Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome

Summary

Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome (MONDO:0013116) is a disease caused by GFER (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GFER (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 20
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000408	Progressive sensorineural hearing impairment	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000519	Developmental cataract	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001315	Reduced tendon reflexes	Frequent (30-79%)
HP:0001583	Rotary nystagmus	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0003128	Lactic acidosis	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0012343	Decreased serum ferritin	Frequent (30-79%)
HP:0030089	Abnormal muscle fiber protein expression	Frequent (30-79%)
HP:0001324	Muscle weakness	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome
Mondo ID	MONDO:0013116
MeSH	C567769
OMIM	613076
Orphanet	330054
UMLS	C2751320
MedGen	416525
GARD	0010522
Is cancer (heuristic)	no

Also known as: congenital cataract-progressive muscular hypotonia-deafness-developmental delay syndrome · congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome · myopathy with cataract and combined respiratory-chain deficiency · myopathy, mitochondrial progressive, with congenital cataract and developmental delay

Data availability: 20 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › congenital structural myopathy › inborn mitochondrial myopathy › congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome

Related subtypes (23): myopathy, lactic acidosis, and sideroblastic anemia, mitochondrial encephalomyopathy, progressive external ophthalmoplegia, mitochondrial myopathy with a defect in mitochondrial-protein transport, Barth syndrome, mitochondrial myopathy with diabetes, mitochondrial myopathy with reversible cytochrome C oxidase deficiency, lethal infantile mitochondrial myopathy, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, mitochondrial trifunctional protein deficiency, adenosine monophosphate deaminase deficiency, autosomal dominant mitochondrial myopathy with exercise intolerance, fatal infantile encephalocardiomyopathy, mitochondrial myopathy-lactic acidosis-deafness syndrome, mitochondrial neurogastrointestinal encephalomyopathy, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, maternally-inherited progressive external ophthalmoplegia, mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy, mitochondrial complex II deficiency, nuclear type, mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome, X-linked recessive mitochondrial myopathy, mitochondrial complex I deficiency, nuclear type 1, COX deficiency, benign infantile mitochondrial myopathy

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
1184607	NM_005262.3(GFER):c.575A>G (p.Asp192Gly)	GFER	Pathogenic	no assertion criteria provided
521763	NM_005262.3(GFER):c.566C>G (p.Ser189Ter)	GFER	Pathogenic	criteria provided, multiple submitters, no conflicts
8691	NM_005262.3(GFER):c.581G>A (p.Arg194His)	GFER	Pathogenic	criteria provided, multiple submitters, no conflicts
559178	NM_005262.3(GFER):c.217del (p.Ala73fs)	LOC130058203	Pathogenic	criteria provided, single submitter
666363	NM_005262.3(GFER):c.219del (p.Cys74fs)	LOC130058203	Pathogenic/Likely pathogenic	no assertion criteria provided
4819609	NM_005262.3(GFER):c.226G>T (p.Asp76Tyr)	GFER	Likely pathogenic	criteria provided, single submitter
666364	NM_005262.3(GFER):c.259-25_259-24del	GFER	Likely pathogenic	criteria provided, single submitter
1592745	NM_005262.3(GFER):c.536G>A (p.Arg179His)	GFER	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1699133	NM_005262.3(GFER):c.580C>T (p.Arg194Cys)	GFER	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214470	NM_005262.3(GFER):c.189G>C (p.Glu63Asp)	GFER	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214471	NM_005262.3(GFER):c.373C>T (p.Gln125Ter)	GFER	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3519805	NM_005262.3(GFER):c.587G>A (p.Arg196His)	GFER	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214476	NM_005262.3(GFER):c.199del (p.Arg67fs)	LOC130058203	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1201370	NM_005262.3(GFER):c.601G>A (p.Asp201Asn)	GFER	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805487	NM_005262.3(GFER):c.258+1G>A	GFER	Uncertain significance	criteria provided, multiple submitters, no conflicts
2052915	NM_005262.3(GFER):c.112G>A (p.Gly38Ser)	GFER	Uncertain significance	criteria provided, multiple submitters, no conflicts
3066171	NM_005262.3(GFER):c.352C>A (p.Pro118Thr)	GFER	Uncertain significance	criteria provided, multiple submitters, no conflicts
426097	NM_005262.3(GFER):c.586C>T (p.Arg196Cys)	GFER	Uncertain significance	criteria provided, multiple submitters, no conflicts
930234	NM_005262.3(GFER):c.280G>A (p.Asp94Asn)	GFER	Uncertain significance	criteria provided, single submitter
676126	NM_005262.3(GFER):c.456-83C>T	GFER	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
GFER	Strong	Autosomal recessive	congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GFER	Orphanet:330054	Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay 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
GFER	HGNC:4236	ENSG00000127554	P55789	FAD-linked sulfhydryl oxidase ALR	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GFER	FAD-linked sulfhydryl oxidase ALR	FAD-dependent sulfhydryl oxidase that regenerates the redox-active disulfide bonds in CHCHD4/MIA40, a chaperone essential for disulfide bond formation and protein folding in the mitochondrial intermembrane space.

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GFER	Enzyme (other)	yes	1.8.3.2	ERV/ALR_sulphydryl_oxidase, ERV/ALR_sulphydryl_oxid_sf, ALR/ERV

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
olfactory bulb	1
type B pancreatic cell	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GFER	197	ubiquitous	marker	olfactory bulb, type B pancreatic cell, vena cava

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GFER	2,065

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GFER	P55789	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Protein localization	1	190.3×	0.006	GFER
Mitochondrial protein import	1	167.9×	0.006	GFER

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
protein import into the intermembrane space via the disulfide relay system	1	5617.3×	4e-04	GFER
liver development	1	221.7×	0.005	GFER

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GFER	FENOLDOPAM MESYLATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GFER	11	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FENOLDOPAM MESYLATE	4	GFER
PROMAZINE HYDROCHLORIDE	4	GFER
PROMETHAZINE HYDROCHLORIDE	4	GFER
PHENELZINE SULFATE	4	GFER
PYRITHIONE	4	GFER
DOPAMINE HYDROCHLORIDE	4	GFER
MEPAZINE ACETATE	4	GFER
CHLORPROMAZINE HYDROCHLORIDE	4	GFER
OLANZAPINE	4	GFER
RESVERATROL	3	GFER
PTEROSTILBENE	2	GFER

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GFER	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GFER	1.8.3.2	thiol oxidase

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

11 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)
FENOLDOPAM MESYLATE	4	GFER
PROMAZINE HYDROCHLORIDE	4	GFER
PROMETHAZINE HYDROCHLORIDE	4	GFER
PHENELZINE SULFATE	4	GFER
PYRITHIONE	4	GFER
DOPAMINE HYDROCHLORIDE	4	GFER
MEPAZINE ACETATE	4	GFER
CHLORPROMAZINE HYDROCHLORIDE	4	GFER
OLANZAPINE	4	GFER
RESVERATROL	3	GFER
PTEROSTILBENE	2	GFER

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GFER
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	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: 0.