Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis

Summary

Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis (MONDO:0014679) is a disease caused by PI4KA (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: PI4KA (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 67

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis
Mondo ID	MONDO:0014679
OMIM	616531
UMLS	C4225295
MedGen	899982
GARD	0016130
Is cancer (heuristic)	no

Also known as: PMGYCHA · polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis

Data availability: 67 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › polymicrogyria › bilateral polymicrogyria › bilateral perisylvian polymicrogyria › polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis

Related subtypes (2): polymicrogyria, bilateral perisylvian, X-linked, polymicrogyria, bilateral perisylvian, autosomal recessive

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

67 retrieved; paginated sample, class counts are floors:

20 benign, 19 uncertain significance, 14 likely pathogenic, 12 pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
102538	NM_000277.3(PAH):c.1157A>G (p.Tyr386Cys)	PAH	Pathogenic	reviewed by expert panel
580	NM_000277.3(PAH):c.838G>A (p.Glu280Lys)	PAH	Pathogenic	criteria provided, multiple submitters, no conflicts
1034208	NM_058004.4(PI4KA):c.3275C>A (p.Ser1092Ter)	PI4KA	Pathogenic	criteria provided, single submitter
1325871	NM_058004.4(PI4KA):c.2624dup (p.Pro876fs)	PI4KA	Pathogenic	no assertion criteria provided
1325873	NM_058004.4(PI4KA):c.3592G>A (p.Ala1198Thr)	PI4KA	Pathogenic	no assertion criteria provided
1325874	NM_058004.4(PI4KA):c.6156_6159del (p.Thr2053fs)	PI4KA	Pathogenic	criteria provided, multiple submitters, no conflicts
1335866	NM_058004.4(PI4KA):c.5774G>A (p.Gly1925Glu)	PI4KA	Pathogenic	no assertion criteria provided
1335867	NM_058004.4(PI4KA):c.6065del (p.Arg2022fs)	PI4KA	Pathogenic	no assertion criteria provided
1335868	NM_058004.4(PI4KA):c.2330T>C (p.Leu777Pro)	PI4KA	Pathogenic	no assertion criteria provided
1335869	NM_058004.4(PI4KA):c.3571C>T (p.Gln1191Ter)	PI4KA	Pathogenic	no assertion criteria provided
1686063	NM_058004.4(PI4KA):c.2575-1G>A	PI4KA	Pathogenic	criteria provided, single submitter
208450	NM_058004.4(PI4KA):c.2386C>T (p.Arg796Ter)	PI4KA	Pathogenic	no assertion criteria provided
1802598	NM_058004.4(PI4KA):c.[1414A>C;355C>T]		Likely pathogenic	criteria provided, single submitter
1325872	NM_058004.4(PI4KA):c.3454G>A (p.Glu1152Lys)	PI4KA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1675874	NM_058004.4(PI4KA):c.5974C>T (p.Pro1992Ser)	PI4KA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1676320	NM_058004.4(PI4KA):c.1852C>T (p.Arg618Ter)	PI4KA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1723895	NM_058004.4(PI4KA):c.4901del (p.Thr1634fs)	PI4KA	Likely pathogenic	criteria provided, single submitter
208451	NM_058004.4(PI4KA):c.5560G>A (p.Asp1854Asn)	PI4KA	Likely pathogenic	criteria provided, single submitter
3256669	NM_058004.4(PI4KA):c.5821C>T (p.Arg1941Ter)	PI4KA	Likely pathogenic	criteria provided, single submitter
3359036	NM_058004.4(PI4KA):c.3976C>T (p.Arg1326Cys)	PI4KA	Likely pathogenic	criteria provided, single submitter
3544366	NM_058004.4(PI4KA):c.2802_2863-40del	PI4KA	Likely pathogenic	criteria provided, single submitter
3587850	NM_058004.4(PI4KA):c.2988-2A>G	PI4KA	Likely pathogenic	criteria provided, single submitter
4532807	NM_058004.4(PI4KA):c.5362G>T (p.Asp1788Tyr)	PI4KA	Likely pathogenic	criteria provided, single submitter
4686728	NM_058004.4(PI4KA):c.1306C>T (p.Gln436Ter)	PI4KA	Likely pathogenic	criteria provided, single submitter
4845912	NM_058004.4(PI4KA):c.4160+1G>A	PI4KA	Likely pathogenic	criteria provided, single submitter
870385	NM_058004.4(PI4KA):c.2386del (p.Arg796fs)	PI4KA	Likely pathogenic	criteria provided, single submitter
733936	NM_058004.4(PI4KA):c.4672C>T (p.Leu1558=)	PI4KA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
733937	NM_058004.4(PI4KA):c.4368C>T (p.Tyr1456=)	PI4KA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030110	NM_058004.4(PI4KA):c.1076A>G (p.Asn359Ser)	PI4KA	Uncertain significance	criteria provided, single submitter
1030111	NM_058004.4(PI4KA):c.501G>T (p.Met167Ile)	PI4KA	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 6 · 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
PI4KA	Definitive	Autosomal recessive	polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PI4KA	Orphanet:436252	Combined immunodeficiency-multiple intestinal atresia
PI4KA	Orphanet:631079	Autosomal recessive spastic paraplegia type 84
PI4KA	Orphanet:98889	Bilateral perisylvian polymicrogyria
PAH	Orphanet:2209	Maternal phenylketonuria syndrome
PAH	Orphanet:293284	Tetrahydrobiopterin-responsive phenylketonuria
PAH	Orphanet:708895	Tetrahydrobiopterin-unresponsive phenylketonuria

