blepharophimosis - intellectual disability syndrome, SBBYS type

Summary

blepharophimosis - intellectual disability syndrome, SBBYS type (MONDO:0011365) is a disease caused by KAT6B (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KAT6B (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 302
• Phenotypes (HPO): 43

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		122	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

43 HPO clinical features (Orphanet curated; top 43 by frequency):

HPO ID	Term	Frequency
HP:0000028	Cryptorchidism	Very frequent (80-99%)
HP:0000269	Prominent occiput	Very frequent (80-99%)
HP:0000278	Retrognathia	Very frequent (80-99%)
HP:0000340	Sloping forehead	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000358	Posteriorly rotated ears	Very frequent (80-99%)
HP:0000369	Low-set ears	Very frequent (80-99%)
HP:0000414	Bulbous nose	Very frequent (80-99%)
HP:0000448	Prominent nose	Very frequent (80-99%)
HP:0000581	Blepharophimosis	Very frequent (80-99%)
HP:0000821	Hypothyroidism	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001328	Specific learning disability	Very frequent (80-99%)
HP:0003189	Long nose	Very frequent (80-99%)
HP:0003510	Severe short stature	Very frequent (80-99%)
HP:0012745	Short palpebral fissure	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0000176	Submucous cleft hard palate	Frequent (30-79%)
HP:0000193	Bifid uvula	Frequent (30-79%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001561	Polyhydramnios	Frequent (30-79%)
HP:0001629	Ventricular septal defect	Frequent (30-79%)
HP:0001631	Atrial septal defect	Frequent (30-79%)
HP:0001643	Patent ductus arteriosus	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0004209	Clinodactyly of the 5th finger	Frequent (30-79%)
HP:0004426	Abnormality of the cheek	Frequent (30-79%)
HP:0005990	Thyroid hypoplasia	Frequent (30-79%)
HP:0006695	Atrioventricular canal defect	Frequent (30-79%)
HP:0007598	Bilateral single transverse palmar creases	Frequent (30-79%)
HP:0008188	Thyroid dysgenesis	Frequent (30-79%)
HP:0008191	Thyroid agenesis	Frequent (30-79%)
HP:0009738	Abnormality of the antihelix	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0100028	Ectopic thyroid	Frequent (30-79%)
HP:0100490	Camptodactyly of finger	Frequent (30-79%)
HP:0000614	Abnormal nasolacrimal system morphology	Occasional (5-29%)
HP:0100648	Neoplasm of the tongue	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	blepharophimosis - intellectual disability syndrome, SBBYS type
Mondo ID	MONDO:0011365
MeSH	C536717
OMIM	603736
Orphanet	3047
DOID	DOID:0060290
SNOMED CT	699298009
UMLS	C1863557
MedGen	350209
GARD	0016618
Is cancer (heuristic)	no

Also known as: blepharophimosis - intellectual disability syndrome, SBBYS type · hypothyroidism-dysmorphism-postaxial polydactyly-intellectual disability syndrome · Ohdo syndrome, SBBYS variant · Say-Barber-Biesecker-Young-Simpson syndrome · SBBYSS · SBBYSS syndrome

Data availability: 302 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

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-intellectual disability › blepharophimosis - intellectual disability syndrome › Ohdo syndrome and variants › blepharophimosis - intellectual disability syndrome, SBBYS type

Related subtypes (2): blepharophimosis - intellectual disability syndrome, Ohdo type, blepharophimosis - intellectual disability syndrome, MKB type

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

302 retrieved; paginated sample, class counts are floors:

