Multiple mitochondrial dysfunctions syndrome 9b

Summary

Multiple mitochondrial dysfunctions syndrome 9b (MONDO:0971174) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 13

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple mitochondrial dysfunctions syndrome 9b
Mondo ID	MONDO:0971174
OMIM	620887
UMLS	C5935635
MedGen	1860851
GARD	0027208
Is cancer (heuristic)	no

Data availability: 13 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › inherited lipoic acid biosynthesis defect › fatal multiple mitochondrial dysfunctions syndrome › multiple mitochondrial dysfunctions syndrome 9b

Related subtypes (8): multiple mitochondrial dysfunctions syndrome 1, multiple mitochondrial dysfunctions syndrome 2, multiple mitochondrial dysfunctions syndrome 3, multiple mitochondrial dysfunctions syndrome 4, multiple mitochondrial dysfunctions syndrome 5, multiple mitochondrial dysfunctions syndrome 6, multiple mitochondrial dysfunctions syndrome 7, multiple mitochondrial dysfunctions syndrome 10

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

13 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 4 pathogenic, 2 pathogenic/likely pathogenic, 2 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1803970	NM_024417.5(FDXR):c.564_575del (p.Leu189_Ala192del)	FDXR	Pathogenic	criteria provided, single submitter
1803971	NM_024417.5(FDXR):c.332T>C (p.Val111Ala)	FDXR	Pathogenic	criteria provided, single submitter
3252085	NM_024417.5(FDXR):c.178-86C>T	FDXR	Pathogenic	no assertion criteria provided
3252092	c.1002+1G-A	FDXR	Pathogenic	no assertion criteria provided
489042	NM_024417.5(FDXR):c.1A>G (p.Met1Val)	FDXR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
520994	NM_024417.5(FDXR):c.1156C>T (p.Arg386Trp)	FDXR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
817643	NM_024417.5(FDXR):c.929del (p.Ser310fs)	FDXR	Likely pathogenic	criteria provided, single submitter
983267	NM_024417.5(FDXR):c.463C>T (p.Arg155Trp)	FDXR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1711446	NM_024417.5(FDXR):c.578G>A (p.Arg193His)	FDXR	Uncertain significance	criteria provided, single submitter
4073424	NM_024417.5(FDXR):c.773A>G (p.Asp258Gly)	FDXR	Uncertain significance	no assertion criteria provided
4073425	NM_024417.5(FDXR):c.247G>A (p.Ala83Thr)	FDXR	Uncertain significance	no assertion criteria provided
4820321	NM_024417.5(FDXR):c.533C>G (p.Thr178Arg)	FDXR	Uncertain significance	criteria provided, single submitter
448685	NM_018105.3(THAP1):c.421G>A (p.Asp141Asn)	THAP1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
THAP1	Orphanet:98806	Primary dystonia, DYT6 type
FDXR	Orphanet:542585	Auditory neuropathy-optic atrophy syndrome
FDXR	Orphanet:543470	Optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome

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
THAP1	HGNC:20856	ENSG00000131931	Q9NVV9	THAP domain-containing protein 1	clinvar
FDXR	HGNC:3642	ENSG00000161513	P22570	NADPH:adrenodoxin oxidoreductase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
THAP1	THAP domain-containing protein 1	DNA-binding transcription regulator that regulates endothelial cell proliferation and G1/S cell-cycle progression.
FDXR	NADPH:adrenodoxin oxidoreductase, mitochondrial	Serves as the first electron transfer protein in all the mitochondrial P450 systems including cholesterol side chain cleavage in all steroidogenic tissues, steroid 11-beta hydroxylation in the adrenal cortex, 25-OH-vitamin D3-24 hydroxylat…

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
THAP1	Transcription factor	no		THAP_Znf, THAP1/10, THAP_Znf_sf
FDXR	Other/Unknown	no		Ferredox_Rdtase_adrenod, FAD/NAD-bd_sf, Ferredox_Rdtase

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
secondary oocyte	1
left adrenal gland cortex	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
THAP1	260	ubiquitous	yes	secondary oocyte, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
FDXR	208	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FDXR	2,373
THAP1	1,682

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
THAP1	Q9NVV9	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FDXR	P22570	91.66

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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
Electron transport from NADPH to Ferredoxin	1	2855.0×	0.003	FDXR
Defective CYP11A1 causes AICSR	1	2284.0×	0.003	FDXR
Metabolic disorders of biological oxidation enzymes	1	878.5×	0.004	FDXR
Mitochondrial iron-sulfur cluster biogenesis	1	815.7×	0.004	FDXR
Pregnenolone biosynthesis	1	815.7×	0.004	FDXR
Cytochrome P450 - arranged by substrate type	1	713.8×	0.004	FDXR
Metabolism of steroid hormones	1	519.1×	0.004	FDXR
Endogenous sterols	1	393.8×	0.005	FDXR
Phase I - Functionalization of compounds	1	219.6×	0.008	FDXR
Metabolism of steroids	1	137.6×	0.011	FDXR
Biological oxidations	1	129.8×	0.011	FDXR
Diseases of metabolism	1	80.4×	0.016	FDXR
Metabolism of lipids	1	31.6×	0.037	FDXR
Disease	1	13.1×	0.082	FDXR
Metabolism	1	11.6×	0.086	FDXR

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
ubiquinone biosynthetic process	1	468.1×	0.012	FDXR
steroid biosynthetic process	1	300.9×	0.012	FDXR
endothelial cell proliferation	1	271.8×	0.012	THAP1
generation of precursor metabolites and energy	1	172.0×	0.015	FDXR
regulation of mitotic cell cycle	1	120.4×	0.015	THAP1
DNA-templated transcription	1	112.3×	0.015	THAP1
cholesterol metabolic process	1	98.0×	0.015	FDXR
regulation of DNA-templated transcription	1	15.8×	0.078	THAP1
negative regulation of transcription by RNA polymerase II	1	8.9×	0.122	THAP1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	THAP1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
THAP1	0	0
FDXR	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	2	THAP1, FDXR

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
THAP1	0	—
FDXR	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.