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PI4KA	HGNC:8983	ENSG00000241973	P42356	Phosphatidylinositol 4-kinase alpha	gencc,clinvar
PAH	HGNC:8582	ENSG00000171759	P00439	Phenylalanine-4-hydroxylase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PI4KA	Phosphatidylinositol 4-kinase alpha	Acts on phosphatidylinositol (PtdIns) in the first committed step in the production of the second messenger inositol-1,4,5,-trisphosphate.
PAH	Phenylalanine-4-hydroxylase	Catalyzes the hydroxylation of L-phenylalanine to L-tyrosine.

Protein-family classification

Druggable: 2 · 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
Kinase	1	13.9×	0.142
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PI4KA	Kinase	yes		PI3/4_kinase_cat_dom, PI3K_accessory_dom, Kinase-like_dom_sf
PAH	Enzyme (other)	yes	1.14.16.1	ArAA_hydroxylase, ACT_dom, Phe-4-hydroxylase_tetra

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 9	1
right frontal lobe	1
superior frontal gyrus	1
gall bladder	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PI4KA	143	ubiquitous	marker	superior frontal gyrus, right frontal lobe, Brodmann (1909) area 9
PAH	175	broad	marker	right lobe of liver, liver, gall bladder

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PAH	1,953
PI4KA	1,755

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PAH	P00439	20
PI4KA	P42356	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 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
Phenylketonuria	1	5710.0×	7e-04	PAH
Synthesis of PIPs at the ER membrane	1	1142.0×	0.001	PI4KA
Phenylalanine metabolism	1	951.7×	0.001	PAH
Synthesis of PIPs at the Golgi membrane	1	317.2×	0.003	PI4KA

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
L-tyrosine biosynthetic process	1	8426.0×	4e-04	PAH
amino acid biosynthetic process	1	8426.0×	4e-04	PAH
reorganization of cellular membranes to establish viral sites of replication	1	8426.0×	4e-04	PI4KA
catecholamine biosynthetic process	1	2808.7×	9e-04	PAH
L-phenylalanine catabolic process	1	1053.2×	0.002	PAH
host-mediated perturbation of viral process	1	936.2×	0.002	PI4KA
phosphatidylinositol-mediated signaling	1	351.1×	0.004	PI4KA
phosphatidylinositol phosphate biosynthetic process	1	240.7×	0.005	PI4KA
phosphatidylinositol biosynthetic process	1	183.2×	0.006	PI4KA
signal transduction	1	8.0×	0.121	PI4KA

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
PI4KA	ADENOSINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PI4KA	1	4
PAH	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADENOSINE	4	PI4KA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PI4KA	86	Binding:83, Functional:2, ADMET:1
PAH	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PAH	1.14.16.1	phenylalanine 4-monooxygenase

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

1 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)
ADENOSINE	4	PI4KA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PI4KA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PAH
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)
PAH	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.