130 uncertain significance, 60 conflicting classifications of pathogenicity, 41 pathogenic, 25 benign/likely benign, 24 likely benign, 18 likely pathogenic, 3 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1215378	NM_012330.4(KAT6B):c.3040C>T (p.Gln1014Ter)	KAT6B	Pathogenic	criteria provided, multiple submitters, no conflicts
1308647	NM_012330.4(KAT6B):c.4461_4470del (p.Ser1487fs)	KAT6B	Pathogenic	criteria provided, single submitter
1335042	NM_012330.4(KAT6B):c.3217G>T (p.Glu1073Ter)	KAT6B	Pathogenic	criteria provided, multiple submitters, no conflicts
140476	NM_012330.4(KAT6B):c.4911_4921del (p.Val1638fs)	KAT6B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1698807	NM_012330.4(KAT6B):c.1993+1G>A	KAT6B	Pathogenic	criteria provided, single submitter
1806175	NM_012330.4(KAT6B):c.5356G>T (p.Glu1786Ter)	KAT6B	Pathogenic	criteria provided, single submitter
216946	NM_012330.4(KAT6B):c.3962_3963del (p.Gln1321fs)	KAT6B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2412710	NM_012330.4(KAT6B):c.3998dup (p.Ser1334fs)	KAT6B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2429920	NM_012330.4(KAT6B):c.3223G>T (p.Glu1075Ter)	KAT6B	Pathogenic	criteria provided, single submitter
2444621	NM_012330.4(KAT6B):c.2347C>T (p.Arg783Ter)	KAT6B	Pathogenic	criteria provided, multiple submitters, no conflicts
2500747	NM_012330.4(KAT6B):c.5302C>T (p.Gln1768Ter)	KAT6B	Pathogenic	criteria provided, multiple submitters, no conflicts
2505580	NM_012330.4(KAT6B):c.1030C>T (p.Arg344Ter)	KAT6B	Pathogenic	criteria provided, single submitter
2628338	NM_012330.4(KAT6B):c.5646del (p.Asn1883fs)	KAT6B	Pathogenic	criteria provided, multiple submitters, no conflicts
2683743	NM_012330.4(KAT6B):c.4592del (p.Asn1531fs)	KAT6B	Pathogenic	criteria provided, single submitter
279815	NM_012330.4(KAT6B):c.3147G>A (p.Pro1049=)	KAT6B	Pathogenic	criteria provided, multiple submitters, no conflicts
30525	NM_012330.4(KAT6B):c.4405dup (p.Ser1469fs)	KAT6B	Pathogenic	no assertion criteria provided
30526	NM_012330.4(KAT6B):c.5370_5373dup (p.Ile1792fs)	KAT6B	Pathogenic	no assertion criteria provided
30527	NM_012330.4(KAT6B):c.3018del (p.Glu1007fs)	KAT6B	Pathogenic	no assertion criteria provided
30528	NM_012330.4(KAT6B):c.4069G>T (p.Glu1357Ter)	KAT6B	Pathogenic	no assertion criteria provided
3236131	NM_012330.4(KAT6B):c.4237G>T (p.Glu1413Ter)	KAT6B	Pathogenic	criteria provided, single submitter
3254795	NM_012330.4(KAT6B):c.5762del (p.Gly1921fs)	KAT6B	Pathogenic	criteria provided, single submitter
3571999	NM_012330.4(KAT6B):c.2623del (p.Asp875fs)	KAT6B	Pathogenic	criteria provided, single submitter
369663	NM_012330.4(KAT6B):c.3664+1G>A	KAT6B	Pathogenic	criteria provided, multiple submitters, no conflicts
3900019	NM_012330.4(KAT6B):c.3887C>A (p.Ser1296Ter)	KAT6B	Pathogenic	no assertion criteria provided
39001	NM_012330.4(KAT6B):c.4205_4206del (p.Ser1402fs)	KAT6B	Pathogenic	criteria provided, multiple submitters, no conflicts
39002	NM_012330.4(KAT6B):c.5201_5210dup (p.Gln1737fs)	KAT6B	Pathogenic	criteria provided, multiple submitters, no conflicts
4277241	NM_012330.4(KAT6B):c.2137del (p.Val713fs)	KAT6B	Pathogenic	criteria provided, single submitter
438296	NM_012330.4(KAT6B):c.3216del (p.Glu1073fs)	KAT6B	Pathogenic	no assertion criteria provided
488535	NM_012330.4(KAT6B):c.4584del (p.Glu1529fs)	KAT6B	Pathogenic	criteria provided, single submitter
489009	NM_012330.4(KAT6B):c.5254C>T (p.Gln1752Ter)	KAT6B	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
KAT6B	Definitive	Autosomal dominant	blepharophimosis - intellectual disability syndrome, SBBYS type	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KAT6B	Orphanet:3047	Blepharophimosis-intellectual disability syndrome, SBBYS type
KAT6B	Orphanet:85201	Genitopatellar syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KAT6B	HGNC:17582	ENSG00000156650	Q8WYB5	Histone acetyltransferase KAT6B	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KAT6B	Histone acetyltransferase KAT6B	Histone acetyltransferase which may be involved in both positive and negative regulation of transcription.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KAT6B	Transcription factor	no	2.3.1.48	Znf_PHD, HAT_MYST-type, Histone_H1/H5_H15

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
sural nerve	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KAT6B	140	ubiquitous	yes	cortical plate, ventricular zone, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KAT6B	2,214

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KAT6B	Q8WYB5	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 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
Chromatin organization	1	81.6×	0.014	KAT6B
HATs acetylate histones	1	79.3×	0.014	KAT6B
Chromatin modifying enzymes	1	72.3×	0.014	KAT6B

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of developmental process	1	2407.4×	0.003	KAT6B
regulation of hemopoiesis	1	1532.0×	0.003	KAT6B
nucleosome assembly	1	140.4×	0.019	KAT6B
regulation of DNA-templated transcription	1	31.6×	0.048	KAT6B
negative regulation of DNA-templated transcription	1	31.6×	0.048	KAT6B
positive regulation of DNA-templated transcription	1	27.9×	0.048	KAT6B
positive regulation of transcription by RNA polymerase II	1	14.9×	0.077	KAT6B
regulation of transcription by RNA polymerase II	1	11.7×	0.086	KAT6B

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KAT6B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
KAT6B	22	Binding:20, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KAT6B	2.3.1.48	histone acetyltransferase

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	1	KAT6B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KAT6B	22	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.