SRD5A3-congenital disorder of glycosylation

Summary

SRD5A3-congenital disorder of glycosylation (MONDO:0012885) is a disease caused by SRD5A3 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SRD5A3 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 170
• Phenotypes (HPO): 33

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0000648	Optic atrophy	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0003642	Type I transferrin isoform profile	Very frequent (80-99%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000572	Visual loss	Frequent (30-79%)
HP:0000589	Coloboma	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001317	Abnormal cerebellum morphology	Frequent (30-79%)
HP:0001935	Microcytic anemia	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0007766	Optic disc hypoplasia	Frequent (30-79%)
HP:0008064	Ichthyosis	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0012443	Abnormality of brain morphology	Frequent (30-79%)
HP:0000510	Rod-cone dystrophy	Occasional (5-29%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0000824	Decreased response to growth hormone stimulation test	Occasional (5-29%)
HP:0000982	Palmoplantar keratoderma	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001928	Abnormality of coagulation	Occasional (5-29%)
HP:0001976	Reduced antithrombin III activity	Occasional (5-29%)
HP:0002334	Abnormality of the cerebellar vermis	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Occasional (5-29%)
HP:0005107	Abnormal sacrum morphology	Occasional (5-29%)
HP:0005585	Spotty hyperpigmentation	Occasional (5-29%)
HP:0030680	Abnormal cardiovascular system morphology	Occasional (5-29%)
HP:0000365	Hearing impairment	Excluded (0%)
HP:0000677	Oligodontia	Excluded (0%)
HP:0001595	Abnormality of the hair	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	SRD5A3-congenital disorder of glycosylation
Mondo ID	MONDO:0012885
OMIM	612379
Orphanet	324737
DOID	DOID:0080568
SNOMED CT	733601006
UMLS	C4317224
MedGen	1392124
GARD	0012397
Is cancer (heuristic)	no

Also known as: CDG syndrome type Iq · CDG-Iq · CDG1Q · CDGIq · congenital disorder of glycosylation due to steroid 5alpha-reductase type 3 deficiency · congenital disorder of glycosylation type 1q · congenital disorder of glycosylation type Iq · congenital disorder of glycosylation, type Iq · SRD5A3-CDG · SRD5A3-CDG (CDG-Iq) · SRD5A3-congenital disorder of glycosylation

Data availability: 170 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › congenital disorder of glycosylation › congenital disorder of glycosylation type I › SRD5A3-congenital disorder of glycosylation

Related subtypes (27): PMM2-congenital disorder of glycosylation, developmental and epileptic encephalopathy, 36, SSR4-congenital disorder of glycosylation, ALG3-congenital disorder of glycosylation, MPI-congenital disorder of glycosylation, ALG6-congenital disorder of glycosylation 1C, ALG12-congenital disorder of glycosylation, ALG2-congenital disorder of glycosylation, DPAGT1-congenital disorder of glycosylation, ALG8-congenital disorder of glycosylation, ALG1-congenital disorder of glycosylation, ALG9-congenital disorder of glycosylation, congenital disorder of glycosylation type 1E, MPDU1-congenital disorder of glycosylation, DK1-congenital disorder of glycosylation, RFT1-congenital disorder of glycosylation, DPM3-congenital disorder of glycosylation, ALG11-congenital disorder of glycosylation, DDOST-congenital disorder of glycosylation, PGM1-congenital disorder of glycosylation, congenital muscular dystrophy with intellectual disability and severe epilepsy, STT3A-congenital disorder of glycosylation, STT3B-congenital disorder of glycosylation, developmental and epileptic encephalopathy, 50, congenital disorder of glycosylation, type IAA, congenital disorder of glycosylation, type ICC, SSR3-CDG

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

170 retrieved; paginated sample, class counts are floors:

