Craniosynostosis-anal anomalies-porokeratosis syndrome

Summary

Craniosynostosis-anal anomalies-porokeratosis syndrome (MONDO:0011287) is a disease caused by RNU12 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RNU12 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 5
• Phenotypes (HPO): 35

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0000047	Hypospadias	Very frequent (80-99%)
HP:0000174	Abnormal palate morphology	Very frequent (80-99%)
HP:0000248	Brachycephaly	Very frequent (80-99%)
HP:0000260	Wide anterior fontanel	Very frequent (80-99%)
HP:0000270	Delayed cranial suture closure	Very frequent (80-99%)
HP:0000561	Absent eyelashes	Very frequent (80-99%)
HP:0000682	Abnormality of dental enamel	Very frequent (80-99%)
HP:0000889	Abnormality of the clavicle	Very frequent (80-99%)
HP:0000964	Eczematoid dermatitis	Very frequent (80-99%)
HP:0002007	Frontal bossing	Very frequent (80-99%)
HP:0002023	Anal atresia	Very frequent (80-99%)
HP:0002223	Absent eyebrow	Very frequent (80-99%)
HP:0002697	Parietal foramina	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0004397	Ectopic anus	Very frequent (80-99%)
HP:0004440	Coronal craniosynostosis	Very frequent (80-99%)
HP:0004491	Large posterior fontanelle	Very frequent (80-99%)
HP:0006482	Abnormal dental morphology	Very frequent (80-99%)
HP:0006660	Aplastic clavicles	Very frequent (80-99%)
HP:0008368	Tarsal synostosis	Very frequent (80-99%)
HP:0010306	Short thorax	Very frequent (80-99%)
HP:0012742	Thin fingernail	Very frequent (80-99%)
HP:0100589	Urogenital fistula	Very frequent (80-99%)
HP:0200044	Porokeratosis	Very frequent (80-99%)
HP:0000154	Wide mouth	Frequent (30-79%)
HP:0000272	Malar flattening	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0012471	Thick vermilion border	Frequent (30-79%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0001357	Plagiocephaly	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	craniosynostosis-anal anomalies-porokeratosis syndrome
Mondo ID	MONDO:0011287
MeSH	C536789
OMIM	603116
Orphanet	85199
SNOMED CT	720812002
UMLS	C1864186
MedGen	351066
GARD	0009506
Is cancer (heuristic)	no

Also known as: CAP syndrome · CDAGS syndrome · craniosynostosis and clavicular hypoplasia, delayed closure of the fontanel, anal anomalies and genitourinary malformations

Data availability: 5 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic craniosynostosis › craniosynostosis-anal anomalies-porokeratosis syndrome

Related subtypes (39): Crouzon syndrome, Beare-Stevenson cutis gyrata syndrome, Shprintzen-Goldberg syndrome, acrocephalopolydactyly, Antley-Bixler syndrome, C syndrome, cranioectodermal dysplasia, cardiocranial syndrome, Pfeiffer type, craniosynostosis-fibular aplasia syndrome, Baller-Gerold syndrome, craniotelencephalic dysplasia, Summitt syndrome, X-linked intellectual disability-plagiocephaly syndrome, Lowry-MacLean syndrome, pseudoaminopterin syndrome, craniosynostosis 4, holoprosencephaly-craniosynostosis syndrome, Hunter-McAlpine craniosynostosis, Curry-Jones syndrome, craniomicromelic syndrome, Muenke syndrome, craniosynostosis 2, cloverleaf skull-multiple congenital anomalies syndrome, craniosynostosis-intracranial calcifications syndrome, Crouzon syndrome-acanthosis nigricans syndrome, craniosynostosis and dental anomalies, lethal occipital encephalocele-skeletal dysplasia syndrome, TCF12-related craniosynostosis, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, cloverleaf skull-asphyxiating thoracic dysplasia syndrome, craniosynostosis, Philadelphia type, craniosynostosis-cataract syndrome, familial scaphocephaly syndrome, craniosynostosis-hydrocephalus-Arnold-Chiari malformation type I-radioulnar synostosis syndrome, osteosclerosis-developmental delay-craniosynostosis syndrome, craniosynostosis, Herrmann-Opitz type, trigonocephaly-broad thumbs syndrome, acrocephalosyndactyly, Weiss-Kruszka syndrome

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

5 retrieved; paginated sample, class counts are floors:

3 pathogenic, 1 likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2443783	NC_000022.11:g.42615396C>T	RNU12	Pathogenic	criteria provided, single submitter
2443785	NR_029422.2(RNU12):n.77T>A	RNU12	Pathogenic	criteria provided, single submitter
2443786	NR_029422.2(RNU12):n.77T>G	RNU12	Pathogenic	no assertion criteria provided
2443784	NR_029422.2(RNU12):n.86G>A	RNU12	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2443787	NR_029422.2(RNU12):n.75A>G	RNU12	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
RNU12	Strong	Autosomal recessive	craniosynostosis-anal anomalies-porokeratosis syndrome	2
RNU12-2P	Strong	Autosomal recessive	craniosynostosis-anal anomalies-porokeratosis syndrome	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RNU12	Orphanet:512260	Congenital cerebellar ataxia due to RNU12 mutation
RNU12	Orphanet:85199	Craniosynostosis-anal anomalies-porokeratosis syndrome

Cohort genes → proteins

2 cohort genes, 0 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNU12-2P	HGNC:10109	ENSG00000201659		RNA, U12 small nuclear 2, pseudogene	gencc,clinvar
RNU12	HGNC:19380	ENSG00000276027		RNA, U12 small nuclear	gencc,clinvar

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNU12-2P	Other/Unknown	no
RNU12	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

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
ganglionic eminence	1
monocyte	1
prefrontal cortex	1
adrenal tissue	1
kidney	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNU12-2P	105	ubiquitous	yes	ganglionic eminence, prefrontal cortex, monocyte
RNU12	93	ubiquitous	yes	adrenal tissue, sural nerve, kidney

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RNU12-2P	0
RNU12	0

Structural data

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

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
RNA polymerase II transcribes snRNA genes	1	154.3×	0.006	RNU12

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
RNU12-2P	0	0
RNU12	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	RNU12-2P, RNU12

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)
RNU12-2P	0	—
RNU12	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.