Bosch-Boonstra-Schaaf optic atrophy syndrome

Summary

Bosch-Boonstra-Schaaf optic atrophy syndrome (MONDO:0014320) is a disease caused by NR2F1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NR2F1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 94
• Phenotypes (HPO): 39

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

39 HPO clinical features (Orphanet curated; top 39 by frequency):

HPO ID	Term	Frequency
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0007663	Reduced visual acuity	Frequent (30-79%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000411	Protruding ear	Occasional (5-29%)
HP:0000426	Prominent nasal bridge	Occasional (5-29%)
HP:0000463	Anteverted nares	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000565	Esotropia	Occasional (5-29%)
HP:0000577	Exotropia	Occasional (5-29%)
HP:0000582	Upslanted palpebral fissure	Occasional (5-29%)
HP:0000609	Optic nerve hypoplasia	Occasional (5-29%)
HP:0000646	Amblyopia	Occasional (5-29%)
HP:0000722	Compulsive behaviors	Occasional (5-29%)
HP:0001123	Visual field defect	Occasional (5-29%)
HP:0001182	Tapered finger	Occasional (5-29%)
HP:0001344	Absent speech	Occasional (5-29%)
HP:0003194	Short nasal bridge	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)
HP:0007766	Optic disc hypoplasia	Occasional (5-29%)
HP:0008762	Repetitive compulsive behavior	Occasional (5-29%)
HP:0011039	Abnormality of the helix	Occasional (5-29%)
HP:0100704	Cerebral visual impairment	Occasional (5-29%)
HP:0000540	Hypermetropia	Very rare (<1-4%)
HP:0000545	Myopia	Very rare (<1-4%)
HP:0000563	Keratoconus	Very rare (<1-4%)
HP:0000639	Nystagmus	Very rare (<1-4%)
HP:0001257	Spasticity	Very rare (<1-4%)
HP:0002750	Delayed skeletal maturation	Very rare (<1-4%)
HP:0004322	Short stature	Very rare (<1-4%)
HP:0012448	Delayed myelination	Very rare (<1-4%)
HP:0025100	Abnormal hippocampus morphology	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Bosch-Boonstra-Schaaf optic atrophy syndrome
Mondo ID	MONDO:0014320
OMIM	615722
Orphanet	401777
DOID	DOID:0112226
UMLS	C3810363
MedGen	816693
GARD	0012903
Is cancer (heuristic)	no

Also known as: BBSOAS · Bosch-Boonstra-Schaaf optic atrophy syndrome · optic atrophy-intellectual disability syndrome

Data availability: 94 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › autosomal dominant syndromic intellectual disability › Bosch-Boonstra-Schaaf optic atrophy syndrome

Related subtypes (33): Myhre syndrome, KBG syndrome, Rubinstein-Taybi syndrome due to CREBBP mutations, Mowat-Wilson syndrome, Schinzel-Giedion syndrome, intellectual disability-sparse hair-brachydactyly syndrome, Pierpont syndrome, Bohring-Opitz syndrome, hereditary cryohydrocytosis with reduced stomatin, intellectual disability-severe speech delay-mild dysmorphism syndrome, Rubinstein-Taybi syndrome due to EP300 haploinsufficiency, DYRK1A-related intellectual disability syndrome, intellectual disability, autosomal dominant 13, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, intellectual developmental disorder with dysmorphic facies and ptosis, intellectual disability, autosomal dominant 48, SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, SIN3A-related intellectual disability syndrome, Ververi-Brady syndrome 1, intellectual developmental disorder with dysmorphic facies and behavioral abnormalities, intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalities, SATB2 associated disorder

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

94 retrieved; paginated sample, class counts are floors:

