Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures

Summary

Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures (MONDO:0030037) is a disease caused by PIGK (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PIGK (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 14

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures
Mondo ID	MONDO:0030037
OMIM	618879
UMLS	C5394372
MedGen	1710849
GARD	0025514
Is cancer (heuristic)	no

Also known as: Glycosylphosphatidylinositol Biosynthesis Defect 22 · NEDHCAS · NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA AND CEREBELLAR ATROPHY, WITH OR WITHOUT SEIZURES · neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures

Data availability: 14 ClinVar variants · 4 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 › neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures

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, 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 15, 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

14 retrieved; paginated sample, class counts are floors:

9 pathogenic, 3 benign, 1 conflicting classifications of pathogenicity, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1272073	NM_005482.3(PIGK):c.610G>C (p.Asp204His)	PIGK	Pathogenic	no assertion criteria provided
1272074	NM_005482.3(PIGK):c.87dup (p.Ile30fs)	PIGK	Pathogenic	no assertion criteria provided
3251832	NM_005482.3(PIGK):c.329_330insTT (p.Leu110_Asn111insTer)	PIGK	Pathogenic	criteria provided, multiple submitters, no conflicts
873117	NM_005482.3(PIGK):c.823T>C (p.Cys275Arg)	PIGK	Pathogenic	no assertion criteria provided
873118	NM_005482.3(PIGK):c.158C>T (p.Ser53Phe)	PIGK	Pathogenic	no assertion criteria provided
873119	NM_005482.3(PIGK):c.260C>T (p.Ala87Val)	PIGK	Pathogenic	no assertion criteria provided
873120	NM_005482.3(PIGK):c.479A>C (p.Tyr160Ser)	PIGK	Pathogenic	no assertion criteria provided
873121	NM_005482.3(PIGK):c.97C>T (p.Gln33Ter)	PIGK	Pathogenic	no assertion criteria provided
873122	NM_005482.3(PIGK):c.94-1G>C	PIGK	Pathogenic	no assertion criteria provided
1305272	NM_005482.3(PIGK):c.551C>T (p.Ala184Val)	PIGK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2260909	NM_005482.3(PIGK):c.397C>T (p.Arg133Trp)	PIGK	Uncertain significance	criteria provided, multiple submitters, no conflicts
1280784	NM_005482.3(PIGK):c.703-6C>T	PIGK	Benign	criteria provided, multiple submitters, no conflicts
1327022	NM_005482.3(PIGK):c.*2C>G	PIGK	Benign	criteria provided, multiple submitters, no conflicts
1327024	NM_005482.3(PIGK):c.372C>T (p.Tyr124=)	PIGK	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 0 · 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
PIGK	Strong	Autosomal recessive	neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures	4

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
PIGK	HGNC:8965	ENSG00000142892	Q92643	GPI-anchor transamidase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PIGK	GPI-anchor transamidase	Catalytic subunit 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: 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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIGK	Protease	yes		Peptidase_C13, GPI_transamidase

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
calcaneal tendon	1
endothelial cell	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIGK	279	ubiquitous	marker	endothelial cell, calcaneal tendon, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIGK	1,064

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIGK	Q92643	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	PIGK

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×	9e-04	PIGK
attachment of GPI anchor to protein	1	2106.5×	9e-04	PIGK
GPI anchor biosynthetic process	1	495.6×	0.003	PIGK
proteolysis	1	34.2×	0.029	PIGK

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
PIGK	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
PIGK	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	1	PIGK
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
PIGK	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.