Growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome

Summary

Growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome (MONDO:0014261) is a disease caused by SFXN4 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SFXN4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome
Mondo ID	MONDO:0014261
OMIM	615578
Orphanet	391348
DOID	DOID:0111484
UMLS	C3810001
MedGen	816331
GARD	0017615
Is cancer (heuristic)	no

Also known as: combined oxidative phosphorylation deficiency 18 · combined oxidative phosphorylation deficiency caused by mutation in SFXN4 · combined oxidative phosphorylation deficiency type 18 · COXPD18 · SFXN4 combined oxidative phosphorylation deficiency

Data availability: 20 ClinVar variants · 4 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 oxidative phosphorylation disorder › combined oxidative phosphorylation deficiency › growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome

Related subtypes (57): severe X-linked mitochondrial encephalomyopathy, hepatoencephalopathy due to combined oxidative phosphorylation defect type 1, combined oxidative phosphorylation defect type 2, fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3, combined oxidative phosphorylation defect type 4, hypotonia with lactic acidemia and hyperammonemia, combined oxidative phosphorylation defect type 7, combined oxidative phosphorylation defect type 8, combined oxidative phosphorylation defect type 9, mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, combined oxidative phosphorylation defect type 11, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, combined oxidative phosphorylation defect type 13, combined oxidative phosphorylation defect type 14, combined oxidative phosphorylation defect type 15, infantile hypertrophic cardiomyopathy due to MRPL44 deficiency, combined oxidative phosphorylation defect type 17, combined oxidative phosphorylation deficiency 19, combined oxidative phosphorylation defect type 20, combined oxidative phosphorylation defect type 21, mitochondrial proton-transporting ATP synthase complex deficiency, combined oxidative phosphorylation defect type 23, combined oxidative phosphorylation defect type 24, combined oxidative phosphorylation defect type 25, combined oxidative phosphorylation defect type 26, combined oxidative phosphorylation defect type 27, combined oxidative phosphorylation deficiency 28, combined oxidative phosphorylation deficiency 29, combined oxidative phosphorylation defect type 30, lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome, combined oxidative phosphorylation deficiency 40, combined oxidative phosphorylation deficiency 41, combined oxidative phosphorylation deficiency 42, combined oxidative phosphorylation deficiency 43, combined oxidative phosphorylation deficiency 44, combined oxidative phosphorylation deficiency 52, combined oxidative phosphorylation deficiency 53, combined oxidative phosphorylation deficiency 54, combined oxidative phosphorylation deficiency 37, combined oxidative phosphorylation deficiency 38, combined oxidative phosphorylation deficiency 39, combined oxidative phosphorylation deficiency 45, combined oxidative phosphorylation deficiency 46, combined oxidative phosphorylation deficiency 47, combined oxidative phosphorylation deficiency 48, combined oxidative phosphorylation deficiency 51, combined oxidative phosphorylation deficiency 32, combined oxidative phosphorylation deficiency 33, combined oxidative phosphorylation deficiency 34, combined oxidative phosphorylation deficiency 35, combined oxidative phosphorylation deficiency 36, combined oxidative phosphorylation deficiency 55, combined oxidative phosphorylation deficiency 56, combined oxidative phosphorylation deficiency 57, combined oxidative phosphorylation deficiency 58, combined oxidative phosphorylation deficiency 59, combined oxidative phosphorylation deficiency 60

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

20 retrieved; paginated sample, class counts are floors:

6 benign, 5 pathogenic, 4 pathogenic/likely pathogenic, 2 likely pathogenic, 2 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323582	NM_213649.2(SFXN4):c.368T>A (p.Leu123Ter)	SFXN4	Pathogenic	criteria provided, single submitter
2964708	NM_213649.2(SFXN4):c.325C>T (p.Arg109Ter)	SFXN4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488593	NM_213649.2(SFXN4):c.414+1G>A	SFXN4	Pathogenic	criteria provided, single submitter
638327	NM_213649.2(SFXN4):c.940C>T (p.Gln314Ter)	SFXN4	Pathogenic	criteria provided, single submitter
689787	NM_213649.2(SFXN4):c.930del (p.Ile310fs)	SFXN4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
92098	NM_213649.2(SFXN4):c.233del (p.Pro78fs)	SFXN4	Pathogenic	criteria provided, single submitter
92099	NM_213649.2(SFXN4):c.739dup (p.Arg247fs)	SFXN4	Pathogenic	no assertion criteria provided
92100	NM_213649.2(SFXN4):c.471+1G>A	SFXN4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
985738	NM_213649.2(SFXN4):c.649C>T (p.Arg217Ter)	SFXN4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3381959	NM_213649.2(SFXN4):c.823C>T (p.Gln275Ter)	SFXN4	Likely pathogenic	criteria provided, single submitter
3767158	NM_213649.2(SFXN4):c.361-2A>T	SFXN4	Likely pathogenic	criteria provided, single submitter
740139	NM_213649.2(SFXN4):c.677C>T (p.Ala226Val)	SFXN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3899877	NM_213649.2(SFXN4):c.271C>T (p.Arg91Trp)	SFXN4	Uncertain significance	criteria provided, single submitter
806576	NM_213649.2(SFXN4):c.410C>T (p.Pro137Leu)	SFXN4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1267837	NM_213649.2(SFXN4):c.472-24T>A	SFXN4	Benign	criteria provided, multiple submitters, no conflicts
1292078	NM_213649.2(SFXN4):c.361-42C>T	SFXN4	Benign	criteria provided, multiple submitters, no conflicts
1332950	NM_213649.2(SFXN4):c.354A>G (p.Ala118=)	SFXN4	Benign	criteria provided, multiple submitters, no conflicts
380006	NM_213649.2(SFXN4):c.258A>G (p.Gln86=)	SFXN4	Benign	criteria provided, multiple submitters, no conflicts
380007	NM_213649.2(SFXN4):c.415-6C>T	SFXN4	Benign	criteria provided, multiple submitters, no conflicts
380008	NM_213649.2(SFXN4):c.617-3C>T	SFXN4	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
SFXN4	Strong	Autosomal recessive	growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SFXN4	Orphanet:391348	Growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome

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
SFXN4	HGNC:16088	ENSG00000183605	Q6P4A7	Sideroflexin-4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SFXN4	Sideroflexin-4	Mitochondrial amino-acid transporter.

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)
SFXN4	Other/Unknown	no		Mtc

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
adrenal tissue	1
apex of heart	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SFXN4	254	ubiquitous	marker	apex of heart, adrenal tissue, tibialis anterior

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SFXN4	1,083

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SFXN4	Q6P4A7	85.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Complex I biogenesis	1	165.5×	0.015	SFXN4
Respiratory electron transport	1	95.2×	0.015	SFXN4
Aerobic respiration and respiratory electron transport	1	88.5×	0.015	SFXN4
Metabolism	1	11.6×	0.086	SFXN4

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
mitochondrial transmembrane transport	1	1685.2×	0.001	SFXN4
amino acid transport	1	312.1×	0.003	SFXN4

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
SFXN4	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	SFXN4

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)
SFXN4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.