Periventricular leukomalacia

Summary

Periventricular leukomalacia (MONDO:0015742) is a disease with 5 cohort genes and 25 clinical trials. Top therapeutic interventions include indomethacin, magnesium sulfate, and oxygen.

At a glance

• Cohort genes: 5
• ClinVar variants: 7
• Clinical trials: 25

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	periventricular leukomalacia
Mondo ID	MONDO:0015742
EFO	EFO:1001101
MeSH	D007969
Orphanet	171676
DOID	DOID:13088
NCIT	C99013
SNOMED CT	230769007
UMLS	C0023529
MedGen	6072
MedDRA	10052594
Is cancer (heuristic)	no

Also known as: PVL

Data availability: 7 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › encephalomalacia › periventricular leukomalacia

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

7 retrieved; paginated sample, class counts are floors:

3 likely pathogenic, 2 uncertain significance, 1 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
373935	NM_020533.3(MCOLN1):c.777+1G>C	MCOLN1	Pathogenic	criteria provided, multiple submitters, no conflicts
373936	NM_020533.3(MCOLN1):c.378C>G (p.Tyr126Ter)	MCOLN1	Likely pathogenic	no assertion criteria provided
242892	NM_012424.6(RPS6KC1):c.2710G>A (p.Gly904Ser)	RPS6KC1	Likely pathogenic	no assertion criteria provided
242893	Single allele	RPS6KC1	Likely pathogenic	no assertion criteria provided
523488	NM_006015.6(ARID1A):c.5090A>G (p.Asp1697Gly)	ARID1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2570663	NM_172230.3(SYVN1):c.38C>T (p.Ala13Val)	SYVN1	Uncertain significance	criteria provided, single submitter
2570664	NM_172230.3(SYVN1):c.68A>G (p.Tyr23Cys)	SYVN1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
PLEKHG1	Limited	Autosomal dominant	periventricular leukomalacia
RPS6KC1	Limited	Autosomal recessive	periventricular leukomalacia

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARID1A	Orphanet:1465	Coffin-Siris syndrome
MCOLN1	Orphanet:578	Mucolipidosis type IV

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RPS6KC1	HGNC:10439	ENSG00000136643	Q96S38	Ribosomal protein S6 kinase delta-1	gencc,clinvar
PLEKHG1	HGNC:20884	ENSG00000120278	Q9ULL1	Pleckstrin homology domain-containing family G member 1	gencc
ARID1A	HGNC:11110	ENSG00000117713	O14497	AT-rich interactive domain-containing protein 1A	clinvar
MCOLN1	HGNC:13356	ENSG00000090674	Q9GZU1	Mucolipin-1	clinvar
SYVN1	HGNC:20738	ENSG00000162298	Q86TM6	E3 ubiquitin-protein ligase synoviolin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RPS6KC1	Ribosomal protein S6 kinase delta-1	May be involved in transmitting sphingosine-1 phosphate (SPP)-mediated signaling into the cell.
PLEKHG1	Pleckstrin homology domain-containing family G member 1	Acts as a guanine nucleotide exchange factor (GEF) for RAC1 and CDC42.
ARID1A	AT-rich interactive domain-containing protein 1A	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
MCOLN1	Mucolipin-1	Nonselective cation channel probably playing a role in the regulation of membrane trafficking events and of metal homeostasis.
SYVN1	E3 ubiquitin-protein ligase synoviolin	E3 ubiquitin-protein ligase which accepts ubiquitin specifically from endoplasmic reticulum-associated UBC7 E2 ligase and transfers it to substrates, promoting their degradation.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.2

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	5.5×	0.515
Scaffold/PPI	1	3.5×	0.515
Transcription factor	1	1.6×	0.634
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RPS6KC1	Kinase	yes		Prot_kinase_dom, PX_dom, MIT_dom
PLEKHG1	Scaffold/PPI	no		DH_dom, PH_domain, PH-like_dom_sf
ARID1A	Other/Unknown	no		ARID_dom, ARM-like, ARM-type_fold
MCOLN1	Other/Unknown	no		PKD1_2_channel, Mucolipin, ML1_ELD
SYVN1	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, HRD1_E3_ubiq-ligases

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ileal mucosa	2
spleen	2
calcaneal tendon	1
male germ cell	1
sperm	1
sural nerve	1
bone marrow cell	1
embryo	1
ventricular zone	1
right adrenal gland	1
right adrenal gland cortex	1
body of pancreas	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RPS6KC1	275	ubiquitous	marker	sperm, male germ cell, calcaneal tendon
PLEKHG1	214	ubiquitous	marker	sural nerve, ileal mucosa, spleen
ARID1A	286	ubiquitous	marker	bone marrow cell, ventricular zone, embryo
MCOLN1	255	ubiquitous	marker	spleen, right adrenal gland cortex, right adrenal gland
SYVN1	255	ubiquitous	marker	ileal mucosa, body of pancreas, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARID1A	3,476
SYVN1	2,205
MCOLN1	1,412
RPS6KC1	1,275
PLEKHG1	991

