Weiss-Kruszka syndrome

Summary

Weiss-Kruszka syndrome (MONDO:0032836) is a disease caused by ZNF462 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ZNF462 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 123
• Phenotypes (HPO): 29

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0000508	Ptosis	Very frequent (80-99%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000289	Broad philtrum	Frequent (30-79%)
HP:0000356	Abnormality of the outer ear	Frequent (30-79%)
HP:0000494	Downslanted palpebral fissures	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0002263	Exaggerated cupid’s bow	Frequent (30-79%)
HP:0002553	Highly arched eyebrow	Frequent (30-79%)
HP:0003196	Short nose	Frequent (30-79%)
HP:0005274	Prominent nasal tip	Frequent (30-79%)
HP:0005487	Prominent metopic ridge	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000824	Decreased response to growth hormone stimulation test	Occasional (5-29%)
HP:0000954	Single transverse palmar crease	Occasional (5-29%)
HP:0001627	Abnormal heart morphology	Occasional (5-29%)
HP:0002870	Obstructive sleep apnea	Occasional (5-29%)
HP:0004209	Clinodactyly of the 5th finger	Occasional (5-29%)
HP:0006989	Dysplastic corpus callosum	Occasional (5-29%)
HP:0033454	Tube feeding	Occasional (5-29%)
HP:0040064	Abnormality of limbs	Occasional (5-29%)
HP:0009623	Proximal placement of thumb	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Weiss-Kruszka syndrome
Mondo ID	MONDO:0032836
OMIM	618619
Orphanet	502430
UMLS	C5568107
MedGen	1799530
GARD	0027945
Is cancer (heuristic)	no

Also known as: metopic ridging-ptosis-facial dysmorphism syndrome · Weiss-Kruszka syndrome · WSKA · ZNF462 disorder

Data availability: 123 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › multiple congenital anomalies/dysmorphic syndrome › multiple congenital anomalies/dysmorphic syndrome-variable intellectual disability syndrome › Weiss-Kruszka syndrome

Related subtypes (68): acromegaloid facial appearance syndrome, Hypoglossia-hypodactyly syndrome, Brachymorphism-onychodysplasia-dysphalangism syndrome, campomelic dysplasia, cerebrocostomandibular syndrome, autosomal dominant popliteal pterygium syndrome, Pallister-Hall syndrome, autosomal dominant primary microcephaly, microgastria-limb reduction defect syndrome, Mobius syndrome, oculodentodigital dysplasia, Char syndrome, Prader-Willi syndrome, Silver-Russell syndrome, ulnar-mammary syndrome, short stature-wormian bones-dextrocardia syndrome, ablepharon macrostomia syndrome, Goodman syndrome, anophthalmia/microphthalmia-esophageal atresia syndrome, microphthalmia with limb anomalies, Antley-Bixler syndrome, campomelia, Cumming type, CHARGE syndrome, Toriello-Carey syndrome, Donnai-Barrow syndrome, lethal faciocardiomelic dysplasia, hypertrichotic osteochondrodysplasia Cantu type, hypomandibular faciocranial dysostosis, isotretinoin-like syndrome, split hand-foot malformation 3, oculotrichoanal syndrome, Hennekam-Beemer syndrome, Mietens syndrome, Schinzel-Giedion syndrome, SHORT syndrome, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, occipital horn syndrome, hydrocephalus-costovertebral dysplasia-Sprengel anomaly syndrome, Potocki-Shaffer syndrome, Marshall-Smith syndrome, PHACE syndrome, Noonan syndrome-like disorder with loose anagen hair, branchiogenic deafness syndrome, combined immunodeficiency with faciooculoskeletal anomalies, chromosome 1p32-p31 deletion syndrome, Malan overgrowth syndrome, dysmorphism-conductive hearing loss-heart defect syndrome, TELO2-related intellectual disability-neurodevelopmental disorder, short stature-heart defect-craniofacial anomalies syndrome, arachnodactyly-intellectual disability-dysmorphism syndrome, polyvalvular heart disease syndrome, Kallmann syndrome-heart disease syndrome, Meier-Gorlin syndrome, symptomatic form of Coffin-Lowry syndrome in female carriers, Prader-Willi-like syndrome, contractures-developmental delay-Pierre Robin syndrome, 22q11.2 deletion syndrome, Noonan syndrome, Carpenter syndrome, Bosley-Salih-Alorainy syndrome, Sotos syndrome, Robinow syndrome, King-Denborough syndrome, retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome, omphalocele-diaphragmatic hernia-cardiovascular anomalies-radial ray defect syndrome, 4q25 proximal deletion syndrome, restrictive dermopathy 1, mosaic SMO 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

123 retrieved; paginated sample, class counts are floors:

