C>G (p.Tyr224Ter)	AGK	Pathogenic	no assertion criteria provided
30831	NM_018238.4(AGK):c.1131+5G>A	AGK	Pathogenic	no assertion criteria provided
3245750	NC_000007.13:g.(?140434397)(141759786_?)del	AGK	Pathogenic	criteria provided, single submitter
3245751	NC_000007.13:g.(?141351305)(141352724_?)del	AGK	Pathogenic	criteria provided, single submitter
3381949	NM_018238.4(AGK):c.871C>T (p.Gln291Ter)	AGK	Pathogenic	criteria provided, single submitter
3756552	NM_018238.4(AGK):c.269T>G (p.Leu90Ter)	AGK	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 24 · Orphanet: 5 · 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
AGK	Definitive	Autosomal recessive	Sengers syndrome	6
SLC25A4	Supportive	Autosomal recessive	Sengers syndrome	14
TKFC	Supportive	Autosomal recessive	Sengers syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AGK	Orphanet:1369	Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome
AGK	Orphanet:98994	Total early-onset cataract
TKFC	Orphanet:1369	Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome
SLC25A4	Orphanet:1369	Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome
SLC25A4	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AGK	HGNC:21869	ENSG00000006530	Q53H12	Acylglycerol kinase, mitochondrial	gencc,clinvar
TKFC	HGNC:24552	ENSG00000149476	Q3LXA3	Triokinase/FMN cyclase	gencc,clinvar
SLC25A4	HGNC:10990	ENSG00000151729	P12235	ADP/ATP translocase 1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AGK	Acylglycerol kinase, mitochondrial	Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively.
TKFC	Triokinase/FMN cyclase	Catalyzes both the phosphorylation of dihydroxyacetone and of glyceraldehyde, and the splitting of ribonucleoside diphosphate-X compounds among which FAD is the best substrate.
SLC25A4	ADP/ATP translocase 1	ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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	2	18.5×	0.008
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AGK	Kinase	yes	2.7.1.94	Diacylglycerol_kinase_cat_dom, NAD/diacylglycerol_kinase_sf, ATP-NAD_kinase_N
TKFC	Kinase	yes	2.7.1.28	DhaK_dom, DhaL_dom, DhaK_ATP
SLC25A4	Other/Unknown	no		MCP, ADT_euk_type, MCP_transmembrane

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
cerebellar cortex	1
cerebellar hemisphere	1
left adrenal gland cortex	1
right adrenal gland	1
right adrenal gland cortex	1
apex of heart	1
heart right ventricle	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AGK	161	ubiquitous	marker	adrenal tissue, cerebellar hemisphere, cerebellar cortex
TKFC	213	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland cortex
SLC25A4	292	ubiquitous	marker	left ventricle myocardium, heart right ventricle, apex of heart

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC25A4	3,085
AGK	2,341
TKFC	1,606

Intra-cohort edges

A	B	Sources
AGK	SLC25A4	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AGK	Q53H12	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TKFC	Q3LXA3	95.40
SLC25A4	P12235	92.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitochondrial Uncoupling	1	1903.3×	0.010	SLC25A4
Vpr-mediated induction of apoptosis by mitochondrial outer membrane permeabilization	1	1268.9×	0.010	SLC25A4
Fructose catabolism	1	761.3×	0.011	TKFC
Interactions of Vpr with host cellular proteins	1	475.8×	0.014	SLC25A4
Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane	1	317.2×	0.016	SLC25A4
Glycerophospholipid biosynthesis	1	112.0×	0.028	AGK
Host Interactions of HIV factors	1	112.0×	0.028	SLC25A4
Transport of vitamins, nucleosides, and related molecules	1	90.6×	0.028	SLC25A4
SARS-CoV-1 activates/modulates innate immune responses	1	90.6×	0.028	TKFC
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1	84.6×	0.028	TKFC
Oncogenic MAPK signaling	1	82.8×	0.028	AGK
Phospholipid metabolism	1	66.8×	0.029	AGK
Protein localization	1	63.4×	0.029	SLC25A4
Signaling by BRAF and RAF1 fusions	1	56.8×	0.029	AGK
Mitochondrial protein import	1	56.0×	0.029	SLC25A4
Disease	2	8.7×	0.029	AGK, SLC25A4
Metabolism	2	7.7×	0.032	AGK, SLC25A4
HIV Infection	1	39.6×	0.036	SLC25A4
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	29.7×	0.044	TKFC
Aerobic respiration and respiratory electron transport	1	29.5×	0.044	SLC25A4
SLC-mediated transmembrane transport	1	19.7×	0.061	SLC25A4
Diseases of signal transduction by growth factor receptors and second messengers	1	18.9×	0.061	AGK
Metabolism of lipids	1	10.5×	0.102	AGK
Viral Infection Pathways	1	10.3×	0.102	SLC25A4
Transport of small molecules	1	8.4×	0.116	SLC25A4
Infectious disease	1	8.3×	0.116	SLC25A4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete fructose catabolic process to hydroxyacetone phosphate and glyceraldehyde-3-phosphate	1	1872.4×	0.004	TKFC
negative regulation of MDA-5 signaling pathway	1	1404.3×	0.004	TKFC
mitochondrial ADP transmembrane transport	1	1123.5×	0.004	SLC25A4
glycerol catabolic process	1	802.5×	0.004	TKFC
ADP transport	1	702.2×	0.004	SLC25A4
glycerolipid metabolic process	1	702.2×	0.004	AGK
carbohydrate phosphorylation	1	702.2×	0.004	TKFC
mitochondrial ATP transmembrane transport	1	624.1×	0.004	SLC25A4
lipid phosphorylation	1	561.7×	0.004	AGK
regulation of mitochondrial membrane permeability	1	468.1×	0.004	SLC25A4
protein insertion into mitochondrial inner membrane	1	432.1×	0.004	AGK
positive regulation of mitophagy	1	374.5×	0.004	SLC25A4
sphingosine biosynthetic process	1	351.1×	0.004	AGK
negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway	1	351.1×	0.004	SLC25A4
adaptive thermogenesis	1	351.1×	0.004	SLC25A4
negative regulation of necroptotic process	1	330.4×	0.004	SLC25A4
apoptotic mitochondrial changes	1	295.6×	0.004	SLC25A4
regulation of innate immune response	1	216.1×	0.005	TKFC
ceramide biosynthetic process	1	140.4×	0.008	AGK
generation of precursor metabolites and energy	1	114.6×	0.009	SLC25A4
carbohydrate metabolic process	1	45.3×	0.022	TKFC

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 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
AGK	0	0
TKFC	0	0
SLC25A4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
AGK	19	Binding:19
TKFC	1	Binding:1
SLC25A4	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AGK	2.7.1.94	acylglycerol kinase
TKFC	2.7.1.28, 2.7.1.29, 4.6.1.15	triokinase, glycerone kinase, FAD-AMP lyase (cyclizing)

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	AGK
D	Druggable family + AlphaFold only, no drug	1	TKFC
E	Difficult family or no structure, no drug	1	SLC25A4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AGK	19	—
TKFC	1	—
SLC25A4	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.