88 uncertain significance, 40 likely benign, 15 benign, 11 conflicting classifications of pathogenicity, 10 pathogenic, 2 likely pathogenic, 2 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1362615	NM_024592.5(SRD5A3):c.279C>A (p.Cys93Ter)	SRD5A3	Pathogenic	criteria provided, single submitter
1456803	NC_000004.11:g.(?56225493)(56225675_?)del	SRD5A3	Pathogenic	criteria provided, single submitter
18404	NM_024592.5(SRD5A3):c.286_288delinsTGAGTAAGGC (p.Gln96Ter)	SRD5A3	Pathogenic	criteria provided, single submitter
18405	NM_024592.5(SRD5A3):c.320G>A (p.Trp107Ter)	SRD5A3	Pathogenic	criteria provided, multiple submitters, no conflicts
18406	NM_024592.5(SRD5A3):c.424C>T (p.Arg142Ter)	SRD5A3	Pathogenic	criteria provided, single submitter
18407	NM_024592.5(SRD5A3):c.489C>A (p.Tyr163Ter)	SRD5A3	Pathogenic	no assertion criteria provided
18408	NM_024592.5(SRD5A3):c.29C>A (p.Ser10Ter)	SRD5A3	Pathogenic	no assertion criteria provided
2446387	NM_024592.5(SRD5A3):c.50_60del (p.Ala17fs)	SRD5A3	Pathogenic	criteria provided, single submitter
804441	NM_024592.5(SRD5A3):c.484C>T (p.Gln162Ter)	SRD5A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
96125	NM_024592.5(SRD5A3):c.57G>A (p.Trp19Ter)	SRD5A3	Pathogenic	criteria provided, multiple submitters, no conflicts
1686229	NM_024592.5(SRD5A3):c.697+1G>C	SRD5A3-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4795116	NM_024592.5(SRD5A3):c.592C>T (p.Gln198Ter)	SRD5A3-AS1	Pathogenic	criteria provided, single submitter
1343405	NM_024592.4:c.(221+1_222-1)_(697+1_698-1)dup	SRD5A3	Likely pathogenic	no assertion criteria provided
4526599	NM_024592.5(SRD5A3):c.653del (p.Tyr218fs)	SRD5A3-AS1	Likely pathogenic	criteria provided, single submitter
1312107	NM_024592.5(SRD5A3):c.869T>C (p.Leu290Pro)	SRD5A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193455	NM_024592.5(SRD5A3):c.51G>T (p.Ala17=)	SRD5A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193456	NM_024592.5(SRD5A3):c.43C>T (p.Leu15=)	SRD5A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
212302	NM_024592.5(SRD5A3):c.480C>T (p.Val160=)	SRD5A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
212303	NM_024592.5(SRD5A3):c.566A>C (p.Tyr189Ser)	SRD5A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2506565	NM_024592.5(SRD5A3):c.506A>G (p.Tyr169Cys)	SRD5A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
349006	NM_024592.5(SRD5A3):c.110C>T (p.Pro37Leu)	SRD5A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
424415	NM_024592.5(SRD5A3):c.562+3del	SRD5A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
424422	NM_024592.5(SRD5A3):c.436G>A (p.Glu146Lys)	SRD5A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
703104	NM_024592.5(SRD5A3):c.108G>T (p.Pro36=)	SRD5A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
899681	NM_024592.5(SRD5A3):c.673G>A (p.Gly225Ser)	SRD5A3-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4278011	NM_012318.3(LETM1):c.1058G>C (p.Arg353Pro)	LETM1	Uncertain significance	criteria provided, single submitter
1016815	NM_024592.5(SRD5A3):c.433T>C (p.Phe145Leu)	SRD5A3	Uncertain significance	criteria provided, single submitter
1028324	NM_024592.5(SRD5A3):c.263G>T (p.Gly88Val)	SRD5A3	Uncertain significance	criteria provided, single submitter
1028325	NM_024592.5(SRD5A3):c.416A>G (p.His139Arg)	SRD5A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1044387	NM_024592.5(SRD5A3):c.77T>G (p.Phe26Cys)	SRD5A3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 2 · 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
SRD5A3	Definitive	Autosomal recessive	SRD5A3-congenital disorder of glycosylation	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SRD5A3	Orphanet:324737	SRD5A3-CDG
LETM1	Orphanet:280	Wolf-Hirschhorn syndrome

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SRD5A3	HGNC:25812	ENSG00000128039	Q9H8P0	Polyprenal reductase	gencc,clinvar
SRD5A3-AS1	HGNC:44138	ENSG00000249700		SRD5A3 antisense RNA 1	clinvar
LETM1	HGNC:6556	ENSG00000168924	O95202	Mitochondrial proton/calcium exchanger protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SRD5A3	Polyprenal reductase	Plays a key role in early steps of protein N-linked glycosylation by being involved in the conversion of polyprenol into dolichol.
LETM1	Mitochondrial proton/calcium exchanger protein	Plays an important role in maintenance of mitochondrial morphology and in mediating either calcium or potassium/proton antiport.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SRD5A3	Enzyme (other)	yes	1.3.1.22	3-oxo-5_a-steroid_4-DH_C, Dfg10/SRD5A3
SRD5A3-AS1	Other/Unknown	no
LETM1	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS