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MCOLN1	Q9GZU1	25
ARID1A	O14497	7
SYVN1	Q86TM6	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RPS6KC1	Q96S38	56.74
PLEKHG1	Q9ULL1	50.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 45. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Hh mutants abrogate ligand secretion	1	356.9×	0.037	SYVN1
Positive Regulation of CDH1 Gene Transcription	1	237.9×	0.037	ARID1A
Calnexin/calreticulin cycle	1	178.4×	0.037	SYVN1
Formation of the canonical BAF (cBAF) complex	1	158.6×	0.037	ARID1A
Formation of the embryonic stem cell BAF (esBAF) complex	1	150.3×	0.037	ARID1A
ER Quality Control Compartment (ERQC)	1	135.9×	0.037	SYVN1
IRE1alpha activates chaperones	1	129.8×	0.037	SYVN1
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	114.2×	0.037	ARID1A
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1	105.7×	0.037	SYVN1
TRP channels	1	102.0×	0.037	MCOLN1
Transferrin endocytosis and recycling	1	92.1×	0.037	MCOLN1
Regulation of endogenous retroelements	1	92.1×	0.037	ARID1A
Unfolded Protein Response (UPR)	1	89.2×	0.037	SYVN1
Iron uptake and transport	1	86.5×	0.037	MCOLN1
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	75.1×	0.040	ARID1A
Regulation of MITF-M-dependent genes involved in pigmentation	1	66.4×	0.042	ARID1A
Hh mutants are degraded by ERAD	1	60.7×	0.043	SYVN1
XBP1(S) activates chaperone genes	1	53.9×	0.044	SYVN1
Hedgehog ligand biogenesis	1	52.9×	0.044	SYVN1
Signaling by Hedgehog	1	46.0×	0.047	SYVN1
MITF-M-dependent gene expression	1	45.3×	0.047	ARID1A
RMTs methylate histone arginines	1	36.6×	0.053	ARID1A
Transcriptional regulation by RUNX1	1	36.6×	0.053	ARID1A
Stimuli-sensing channels	1	34.0×	0.055	MCOLN1
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	1	29.4×	0.060	ARID1A
MITF-M-regulated melanocyte development	1	28.6×	0.060	ARID1A
Ion channel transport	1	24.0×	0.068	MCOLN1
Chromatin organization	1	20.4×	0.077	ARID1A
Chromatin modifying enzymes	1	18.1×	0.080	ARID1A
CDC42 GTPase cycle	1	18.1×	0.080	PLEKHG1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
calcium ion export	1	842.6×	0.019	MCOLN1
positive regulation of lysosome organization	1	842.6×	0.019	MCOLN1
immature B cell differentiation	1	481.5×	0.019	SYVN1
iron ion transmembrane transport	1	481.5×	0.019	MCOLN1
cellular response to pH	1	421.3×	0.019	MCOLN1
transferrin transport	1	306.4×	0.021	MCOLN1
phagosome maturation	1	240.7×	0.021	MCOLN1
endoplasmic reticulum mannose trimming	1	240.7×	0.021	SYVN1
retrograde protein transport, ER to cytosol	1	198.3×	0.022	SYVN1
negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1	168.5×	0.022	SYVN1
nucleosome disassembly	1	160.5×	0.022	ARID1A
monoatomic cation transport	1	153.2×	0.022	MCOLN1
regulation of G0 to G1 transition	1	134.8×	0.023	ARID1A
regulation of nucleotide-excision repair	1	120.4×	0.024	ARID1A
regulation of mitotic metaphase/anaphase transition	1	99.1×	0.026	ARID1A
intracellular zinc ion homeostasis	1	96.3×	0.026	MCOLN1
positive regulation of T cell differentiation	1	91.1×	0.026	ARID1A
transcription initiation-coupled chromatin remodeling	1	76.6×	0.026	ARID1A
positive regulation of myoblast differentiation	1	73.3×	0.026	ARID1A
autophagosome maturation	1	70.2×	0.026	MCOLN1
release of sequestered calcium ion into cytosol	1	68.8×	0.026	MCOLN1
positive regulation of stem cell population maintenance	1	68.8×	0.026	ARID1A
positive regulation of double-strand break repair	1	68.8×	0.026	ARID1A
regulation of G1/S transition of mitotic cell cycle	1	61.3×	0.028	ARID1A
positive regulation of cell differentiation	1	53.5×	0.030	ARID1A
protein homotetramerization	1	47.5×	0.033	MCOLN1
calcium ion transmembrane transport	1	42.1×	0.036	MCOLN1
cellular response to calcium ion	1	40.1×	0.036	MCOLN1
ERAD pathway	1	36.2×	0.039	SYVN1
protein K48-linked ubiquitination	1	33.7×	0.040	SYVN1