56 uncertain significance, 33 pathogenic, 22 likely pathogenic, 5 benign, 3 benign/likely benign, 2 pathogenic/likely pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2579281	GRCh38/hg38 9q31.1-31.3(chr9:102995214-108903040)x1	ABCA1	Pathogenic	criteria provided, single submitter
1285511	NM_021224.6(ZNF462):c.3700C>T (p.Arg1234Ter)	ZNF462	Pathogenic	criteria provided, multiple submitters, no conflicts
1299321	NM_021224.6(ZNF462):c.220+1G>A	ZNF462	Pathogenic	criteria provided, single submitter
1343244	NM_021224.6(ZNF462):c.2029del (p.Arg677fs)	ZNF462	Pathogenic	criteria provided, single submitter
1709341	NM_021224.6(ZNF462):c.4825dup (p.Ser1609fs)	ZNF462	Pathogenic	criteria provided, single submitter
1803088	NM_021224.6(ZNF462):c.5941C>T (p.Arg1981Ter)	ZNF462	Pathogenic	criteria provided, single submitter
1992398	NM_021224.6(ZNF462):c.3937del (p.His1313fs)	ZNF462	Pathogenic	criteria provided, single submitter
2499557	NM_021224.6(ZNF462):c.718C>T (p.Arg240Ter)	ZNF462	Pathogenic	criteria provided, single submitter
2500924	NM_021224.6(ZNF462):c.3502dup (p.Arg1168fs)	ZNF462	Pathogenic	criteria provided, single submitter
2631549	NM_021224.6(ZNF462):c.6163C>T (p.Arg2055Ter)	ZNF462	Pathogenic	criteria provided, single submitter
2671804	NM_021224.6(ZNF462):c.4180del (p.Trp1394fs)	ZNF462	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2671805	NM_021224.6(ZNF462):c.1690C>T (p.Gln564Ter)	ZNF462	Pathogenic	criteria provided, single submitter
2671806	NM_021224.6(ZNF462):c.1151del (p.Asn384fs)	ZNF462	Pathogenic	criteria provided, single submitter
2671807	NM_021224.6(ZNF462):c.507C>A (p.Tyr169Ter)	ZNF462	Pathogenic	criteria provided, single submitter
2671810	NM_021224.6(ZNF462):c.2726del (p.His909fs)	ZNF462	Pathogenic	criteria provided, single submitter
3027495	NM_021224.6(ZNF462):c.5323C>T (p.Gln1775Ter)	ZNF462	Pathogenic	criteria provided, single submitter
3195930	NM_021224.6(ZNF462):c.3305dup (p.Gln1103fs)	ZNF462	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3254949	NM_021224.6(ZNF462):c.1937_1940del (p.Asp646fs)	ZNF462	Pathogenic	criteria provided, single submitter
3359072	NM_021224.6(ZNF462):c.1975C>T (p.Gln659Ter)	ZNF462	Pathogenic	criteria provided, single submitter
3376290	NM_021224.6(ZNF462):c.3111_3131delinsA (p.Phe1037fs)	ZNF462	Pathogenic	criteria provided, single submitter
3377166	NM_021224.6(ZNF462):c.2987del (p.Arg996fs)	ZNF462	Pathogenic	criteria provided, single submitter
402116	NM_021224.6(ZNF462):c.3787C>T (p.Arg1263Ter)	ZNF462	Pathogenic	no assertion criteria provided
402118	NM_021224.6(ZNF462):c.2979_2980delinsA (p.Val994fs)	ZNF462	Pathogenic	criteria provided, single submitter
4279003	NM_021224.6(ZNF462):c.4779_4780insC (p.Ile1594fs)	ZNF462	Pathogenic	criteria provided, single submitter
4530618	NM_021224.6(ZNF462):c.4460_4463del (p.Thr1487fs)	ZNF462	Pathogenic	criteria provided, single submitter
4532107	NM_021224.6(ZNF462):c.1910_1911dup (p.Ser638fs)	ZNF462	Pathogenic	criteria provided, single submitter
4685556	NM_021224.6(ZNF462):c.3414del (p.Glu1139fs)	ZNF462	Pathogenic	criteria provided, single submitter
4795247	NM_021224.6(ZNF462):c.6832+2T>C	ZNF462	Pathogenic	criteria provided, single submitter
691878	NM_021224.6(ZNF462):c.5145del (p.Tyr1716fs)	ZNF462	Pathogenic	no assertion criteria provided
691879	NM_021224.6(ZNF462):c.2542del (p.Cys848fs)	ZNF462	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 3 · 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
ZNF462	Definitive	Autosomal dominant	Weiss-Kruszka syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZNF462	Orphanet:502430	Weiss-Kruszka Syndrome
ABCA1	Orphanet:31150	Tangier disease
ABCA1	Orphanet:425	Apolipoprotein A-I deficiency

