Diencephalic-mesencephalic junction dysplasia syndrome 1

Summary

Diencephalic-mesencephalic junction dysplasia syndrome 1 (MONDO:0009625) is a disease caused by PCDH12 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: PCDH12 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 44

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	diencephalic-mesencephalic junction dysplasia syndrome 1
Mondo ID	MONDO:0009625
MeSH	C537546
OMIM	251280
UMLS	C4538630
MedGen	1615973
GARD	0008510
Is cancer (heuristic)	no

Also known as: DMJDS1 · microcephaly with spastic quadriplegia · MISSBC · recessive microcephaly with spastic quadriplegia

Data availability: 44 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 › diencephalic-mesencephalic junction dysplasia › diencephalic-mesencephalic junction dysplasia syndrome 1

Related subtypes (1): diencephalic-mesencephalic junction dysplasia syndrome 2

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

44 retrieved; paginated sample, class counts are floors:

10 likely pathogenic, 9 uncertain significance, 8 benign, 7 conflicting classifications of pathogenicity, 6 pathogenic, 3 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065612	NM_016580.4(PCDH12):c.2433C>A (p.Cys811Ter)	PCDH12	Pathogenic	criteria provided, single submitter
1323420	NM_016580.4(PCDH12):c.2563C>T (p.Gln855Ter)	PCDH12	Pathogenic	criteria provided, single submitter
1342872	NM_016580.4(PCDH12):c.451C>T (p.Arg151Ter)	PCDH12	Pathogenic	criteria provided, multiple submitters, no conflicts
440889	NM_016580.4(PCDH12):c.2515C>T (p.Arg839Ter)	PCDH12	Pathogenic	criteria provided, multiple submitters, no conflicts
620173	NM_016580.4(PCDH12):c.922C>T (p.Arg308Ter)	PCDH12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
684718	NM_016580.4(PCDH12):c.2511del (p.Ser838fs)	PCDH12	Pathogenic	no assertion criteria provided
694061	PCDH12, ARG151TER	PCDH12	Pathogenic	no assertion criteria provided
817069	NM_016580.4(PCDH12):c.669dup (p.Lys224fs)	PCDH12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452242	NM_016580.4(PCDH12):c.1148C>G (p.Ser383Ter)	RNF14	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1030562	NM_016580.4(PCDH12):c.115G>T (p.Glu39Ter)	PCDH12	Likely pathogenic	criteria provided, single submitter
1343191	NM_016580.4(PCDH12):c.643A>C (p.Thr215Pro)	PCDH12	Likely pathogenic	criteria provided, single submitter
1679306	NM_016580.4(PCDH12):c.207dup (p.Gln70fs)	PCDH12	Likely pathogenic	criteria provided, single submitter
1804020	NM_016580.4(PCDH12):c.311G>A (p.Cys104Tyr)	PCDH12	Likely pathogenic	criteria provided, single submitter
3256111	NM_016580.4(PCDH12):c.2675del (p.Gly892fs)	PCDH12	Likely pathogenic	criteria provided, single submitter
3382378	NM_016580.4(PCDH12):c.2581G>T (p.Glu861Ter)	PCDH12	Likely pathogenic	criteria provided, single submitter
3780103	NM_016580.4(PCDH12):c.2072del (p.Leu690_Leu691insTer)	PCDH12	Likely pathogenic	criteria provided, single submitter
4277803	NM_016580.4(PCDH12):c.39dup (p.Pro14fs)	PCDH12	Likely pathogenic	criteria provided, single submitter
2690666	NM_016580.4(PCDH12):c.1082C>G (p.Ser361Ter)	RNF14	Likely pathogenic	criteria provided, single submitter
4081579	NM_016580.4(PCDH12):c.669del (p.Lys224fs)	RNF14	Likely pathogenic	criteria provided, single submitter
1656563	NM_016580.4(PCDH12):c.2051C>A (p.Pro684His)	PCDH12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1805761	NM_016580.4(PCDH12):c.2374G>A (p.Gly792Arg)	PCDH12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1878726	NM_016580.4(PCDH12):c.1972G>A (p.Val658Ile)	PCDH12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2148455	NM_016580.4(PCDH12):c.3404C>T (p.Ala1135Val)	PCDH12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
587639	NM_016580.4(PCDH12):c.2734C>T (p.Arg912Trp)	PCDH12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
996904	NM_016580.4(PCDH12):c.152A>G (p.Gln51Arg)	PCDH12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1441567	NM_016580.4(PCDH12):c.1758C>T (p.Gly586=)	RNF14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030564	NM_016580.4(PCDH12):c.1951C>G (p.Pro651Ala)	PCDH12	Uncertain significance	criteria provided, single submitter
1030565	NM_016580.4(PCDH12):c.3146G>A (p.Arg1049Gln)	PCDH12	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030566	NM_016580.4(PCDH12):c.3370C>T (p.Arg1124Cys)	PCDH12	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434597	NM_016580.4(PCDH12):c.3419C>T (p.Ser1140Leu)	PCDH12	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
PCDH12	Definitive	Autosomal recessive	diencephalic-mesencephalic junction dysplasia syndrome 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PCDH12	Orphanet:319192	Diencephalic-mesencephalic junction dysplasia