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
gall bladder	1
olfactory segment of nasal mucosa	1
palpebral conjunctiva	1
left testis	1
right testis	1
sperm	1
buccal mucosa cell	1
mucosa of transverse colon	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SRD5A3	254	ubiquitous	marker	palpebral conjunctiva, gall bladder, olfactory segment of nasal mucosa
SRD5A3-AS1	162	tissue_specific	marker	sperm, left testis, right testis
LETM1	268	ubiquitous	marker	mucosa of transverse colon, sural nerve, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LETM1	2,029
SRD5A3	877
SRD5A3-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LETM1	O95202	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SRD5A3	Q9H8P0	89.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SRD5A3 causes SRD5A3-CDG, KHRZ	1	5710.0×	0.005	SRD5A3
Diseases associated with glycosylation precursor biosynthesis	1	2855.0×	0.005	SRD5A3
Synthesis of dolichyl-phosphate	1	815.7×	0.011	SRD5A3
Androgen biosynthesis	1	519.1×	0.013	SRD5A3
Mitochondrial calcium ion transport	1	271.9×	0.017	LETM1
Metabolism of steroid hormones	1	259.6×	0.017	SRD5A3
Complex III assembly	1	219.6×	0.017	LETM1
Synthesis of substrates in N-glycan biosythesis	1	146.4×	0.021	SRD5A3
Metabolism	2	11.6×	0.021	SRD5A3, LETM1
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	103.8×	0.025	SRD5A3
RHOG GTPase cycle	1	74.2×	0.030	LETM1
Metabolism of steroids	1	68.8×	0.030	SRD5A3
Diseases of glycosylation	1	65.6×	0.030	SRD5A3
Respiratory electron transport	1	47.6×	0.039	LETM1
Aerobic respiration and respiratory electron transport	1	44.3×	0.039	LETM1
Diseases of metabolism	1	40.2×	0.040	SRD5A3
Asparagine N-linked glycosylation	1	30.1×	0.048	SRD5A3
RHO GTPase cycle	1	30.1×	0.048	LETM1
Signaling by Rho GTPases	1	17.1×	0.076	LETM1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.076	LETM1
Metabolism of lipids	1	15.8×	0.077	SRD5A3
Transport of small molecules	1	12.6×	0.092	LETM1
Post-translational protein modification	1	9.6×	0.115	SRD5A3
Disease	1	6.5×	0.159	SRD5A3
Metabolism of proteins	1	6.2×	0.161	SRD5A3
Signal Transduction	1	5.1×	0.187	LETM1

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
polyprenol catabolic process	1	8426.0×	0.002	SRD5A3
calcium export from the mitochondrion	1	2808.7×	0.002	LETM1
negative regulation of mitochondrial calcium ion concentration	1	2106.5×	0.002	LETM1
mitochondrial potassium ion transmembrane transport	1	2106.5×	0.002	LETM1
regulation of cellular hyperosmotic salinity response	1	1685.2×	0.002	LETM1
androgen biosynthetic process	1	936.2×	0.002	SRD5A3
dolichyl monophosphate biosynthetic process	1	936.2×	0.002	SRD5A3
protein hexamerization	1	702.2×	0.003	LETM1
cristae formation	1	526.6×	0.003	LETM1
mitochondrial calcium ion transmembrane transport	1	495.6×	0.003	LETM1
mitochondrial calcium ion homeostasis	1	495.6×	0.003	LETM1
dolichol-linked oligosaccharide biosynthetic process	1	421.3×	0.003	SRD5A3
inner mitochondrial membrane organization	1	421.3×	0.003	LETM1
calcium ion transport	1	90.6×	0.013	LETM1
mitochondrion organization	1	75.9×	0.014	LETM1
protein homooligomerization	1	61.1×	0.016	LETM1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SRD5A3	0	0
SRD5A3-AS1	0	0
LETM1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SRD5A3	1	Binding:1
LETM1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SRD5A3	1.3.1.22, 1.3.1.94, 1.3.1.B13	3-oxo-5alpha-steroid 4-dehydrogenase (NADP+), polyprenal reductase,

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	1	SRD5A3
E	Difficult family or no structure, no drug	2	SRD5A3-AS1, LETM1

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)
SRD5A3	1	—
SRD5A3-AS1	0	—
LETM1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.