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
ZNF462	HGNC:21684	ENSG00000148143	Q96JM2	Zinc finger protein 462	gencc,clinvar
ABCA1	HGNC:29	ENSG00000165029	O95477	Phospholipid-transporting ATPase ABCA1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZNF462	Zinc finger protein 462	Zinc finger nuclear factor involved in transcription by regulating chromatin structure and organization.
ABCA1	Phospholipid-transporting ATPase ABCA1	Catalyzes the translocation of specific phospholipids from the cytoplasmic to the extracellular/lumenal leaflet of membrane coupled to the hydrolysis of ATP.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Transporter	1	38.9×	0.051
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZNF462	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Zinc_finger/UBP_domain
ABCA1	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM

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
buccal mucosa cell	1
corpus callosum	1
oviduct epithelium	1
adrenal tissue	1
left adrenal gland	1
skin of hip	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZNF462	258	ubiquitous	marker	buccal mucosa cell, oviduct epithelium, corpus callosum
ABCA1	272	ubiquitous	marker	adrenal tissue, skin of hip, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCA1	3,551
ZNF462	1,141

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCA1	O95477	7
ZNF462	Q96JM2	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
Defective ABCA1 causes TGD	1	5710.0×	0.003	ABCA1
HDL assembly	1	1427.5×	0.006	ABCA1
Plasma lipoprotein assembly	1	713.8×	0.007	ABCA1
ABC transporter disorders	1	439.2×	0.008	ABCA1
NR1H2 and NR1H3-mediated signaling	1	393.8×	0.008	ABCA1
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	308.6×	0.009	ABCA1
Plasma lipoprotein assembly, remodeling, and clearance	1	228.4×	0.010	ABCA1
Regulation of lipid metabolism by PPARalpha	1	141.0×	0.013	ABCA1
Disorders of transmembrane transporters	1	139.3×	0.013	ABCA1
Signaling by Nuclear Receptors	1	102.0×	0.015	ABCA1
PPARA activates gene expression	1	94.4×	0.015	ABCA1
Metabolism of lipids	1	31.6×	0.042	ABCA1
Transport of small molecules	1	25.1×	0.049	ABCA1
Disease	1	13.1×	0.087	ABCA1
Metabolism	1	11.6×	0.092	ABCA1
Signal Transduction	1	10.2×	0.098	ABCA1

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
response to vitamin B3	1	4213.0×	0.003	ABCA1
regulation of high-density lipoprotein particle assembly	1	4213.0×	0.003	ABCA1
positive regulation of high-density lipoprotein particle assembly	1	4213.0×	0.003	ABCA1
signal release	1	2808.7×	0.003	ABCA1
peptide secretion	1	2106.5×	0.003	ABCA1
response to laminar fluid shear stress	1	2106.5×	0.003	ABCA1
lipoprotein biosynthetic process	1	1404.3×	0.004	ABCA1
high-density lipoprotein particle assembly	1	842.6×	0.004	ABCA1
export across plasma membrane	1	842.6×	0.004	ABCA1
negative regulation of cholesterol storage	1	766.0×	0.004	ABCA1
regulation of Cdc42 protein signal transduction	1	702.2×	0.004	ABCA1
negative regulation of macrophage derived foam cell differentiation	1	648.1×	0.004	ABCA1
intracellular cholesterol transport	1	648.1×	0.004	ABCA1
protein transmembrane transport	1	648.1×	0.004	ABCA1
phospholipid efflux	1	561.7×	0.004	ABCA1
phospholipid homeostasis	1	495.6×	0.005	ABCA1
reverse cholesterol transport	1	468.1×	0.005	ABCA1
cellular response to low-density lipoprotein particle stimulus	1	443.5×	0.005	ABCA1
cellular response to cholesterol	1	421.3×	0.005	ABCA1
phagocytosis, engulfment	1	337.0×	0.005	ABCA1
platelet dense granule organization	1	337.0×	0.005	ABCA1
positive regulation of cholesterol efflux	1	312.1×	0.005	ABCA1
phospholipid translocation	1	312.1×	0.005	ABCA1
cellular response to cytokine stimulus	1	271.8×	0.006	ABCA1
cholesterol efflux	1	263.3×	0.006	ABCA1
lysosome organization	1	153.2×	0.009	ABCA1
protein secretion	1	131.7×	0.010	ABCA1
endosomal transport	1	122.1×	0.011	ABCA1
cellular response to xenobiotic stimulus	1	120.4×	0.011	ABCA1
cellular response to retinoic acid	1	117.0×	0.011	ABCA1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 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
ZNF462	0	0
ABCA1	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
ABCA1	2	Binding:2

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	1	ABCA1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ZNF462

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)
ZNF462	0	—
ABCA1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.