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Magnesium Sulfate Anhydrous	Phase 3 (in late-stage trials)

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 4 of 5 evidence-associated genes (80%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RPS6KC1	0	0
PLEKHG1	0	0
ARID1A	0	0
MCOLN1	0	0
SYVN1	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
RPS6KC1	22	Binding:22
MCOLN1	9	Binding:9
ARID1A	6	Binding:6
SYVN1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	RPS6KC1
E	Difficult family or no structure, no drug	4	PLEKHG1, ARID1A, MCOLN1, SYVN1

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RPS6KC1	22	—
PLEKHG1	0	—
ARID1A	6	—
MCOLN1	9	—
SYVN1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 25.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	14
PHASE3	3
PHASE2	3
PHASE1/PHASE2	2
PHASE4	1
PHASE2/PHASE3	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00120588	PHASE4	COMPLETED	Neuroprotection by Magnesium Sulfate Given to Women at Risk of Very Preterm Birth
NCT00014989	PHASE3	COMPLETED	Beneficial Effects of Antenatal Magnesium Sulfate (BEAM Trial)
NCT00303082	PHASE3	TERMINATED	Probiotics for the Prevention of Premature Birth and Neonatal Related Morbidity
NCT00515281	PHASE2/PHASE3	TERMINATED	Inhaled Nitric Oxide and Neuroprotection in Premature Infants
NCT03110341	PHASE3	UNKNOWN	Effect of Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome
NCT00413946	PHASE2	COMPLETED	Does Erythropoietin Improve Outcome in Very Preterm Infants?
NCT00589953	PHASE2	TERMINATED	High-Dose Erythropoietin in Extremely Premature Infants to Prevent/Attenuate Brain Injury: A Phase II Study
NCT02221219	PHASE1/PHASE2	COMPLETED	Effects of Delayed Cord Clamp and/or Indomethacin on Preterm Infant Brain Injury
NCT02784821	PHASE2	COMPLETED	Antibiotic Dysbiosis in Preterm Infants
NCT04873752	PHASE1/PHASE2	COMPLETED	A Study to Investigate the Safety and Efficacy of UC-MSCs in Pediatric Patients With Cerebral Palsy
NCT06985303	EARLY_PHASE1	WITHDRAWN	Cell-Based Therapy for White Matter Repair in Periventricular Leukomalacia
NCT03672877	Not specified	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Early Intensive Leg Exercise to Improve Walking in Children With Diplegia
NCT05520359	Not specified	RECRUITING	Spinal Stimulation and Mobility Devices
NCT06045130	Not specified	NOT_YET_RECRUITING	PUFAs in Preterm Infants
NCT07275021	Not specified	RECRUITING	Cerebral/ Cortical Visual Impairment: Screening, Identification and Outcome Prediction in Neonates
NCT00375908	Not specified	COMPLETED	Umbilical Cord Blood Proteomic Analysis and Neonatal Brain Injury
NCT02082535	Not specified	UNKNOWN	S100B as a Marker of Brain Injury of Preterm Infants
NCT02342990	Not specified	COMPLETED	Telerehabilitation of Working Memory in Children With Periventricular Leukomalacia and Bilateral Cerebral Palsy
NCT02814383	Not specified	COMPLETED	Prediction of Brain Injury in Premature Infants
NCT03230032	Not specified	COMPLETED	Pacifier Activated Device and Mother’s Voice in Infants at High-risk for Cerebral Palsy
NCT03527498	Not specified	WITHDRAWN	Evaluation of Long-term Neurodevelopment in Neonatal Encephalopathy by Infant Treadmill
NCT03534466	Not specified	TERMINATED	Evaluation of Long-Term Gait Development in Infants With Neonatal Encephalopathy Using Infant Treadmill
NCT03635775	Not specified	COMPLETED	Single-session tDCS in Cerebral Palsy
NCT04077333	Not specified	COMPLETED	MISA to NRDS：a Multicenter Study in China
NCT04535375	Not specified	COMPLETED	Sonographic QUantification of Venous Circulation In the Preterm Brain

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
INDOMETHACIN	4	1
MAGNESIUM SULFATE	4	1
OXYGEN	4	1
MAGNESIUM	3	1
17	0	1