Hydrocephalus, nonsyndromic, autosomal recessive 2

Summary

Hydrocephalus, nonsyndromic, autosomal recessive 2 (MONDO:0014085) is a disease caused by MPDZ (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: MPDZ (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 102

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hydrocephalus, nonsyndromic, autosomal recessive 2
Mondo ID	MONDO:0014085
OMIM	615219
UMLS	C3554691
MedGen	767605
GARD	0024970
Is cancer (heuristic)	no

Also known as: congenital hydrocephalus caused by mutation in MPDZ · HYC2 · hydrocephalus, congenital, 2, with or without brain or eye anomalies · hydrocephalus, nonsyndromic, autosomal recessive 2 · hydrocephalus, nonsyndromic, autosomal recessive type 2 · MPDZ congenital hydrocephalus

Data availability: 102 ClinVar variants · 6 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 › hydrocephalus › congenital hydrocephalus › hydrocephalus, nonsyndromic, autosomal recessive 2

Related subtypes (7): hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, hydrocephalus-blue sclerae-nephropathy syndrome, congenital communicating hydrocephalus, congenital non-communicating hydrocephalus, hydrocephalus, congenital, 3, with brain anomalies

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

102 retrieved; paginated sample, class counts are floors:

43 uncertain significance, 16 pathogenic, 14 likely pathogenic, 12 pathogenic/likely pathogenic, 12 conflicting classifications of pathogenicity, 4 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
203539	NM_000016.6(ACADM):c.698T>C (p.Ile233Thr)	ACADM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3062634	GRCh37/hg19 2p23.3(chr2:25437125-25487783)x1	DNMT3A	Pathogenic	criteria provided, single submitter
1027378	NM_001378778.1(MPDZ):c.5125_5126insGTAT (p.Tyr1709fs)	MPDZ	Pathogenic	no assertion criteria provided
1029761	NM_001378778.1(MPDZ):c.3360-2A>G	MPDZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068747	NM_001378778.1(MPDZ):c.1338_1341dup (p.Leu448fs)	MPDZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1204727	NM_001378778.1(MPDZ):c.1735C>T (p.Arg579Ter)	MPDZ	Pathogenic	criteria provided, multiple submitters, no conflicts
1323286	NM_001378778.1(MPDZ):c.414del (p.Phe138fs)	MPDZ	Pathogenic	criteria provided, multiple submitters, no conflicts
1374316	NM_001378778.1(MPDZ):c.3820_3821del (p.Leu1274fs)	MPDZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1409768	NM_001378778.1(MPDZ):c.4804C>T (p.Arg1602Ter)	MPDZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1703122	NM_001378778.1(MPDZ):c.1445T>A (p.Leu482Ter)	MPDZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208595	NM_001378778.1(MPDZ):c.4906C>T (p.Arg1636Ter)	MPDZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
211521	NM_001378778.1(MPDZ):c.755G>A (p.Trp252Ter)	MPDZ	Pathogenic	criteria provided, single submitter
2691339	NC_000009.11:g.(13133904_13136090)_(13136182_13136710)del	MPDZ	Pathogenic	criteria provided, single submitter
3383154	NM_001378778.1(MPDZ):c.2633dup (p.Ser879fs)	MPDZ	Pathogenic	criteria provided, single submitter
3383155	NM_001378778.1(MPDZ):c.3382C>T (p.Arg1128Ter)	MPDZ	Pathogenic	criteria provided, single submitter
3773768	NM_001378778.1(MPDZ):c.1354G>T (p.Gly452Ter)	MPDZ	Pathogenic	criteria provided, single submitter
4803681	NM_001378778.1(MPDZ):c.5897del (p.Ser1966fs)	MPDZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4819825	NM_001378778.1(MPDZ):c.5380-1G>A	MPDZ	Pathogenic	criteria provided, single submitter
4819847	NM_001378778.1(MPDZ):c.2383del (p.Tyr795fs)	MPDZ	Pathogenic	criteria provided, single submitter
50213	NM_001378778.1(MPDZ):c.628C>T (p.Gln210Ter)	MPDZ	Pathogenic	criteria provided, single submitter
548147	NM_001378778.1(MPDZ):c.4469del (p.Gln1490fs)	MPDZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
548148	NM_001378778.1(MPDZ):c.2230C>T (p.Arg744Ter)	MPDZ	Pathogenic	criteria provided, single submitter
548149	NM_001378778.1(MPDZ):c.3211C>T (p.Arg1071Ter)	MPDZ	Pathogenic	criteria provided, multiple submitters, no conflicts
804414	NM_001378778.1(MPDZ):c.4003A>T (p.Lys1335Ter)	MPDZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
929452	NM_001378778.1(MPDZ):c.2882_2885dup (p.Ser963fs)	MPDZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
929453	NM_001378778.1(MPDZ):c.4003+1G>A	MPDZ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
982061	NM_001378778.1(MPDZ):c.5305G>T (p.Gly1769Ter)	MPDZ	Pathogenic	criteria provided, multiple submitters, no conflicts
993002	NM_001378778.1(MPDZ):c.1502dup (p.Leu501fs)	MPDZ	Pathogenic	criteria provided, single submitter
3390955	NM_001025356.3(ANO6):c.1518del (p.Ala507fs)	ANO6	Likely pathogenic	criteria provided, single submitter
1519376	NM_001378778.1(MPDZ):c.3359+1G>A	MPDZ	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 7 · 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
MPDZ	Strong	Autosomal recessive	hydrocephalus, nonsyndromic, autosomal recessive 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MPDZ	Orphanet:269505	Congenital communicating hydrocephalus
ANO6	Orphanet:806	Scott syndrome
DNMT3A	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
DNMT3A	Orphanet:404443	Tatton-Brown-Rahman syndrome
DNMT3A	Orphanet:658595	DNMT3A-related microcephalic dwarfism
DNMT3A	Orphanet:86845	Acute myeloid leukaemia with myelodysplasia-related features
ACADM	Orphanet:42	Medium chain acyl-CoA dehydrogenase deficiency

