Glycosylphosphatidylinositol biosynthesis defect 15

Summary

Glycosylphosphatidylinositol biosynthesis defect 15 (MONDO:0060627) is a disease caused by GPAA1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GPAA1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 36
• Phenotypes (HPO): 31

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Very frequent (80-99%)
HP:0002353	EEG abnormality	Very frequent (80-99%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000341	Narrow forehead	Frequent (30-79%)
HP:0000455	Broad nasal tip	Frequent (30-79%)
HP:0000463	Anteverted nares	Frequent (30-79%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000657	Oculomotor apraxia	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0001321	Cerebellar hypoplasia	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0003698	Difficulty standing	Frequent (30-79%)
HP:0011220	Prominent forehead	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0003155	Elevated circulating alkaline phosphatase concentration	Excluded (0%)
HP:0000505	Visual impairment	Very rare (<1-4%)
HP:0000648	Optic atrophy	Very rare (<1-4%)
HP:0002133	Status epilepticus	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	glycosylphosphatidylinositol biosynthesis defect 15
Mondo ID	MONDO:0060627
OMIM	617810
Orphanet	529665
UMLS	C4540520
MedGen	1615160
GARD	0017969
Is cancer (heuristic)	no

Also known as: glycosylphosphatidylinositol biosynthesis defect 15 · GPIBD15

Data availability: 36 ClinVar variants · 5 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 › inherited lipid metabolism disorder › glycosylphosphatidylinositol biosynthesis defect 15

Related subtypes (28): cortisone reductase deficiency, familial hyperlipidemia, hypolipoproteinemia, steroid inherited metabolic disorder, corticosterone methyloxidase type 1 deficiency, lipoid proteinosis, 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency, vitamin D hydroxylation-deficient rickets, type 1B, mitochondrial trifunctional protein deficiency, pancreatic triacylglycerol lipase deficiency, glucocorticoid resistance, syndromic dyslipidemia, inborn disorder of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation, disorder of plasmalogens biosynthesis, disorder of phospholipids, sphingolipids and fatty acids biosynthesis, inborn disorder of ketolysis, lysosomal lipid storage disorder, sterol metabolism disorder, disorder of sphingolipid biosynthesis, glycosylphosphatidylinositol biosynthesis defect 18, neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures, developmental and epileptic encephalopathy, 77, developmental and epileptic encephalopathy, 80, developmental and epileptic encephalopathy, 55, inherited fatty acid metabolism disorder, glycosylphosphatidylinositol biosynthesis defect 16, glycosylphosphatidylinositol biosynthesis defect 17, CYP7B1-related disorder of oxysterol accumulation

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

36 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 7 conflicting classifications of pathogenicity, 7 likely pathogenic, 6 pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028657	NM_003801.4(GPAA1):c.319_320del (p.Ser107fs)	GPAA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1324501	NM_003801.4(GPAA1):c.643C>T (p.Arg215Ter)	GPAA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451609	NM_003801.4(GPAA1):c.43del (p.Arg15fs)	GPAA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685859	NM_003801.4(GPAA1):c.1826C>T (p.Pro609Leu)	GPAA1	Pathogenic	criteria provided, single submitter
1805088	NM_003801.4(GPAA1):c.1465C>T (p.Gln489Ter)	GPAA1	Pathogenic	criteria provided, single submitter
453248	NM_003801.4(GPAA1):c.981_993del (p.Gln327fs)	GPAA1	Pathogenic	no assertion criteria provided
453249	NM_003801.4(GPAA1):c.920del (p.Gly307fs)	GPAA1	Pathogenic	criteria provided, single submitter
523980	NM_003801.4(GPAA1):c.619del (p.Met207fs)	GPAA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1324502	NM_003801.4(GPAA1):c.616+1G>T	GPAA1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1394986	NM_003801.4(GPAA1):c.1165-1C>T	GPAA1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1710054	NM_003801.4(GPAA1):c.367-1G>A	GPAA1	Likely pathogenic	criteria provided, single submitter
453247	NM_003801.4(GPAA1):c.872T>C (p.Leu291Pro)	GPAA1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
453250	NM_003801.4(GPAA1):c.1165G>C (p.Ala389Pro)	GPAA1	Likely pathogenic	criteria provided, single submitter
453251	NM_003801.4(GPAA1):c.527G>C (p.Trp176Ser)	GPAA1	Likely pathogenic	criteria provided, single submitter
617925	NM_003801.4(GPAA1):c.152C>T (p.Ser51Leu)	GPAA1	Likely pathogenic	criteria provided, single submitter
1111831	NM_003801.4(GPAA1):c.1863G>T (p.Lys621Asn)	GPAA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1187326	NM_003801.4(GPAA1):c.149T>A (p.Met50Lys)	GPAA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1378945	NM_003801.4(GPAA1):c.541G>A (p.Val181Ile)	GPAA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1600574	NM_003801.4(GPAA1):c.1622+3A>G	GPAA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
453253	NM_003801.4(GPAA1):c.869T>C (p.Leu290Pro)	GPAA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
802446	NM_003801.4(GPAA1):c.719A>G (p.Glu240Gly)	GPAA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
802447	NM_003801.4(GPAA1):c.1477_1478del (p.Arg493fs)	GPAA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028655	NM_003801.4(GPAA1):c.1723G>T (p.Ala575Ser)	GPAA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028656	NM_003801.4(GPAA1):c.29G>A (p.Arg10Gln)	GPAA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1034025	NM_003801.4(GPAA1):c.1268G>A (p.Gly423Glu)	GPAA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1034026	NM_003801.4(GPAA1):c.1658C>T (p.Pro553Leu)	GPAA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1098687	NM_003801.4(GPAA1):c.1051G>C (p.Glu351Gln)	GPAA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1407979	NM_003801.4(GPAA1):c.1372G>A (p.Val458Met)	GPAA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1435332	NM_003801.4(GPAA1):c.1680C>G (p.Ser560Arg)	GPAA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1480071	NM_003801.4(GPAA1):c.1598C>T (p.Ala533Val)	GPAA1	Uncertain significance	criteria provided, multiple submitters, no conflicts

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
GPAA1	Definitive	Autosomal recessive	glycosylphosphatidylinositol biosynthesis defect 15	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GPAA1	Orphanet:529665	Neurodevelopmental delay-seizures-ophthalmic anomalies-osteopenia-cerebellar atrophy 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
GPAA1	HGNC:4446	ENSG00000197858	O43292	GPI-anchor transamidase component GPAA1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GPAA1	GPI-anchor transamidase component GPAA1	Component of the glycosylphosphatidylinositol-anchor (GPI-anchor) transamidase (GPI-T) complex that catalyzes the formation of the linkage between a proprotein and a GPI-anchor and participates in GPI anchored protein biosynthesis.

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)
GPAA1	Other/Unknown	no		Gaa1

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
apex of heart	1
right lobe of thyroid gland	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GPAA1	285	ubiquitous	marker	stromal cell of endometrium, right lobe of thyroid gland, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GPAA1	1,281

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GPAA1	O43292	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Attachment of GPI anchor to uPAR	1	1268.9×	8e-04	GPAA1

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
GPI anchored protein biosynthesis	1	2808.7×	6e-04	GPAA1
protein retention in ER lumen	1	2407.4×	6e-04	GPAA1
attachment of GPI anchor to protein	1	2106.5×	6e-04	GPAA1
GPI anchor biosynthetic process	1	495.6×	0.002	GPAA1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GPAA1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GPAA1	1	Binding:1

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	GPAA1

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)
GPAA1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.