Multiple mitochondrial dysfunctions syndrome 4

Summary

Multiple mitochondrial dysfunctions syndrome 4 (MONDO:0014611) is a disease caused by ISCA2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ISCA2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple mitochondrial dysfunctions syndrome 4
Mondo ID	MONDO:0014611
OMIM	616370
Orphanet	457406
DOID	DOID:0080136
UMLS	C4225348
MedGen	899010
GARD	0017809
Is cancer (heuristic)	no

Also known as: fatal multiple mitochondrial dysfunctions syndrome caused by mutation in ISCA2 · ISCA2 fatal multiple mitochondrial dysfunctions syndrome · MMDS4 · multiple mitochondrial dysfunctions syndrome 4 · multiple mitochondrial dysfunctions syndrome type 4

Data availability: 11 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › eye degenerative disorder › multiple mitochondrial dysfunctions syndrome 4

Related subtypes (8): blind hypertensive eye, vitreous syneresis, degenerative myopia, choroidal sclerosis, muscular atrophy-ataxia-retinitis pigmentosa-diabetes mellitus syndrome, Krabbe disease, corneal-cerebellar syndrome, tremor-ataxia-central hypomyelination syndrome

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

11 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 3 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
183353	NM_194279.4(ISCA2):c.229G>A (p.Gly77Ser)	ISCA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2581360	NM_194279.4(ISCA2):c.313A>G (p.Arg105Gly)	ISCA2	Likely pathogenic	criteria provided, single submitter
1031786	NM_194279.4(ISCA2):c.361G>T (p.Val121Leu)	ISCA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
545531	NM_194279.4(ISCA2):c.297del (p.Phe99fs)	ISCA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
638308	NM_194279.4(ISCA2):c.355G>A (p.Ala119Thr)	ISCA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2143472	NM_194279.4(ISCA2):c.422A>T (p.Gln141Leu)	ISCA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2628077	NM_194279.4(ISCA2):c.314G>T (p.Arg105Ile)	ISCA2	Uncertain significance	criteria provided, single submitter
2740585	NM_194279.4(ISCA2):c.154C>T (p.Leu52Phe)	ISCA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3064676	NM_194279.4(ISCA2):c.71+3A>T	ISCA2	Uncertain significance	criteria provided, single submitter
3234879	NM_194279.4(ISCA2):c.221T>C (p.Val74Ala)	ISCA2	Uncertain significance	criteria provided, single submitter
523611	NM_194279.4(ISCA2):c.334A>G (p.Ser112Gly)	ISCA2	Uncertain significance	criteria provided, single submitter

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
ISCA2	Strong	Autosomal recessive	multiple mitochondrial dysfunctions syndrome 4	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ISCA2	Orphanet:457406	Multiple mitochondrial dysfunctions syndrome type 4

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
ISCA2	HGNC:19857	ENSG00000165898	Q86U28	Iron-sulfur cluster assembly 2 homolog, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ISCA2	Iron-sulfur cluster assembly 2 homolog, mitochondrial	Involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the iron-sulfur cluster assembly pathway.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ISCA2	Other/Unknown	no		ATAP_core_dom, ATAP, FeS_cluster_insertion_CS

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
cardiac muscle of right atrium	1
deltoid	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ISCA2	257	ubiquitous	marker	left ventricle myocardium, deltoid, cardiac muscle of right atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ISCA2	1,444

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ISCA2	Q86U28	77.98

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Mitochondrial iron-sulfur cluster biogenesis	1	815.7×	0.004	ISCA2
Maturation of TCA enzymes and regulation of TCA cycle	1	571.0×	0.004	ISCA2
Citric acid cycle (TCA cycle)	1	423.0×	0.004	ISCA2
Aerobic respiration and respiratory electron transport	1	88.5×	0.014	ISCA2
Metabolism	1	11.6×	0.086	ISCA2

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
iron-sulfur cluster assembly	1	601.9×	0.003	ISCA2
protein maturation	1	163.6×	0.006	ISCA2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ISCA2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ISCA2

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)
ISCA2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.