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MPDZ	HGNC:7208	ENSG00000107186	O75970	Multiple PDZ domain protein	gencc,clinvar
ANO6	HGNC:25240	ENSG00000177119	Q4KMQ2	Anoctamin-6	clinvar
DNMT3A	HGNC:2978	ENSG00000119772	Q9Y6K1	DNA (cytosine-5)-methyltransferase 3A	clinvar
ACADM	HGNC:89	ENSG00000117054	P11310	Medium-chain specific acyl-CoA dehydrogenase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MPDZ	Multiple PDZ domain protein	Member of the NMDAR signaling complex that may play a role in control of AMPAR potentiation and synaptic plasticity in excitatory synapses.
ANO6	Anoctamin-6	Small-conductance calcium-activated nonselective cation (SCAN) channel which acts as a regulator of phospholipid scrambling in platelets and osteoblasts.
DNMT3A	DNA (cytosine-5)-methyltransferase 3A	Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development.
ACADM	Medium-chain specific acyl-CoA dehydrogenase, mitochondrial	Medium-chain specific acyl-CoA dehydrogenase is one of the acyl-CoA dehydrogenases that catalyze the first step of mitochondrial fatty acid beta-oxidation (FAO), breaking down fatty acids into acetyl-CoA and allowing the production of ener…

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

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
Complement	1	67.0×	0.059
Scaffold/PPI	1	4.3×	0.392
Enzyme (other)	1	3.0×	0.392
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MPDZ	Scaffold/PPI	no		PDZ, L27_dom, L27_2
ANO6	Other/Unknown	no		Anoctamin, Anoct_dimer, Anoctamin_TM
DNMT3A	Complement	yes	2.1.1.37	PWWP_dom, C5_MeTfrase, C5_DNA_meth_AS
ACADM	Enzyme (other)	yes	1.3.8.7	Acyl-CoA_DH_CS, AcylCoA_DH/ox_M, AcylCo_DH/oxidase_C

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	2
calcaneal tendon	1
corpus callosum	1
epithelial cell of pancreas	1
secondary oocyte	1
tibialis anterior	1
ganglionic eminence	1
sural nerve	1
biceps brachii	1
jejunal mucosa	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MPDZ	274	ubiquitous	marker	calcaneal tendon, corpus callosum, ventricular zone
ANO6	254	ubiquitous	marker	epithelial cell of pancreas, secondary oocyte, tibialis anterior
DNMT3A	223	ubiquitous	marker	sural nerve, ganglionic eminence, ventricular zone
ACADM	292	ubiquitous	marker	jejunal mucosa, skeletal muscle tissue of rectus abdominis, biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNMT3A	4,771
MPDZ	3,527
ACADM	3,245
ANO6	1,218

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNMT3A	Q9Y6K1	43
MPDZ	O75970	9
ACADM	P11310	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANO6	Q4KMQ2	82.00