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
PCDH12	HGNC:8657	ENSG00000113555	Q9NPG4	Protocadherin-12	gencc,clinvar
RNF14	HGNC:10058	ENSG00000013561	Q9UBS8	E3 ubiquitin-protein ligase RNF14	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PCDH12	Protocadherin-12	Cellular adhesion molecule that may play an important role in cell-cell interactions at interendothelial junctions.
RNF14	E3 ubiquitin-protein ligase RNF14	E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway, a pathway that takes place when a ribosome has stalled during translation, and which promotes ubiquitination and degradation of trans…

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PCDH12	Other/Unknown	no		Cadherin-like_dom, Cadherin_N, Cadherin-like_sf
RNF14	Transcription factor	no		Znf_RING, IBR_dom, RWD_dom

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
olfactory bulb	1
tendon of biceps brachii	1
type B pancreatic cell	1
adrenal tissue	1
endothelial cell	1
oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PCDH12	217	broad	marker	tendon of biceps brachii, type B pancreatic cell, olfactory bulb
RNF14	289	ubiquitous	marker	adrenal tissue, endothelial cell, oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RNF14	1,270
PCDH12	657

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RNF14	Q9UBS8	83.00
PCDH12	Q9NPG4	66.22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 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
Class I MHC mediated antigen processing & presentation	1	70.1×	0.045	RNF14
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.045	RNF14
Adaptive Immune System	1	29.8×	0.045	RNF14
Immune System	1	13.0×	0.077	RNF14

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
protein-RNA covalent cross-linking repair	1	2808.7×	0.005	RNF14
neuron recognition	1	1685.2×	0.005	PCDH12
labyrinthine layer development	1	1053.2×	0.005	PCDH12
regulation of androgen receptor signaling pathway	1	495.6×	0.007	RNF14
protein K6-linked ubiquitination	1	495.6×	0.007	RNF14
androgen receptor signaling pathway	1	351.1×	0.007	RNF14
regulation of canonical Wnt signaling pathway	1	271.8×	0.007	RNF14
glycogen metabolic process	1	263.3×	0.007	PCDH12
calcium-dependent cell-cell adhesion	1	240.7×	0.007	PCDH12
rescue of stalled cytosolic ribosome	1	240.7×	0.007	RNF14
homophilic cell-cell adhesion	1	70.2×	0.022	PCDH12
ubiquitin-dependent protein catabolic process	1	37.1×	0.038	RNF14
protein ubiquitination	1	20.7×	0.062	RNF14
regulation of DNA-templated transcription	1	15.8×	0.076	RNF14
positive regulation of DNA-templated transcription	1	14.0×	0.080	RNF14
signal transduction	1	8.0×	0.128	RNF14
regulation of transcription by RNA polymerase II	1	5.8×	0.164	RNF14

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PCDH12	0	0
RNF14	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	2	PCDH12, RNF14

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PCDH12	0	—
RNF14	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.