32 likely pathogenic, 30 pathogenic, 19 uncertain significance, 8 conflicting classifications of pathogenicity, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4685561	GRCh38/hg38 5q14.3-21.2(chr5:90079852-103658165)x1	LOC123497944	Pathogenic	criteria provided, single submitter
1048564	NM_005654.6(NR2F1):c.513C>G (p.Tyr171Ter)	NR2F1	Pathogenic	no assertion criteria provided
126493	NM_005654.6(NR2F1):c.344G>C (p.Arg115Pro)	NR2F1	Pathogenic	criteria provided, single submitter
126494	NM_005654.6(NR2F1):c.339C>A (p.Ser113Arg)	NR2F1	Pathogenic	criteria provided, single submitter
1699474	NM_005654.6(NR2F1):c.827T>A (p.Leu276Ter)	NR2F1	Pathogenic	criteria provided, single submitter
1708261	NM_005654.6(NR2F1):c.1077_1084del (p.Tyr360fs)	NR2F1	Pathogenic	criteria provided, single submitter
1711198	NM_005654.6(NR2F1):c.907C>T (p.Gln303Ter)	NR2F1	Pathogenic	criteria provided, single submitter
2572229	NM_005654.6(NR2F1):c.282C>A (p.Ser94Arg)	NR2F1	Pathogenic	criteria provided, single submitter
2683748	NM_005654.6(NR2F1):c.3G>A (p.Met1Ile)	NR2F1	Pathogenic	no assertion criteria provided
280552	NM_005654.6(NR2F1):c.424C>T (p.Arg142Cys)	NR2F1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3237371	NM_005654.6(NR2F1):c.1065del (p.Glu354_Tyr355insTer)	NR2F1	Pathogenic	criteria provided, single submitter
3254585	NM_005654.6(NR2F1):c.274A>T (p.Lys92Ter)	NR2F1	Pathogenic	criteria provided, single submitter
3377104	NM_005654.6(NR2F1):c.763dup (p.Thr255fs)	NR2F1	Pathogenic	criteria provided, single submitter
3897853	NM_005654.6(NR2F1):c.404G>C (p.Arg135Pro)	NR2F1	Pathogenic	criteria provided, single submitter
4086074	NM_005654.6(NR2F1):c.415C>T (p.Gln139Ter)	NR2F1	Pathogenic	criteria provided, single submitter
452994	NM_005654.6(NR2F1):c.313G>A (p.Gly105Ser)	NR2F1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4683092	NM_005654.6(NR2F1):c.835_844dup (p.Leu282fs)	NR2F1	Pathogenic	criteria provided, single submitter
4813542	NM_005654.6(NR2F1):c.1036_1038del (p.Glu346del)	NR2F1	Pathogenic	criteria provided, single submitter
800977	NM_005654.6(NR2F1):c.1117C>T (p.Arg373Ter)	NR2F1	Pathogenic	criteria provided, single submitter
827802	NM_005654.6(NR2F1):c.968_969del (p.Lys323fs)	NR2F1	Pathogenic	criteria provided, single submitter
928681	NM_005654.6(NR2F1):c.256T>C (p.Cys86Arg)	NR2F1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
930895	NM_005654.6(NR2F1):c.120del (p.Gln40fs)	NR2F1	Pathogenic	criteria provided, single submitter
976204	NM_005654.6(NR2F1):c.437G>A (p.Cys146Tyr)	NR2F1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
988711	NM_005654.6(NR2F1):c.452T>A (p.Met151Lys)	NR2F1	Pathogenic	no assertion criteria provided
1048563	NM_005654.6(NR2F1):c.286A>G (p.Lys96Glu)	NR2F1-AS1	Pathogenic	no assertion criteria provided
1048565	NM_005654.6(NR2F1):c.82C>T (p.Gln28Ter)	NR2F1-AS1	Pathogenic	no assertion criteria provided
1804906	NM_005654.6(NR2F1):c.307T>C (p.Cys103Arg)	NR2F1-AS1	Pathogenic	criteria provided, single submitter
1992335	NM_005654.6(NR2F1):c.442A>T (p.Lys148Ter)	NR2F1-AS1	Pathogenic	criteria provided, single submitter
279855	NM_005654.6(NR2F1):c.2T>C (p.Met1Thr)	NR2F1-AS1	Pathogenic	criteria provided, multiple submitters, no conflicts
3254586	NM_005654.6(NR2F1):c.53del (p.Gly18fs)	NR2F1-AS1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
NR2F1	Definitive	Autosomal dominant	Bosch-Boonstra-Schaaf optic atrophy syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NR2F1	Orphanet:401777	Optic atrophy-intellectual disability syndrome
KIAA0825	Orphanet:93334	Postaxial polydactyly type A

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NR2F1	HGNC:7975	ENSG00000175745	P10589	COUP transcription factor 1	gencc,clinvar
KIAA0825	HGNC:28532	ENSG00000185261	Q8IV33	Uncharacterized protein KIAA0825	clinvar
NR2F1-AS1	HGNC:48622	ENSG00000237187		NR2F1 regulatory antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NR2F1	COUP transcription factor 1	Coup (chicken ovalbumin upstream promoter) transcription factor binds to the ovalbumin promoter and, in conjunction with another protein (S300-II) stimulates initiation of transcription.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Nuclear receptor	1	128.6×	0.016
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NR2F1	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
KIAA0825	Other/Unknown	no		DUF4495
NR2F1-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cranial nerve II	1
seminal vesicle	1
ventricular zone	1
adrenal tissue	1
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1
anterior cingulate cortex	1
dorsolateral prefrontal cortex	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NR2F1	259	ubiquitous	marker	ventricular zone, cranial nerve II, seminal vesicle
KIAA0825	167	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue, calcaneal tendon
NR2F1-AS1	204	ubiquitous	marker	anterior cingulate cortex, right frontal lobe, dorsolateral prefrontal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NR2F1	1,942
KIAA0825	469
NR2F1-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NR2F1	P10589	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KIAA0825	Q8IV33	74.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 3 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
Nuclear Receptor transcription pathway	1	200.3×	0.005	NR2F1

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
negative regulation of neuron projection development	1	237.3×	0.025	NR2F1
nervous system development	1	45.9×	0.065	NR2F1
cell differentiation	1	29.1×	0.067	NR2F1
negative regulation of transcription by RNA polymerase II	1	17.7×	0.067	NR2F1
signal transduction	1	16.1×	0.067	NR2F1
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	NR2F1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NR2F1	0	0
KIAA0825	0	0
NR2F1-AS1	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
NR2F1	4	Binding:4

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	NR2F1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	KIAA0825, NR2F1-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NR2F1	4	—
KIAA0825	0	—
NR2F1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.