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 32. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ANO6 does not expose PS, PE on the platelet membrane	1	3806.7×	0.008	ANO6
Beta oxidation of octanoyl-CoA to hexanoyl-CoA	1	761.3×	0.012	ACADM
mitochondrial fatty acid beta-oxidation of unsaturated fatty acids	1	634.4×	0.012	ACADM
Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA	1	634.4×	0.012	ACADM
mitochondrial fatty acid beta-oxidation of saturated fatty acids	1	543.8×	0.012	ACADM
Induction of Cell-Cell Fusion	1	292.8×	0.018	ANO6
SUMOylation of DNA methylation proteins	1	223.9×	0.019	DNMT3A
Amplification and propagation of coagulation cascade	1	211.5×	0.019	ANO6
Mitochondrial Fatty Acid Beta-Oxidation	1	126.9×	0.028	ACADM
Late SARS-CoV-2 Infection Events	1	97.6×	0.033	ANO6
Regulation of clotting cascade	1	77.7×	0.037	ANO6
DNA methylation	1	59.5×	0.040	DNMT3A
Defective pyroptosis	1	52.1×	0.040	DNMT3A
PRC2 methylates histones and DNA	1	50.8×	0.040	DNMT3A
RMTs methylate histone arginines	1	48.8×	0.040	DNMT3A
Regulation of lipid metabolism by PPARalpha	1	47.0×	0.040	ACADM
Stimuli-sensing channels	1	45.3×	0.040	ANO6
Fatty acid metabolism	1	43.8×	0.040	ACADM
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	1	39.2×	0.043	DNMT3A
Ion channel transport	1	32.0×	0.048	ANO6
PPARA activates gene expression	1	31.5×	0.048	ACADM
SARS-CoV-2 Infection	1	26.8×	0.054	ANO6
SARS-CoV Infections	1	18.5×	0.074	ANO6
Metabolism of lipids	1	10.5×	0.121	ACADM
Viral Infection Pathways	1	10.3×	0.121	ANO6
Innate Immune System	1	8.5×	0.133	ANO6
Transport of small molecules	1	8.4×	0.133	ANO6
Infectious disease	1	8.3×	0.133	ANO6
Neutrophil degranulation	1	7.7×	0.137	ANO6
Disease	1	4.4×	0.221	ANO6

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
phosphatidylserine exposure on blood platelet	1	4213.0×	0.005	ANO6
positive regulation of monoatomic ion transmembrane transport	1	2106.5×	0.005	ANO6
activation of blood coagulation via clotting cascade	1	1404.3×	0.005	ANO6
carnitine metabolic process, CoA-linked	1	1404.3×	0.005	ACADM
positive regulation of cellular response to hypoxia	1	1404.3×	0.005	DNMT3A
positive regulation of potassium ion export across plasma membrane	1	1404.3×	0.005	ANO6
purinergic nucleotide receptor signaling pathway	1	1053.2×	0.005	ANO6
calcium activated phosphatidylserine scrambling	1	1053.2×	0.005	ANO6
carnitine biosynthetic process	1	842.6×	0.005	ACADM
negative regulation of cell volume	1	842.6×	0.005	ANO6
medium-chain fatty acid catabolic process	1	842.6×	0.005	ACADM
calcium activated phosphatidylcholine scrambling	1	842.6×	0.005	ANO6
cellular response to bisphenol A	1	842.6×	0.005	DNMT3A
post-embryonic development	2	102.8×	0.005	DNMT3A, ACADM
medium-chain fatty acid metabolic process	1	702.2×	0.006	ACADM
tight junction assembly	1	601.9×	0.006	MPDZ
autosome genomic imprinting	1	601.9×	0.006	DNMT3A
regulatory ncRNA-mediated heterochromatin formation	1	468.1×	0.007	DNMT3A
pore complex assembly	1	468.1×	0.007	ANO6
plasma membrane phospholipid scrambling	1	383.0×	0.007	ANO6
bleb assembly	1	383.0×	0.007	ANO6
fatty acid beta-oxidation using acyl-CoA dehydrogenase	1	351.1×	0.008	ACADM
positive regulation of phagocytosis, engulfment	1	324.1×	0.008	ANO6
regulation of gluconeogenesis	1	280.9×	0.008	ACADM
transposable element silencing by piRNA-mediated DNA methylation	1	280.9×	0.008	DNMT3A
response to vitamin A	1	263.3×	0.008	DNMT3A
negative regulation of gene expression via chromosomal CpG island methylation	1	263.3×	0.008	DNMT3A
cellular response to ethanol	1	263.3×	0.008	DNMT3A
hepatocyte apoptotic process	1	263.3×	0.008	DNMT3A
glycogen biosynthetic process	1	234.1×	0.008	ACADM

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MPDZ	0	0
ANO6	0	0
DNMT3A	0	0
ACADM	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
DNMT3A	120	Binding:118, ADMET:1, Functional:1
ACADM	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DNMT3A	2.1.1.37	DNA (cytosine-5-)-methyltransferase
ACADM	1.3.8.7	medium-chain acyl-CoA dehydrogenase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
DNMT3A	120

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	2	DNMT3A, ACADM
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MPDZ, ANO6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DNMT3A	120	—
MPDZ	0	—
ANO6	0	—
ACADM	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.