Adams-Oliver syndrome 3

Summary

Adams-Oliver syndrome 3 (MONDO:0013895) is a disease caused by RBPJ (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: RBPJ (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Adams-Oliver syndrome 3
Mondo ID	MONDO:0013895
OMIM	614814
DOID	DOID:0061179
UMLS	C3553748
MedGen	766662
GARD	0015842
Is cancer (heuristic)	no

Also known as: Adams-Oliver syndrome 3 · Adams-Oliver syndrome caused by mutation in RBPJ · Adams-Oliver syndrome type 3 · AOS3 · RBPJ Adams-Oliver syndrome

Data availability: 12 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 › Adams-Oliver syndrome › Adams-Oliver syndrome 3

Related subtypes (5): Adams-Oliver syndrome 2, Adams-Oliver syndrome 4, Adams-Oliver syndrome 5, Adams-Oliver syndrome 6, Adams-Oliver syndrome 1

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

12 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 4 likely pathogenic, 2 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
37053	NM_015874.6(RBPJ):c.149A>G (p.Glu50Gly)	LOC126807011	Pathogenic	no assertion criteria provided
37054	NM_015874.6(RBPJ):c.466A>G (p.Lys156Glu)	RBPJ	Pathogenic	no assertion criteria provided
65417	NM_001283009.2(RTEL1):c.2956C>T (p.Arg986Ter)	RTEL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1803755	NM_015874.6(RBPJ):c.155G>C (p.Arg52Thr)	RBPJ	Likely pathogenic	criteria provided, single submitter
523586	NM_015874.6(RBPJ):c.154A>G (p.Arg52Gly)	RBPJ	Likely pathogenic	criteria provided, multiple submitters, no conflicts
523587	NM_015874.6(RBPJ):c.157T>G (p.Phe53Val)	RBPJ	Likely pathogenic	criteria provided, single submitter
523588	NM_015874.6(RBPJ):c.957C>A (p.Ser319Arg)	RBPJ	Likely pathogenic	criteria provided, single submitter
1805553	NM_015874.6(RBPJ):c.140A>G (p.Tyr47Cys)	LOC126807011	Uncertain significance	criteria provided, single submitter
1342378	NM_015874.6(RBPJ):c.50G>A (p.Arg17Gln)	RBPJ	Uncertain significance	criteria provided, multiple submitters, no conflicts
1696469	NM_015874.6(RBPJ):c.1375G>A (p.Glu459Lys)	RBPJ	Uncertain significance	criteria provided, multiple submitters, no conflicts
2435387	NM_005349.4(RBPJ):c.20C>A (p.Ser7Ter)	RBPJ	Uncertain significance	criteria provided, single submitter
3898012	NM_015874.6(RBPJ):c.771G>T (p.Gln257His)	RBPJ	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 4 · 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
RBPJ	Strong	Autosomal dominant	Adams-Oliver syndrome 3	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RBPJ	Orphanet:974	Adams-Oliver syndrome
RTEL1	Orphanet:1775	Dyskeratosis congenita
RTEL1	Orphanet:2032	Idiopathic pulmonary fibrosis
RTEL1	Orphanet:3322	Hoyeraal-Hreidarsson syndrome

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
RBPJ	HGNC:5724	ENSG00000168214	Q06330	Recombining binding protein suppressor of hairless	gencc,clinvar
RTEL1	HGNC:15888	ENSG00000258366	Q9NZ71	Regulator of telomere elongation helicase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RBPJ	Recombining binding protein suppressor of hairless	Transcriptional regulator that plays a central role in Notch signaling, a signaling pathway involved in cell-cell communication that regulates a broad spectrum of cell-fate determinations.
RTEL1	Regulator of telomere elongation helicase 1	A probable ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair and the maintenance of genomic stability.

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)
RBPJ	Transcription factor	no		p53-like_TF_DNA-bd_sf, Ig-like_fold, Ig_E-set
RTEL1	Other/Unknown	no		Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
calcaneal tendon	1
inferior olivary complex	1
nipple	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RBPJ	295	ubiquitous	marker	inferior olivary complex, nipple, calcaneal tendon
RTEL1	134	ubiquitous	yes	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RBPJ	4,036
RTEL1	2,324

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RBPJ	Q06330	4
RTEL1	Q9NZ71	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 46. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
NOTCH2 intracellular domain regulates transcription	1	475.8×	0.012	RBPJ
RUNX3 regulates NOTCH signaling	1	407.9×	0.012	RBPJ
Cytosolic iron-sulfur cluster assembly	1	380.7×	0.012	RTEL1
Regulation of beta-cell development	1	356.9×	0.012	RBPJ
Signaling by NOTCH2	1	356.9×	0.012	RBPJ
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	356.9×	0.012	RBPJ
Resolution of D-Loop Structures	1	317.2×	0.012	RTEL1
Extension of Telomeres	1	300.5×	0.012	RTEL1
NOTCH4 Intracellular Domain Regulates Transcription	1	285.5×	0.012	RBPJ
Signaling by NOTCH3	1	259.6×	0.012	RBPJ
Signaling by NOTCH4	1	248.3×	0.012	RBPJ
Telomere Extension By Telomerase	1	228.4×	0.012	RTEL1
NOTCH3 Intracellular Domain Regulates Transcription	1	219.6×	0.012	RBPJ
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	203.9×	0.012	RBPJ
Signaling by NOTCH1 in Cancer	1	203.9×	0.012	RBPJ
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	203.9×	0.012	RBPJ
Notch-HLH transcription pathway	1	203.9×	0.012	RBPJ
Formation of paraxial mesoderm	1	203.9×	0.012	RBPJ
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	196.9×	0.012	RTEL1
Telomere Maintenance	1	184.2×	0.012	RTEL1
Pre-NOTCH Expression and Processing	1	184.2×	0.012	RBPJ
Signaling by NOTCH1	1	178.4×	0.012	RBPJ
Homology Directed Repair	1	154.3×	0.012	RTEL1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	154.3×	0.012	RTEL1
Transcriptional regulation by RUNX3	1	135.9×	0.014	RBPJ
Gastrulation	1	129.8×	0.014	RBPJ
DNA Double-Strand Break Repair	1	124.1×	0.014	RTEL1
NOTCH1 Intracellular Domain Regulates Transcription	1	119.0×	0.014	RBPJ
Somitogenesis	1	116.5×	0.014	RBPJ
Chromosome Maintenance	1	105.7×	0.014	RTEL1

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
DNA strand displacement	1	8426.0×	0.001	RTEL1
arterial endothelial cell fate commitment	1	8426.0×	0.001	RBPJ
blood vessel endothelial cell fate specification	1	8426.0×	0.001	RBPJ
positive regulation of ERBB signaling pathway	1	8426.0×	0.001	RBPJ
positive regulation of ephrin receptor signaling pathway	1	8426.0×	0.001	RBPJ
negative regulation of telomere maintenance in response to DNA damage	1	8426.0×	0.001	RTEL1
positive regulation of telomeric loop disassembly	1	8426.0×	0.001	RTEL1
endocardium morphogenesis	1	4213.0×	0.002	RBPJ
blood vessel lumenization	1	4213.0×	0.002	RBPJ
telomeric loop disassembly	1	4213.0×	0.002	RTEL1
auditory receptor cell fate commitment	1	2808.7×	0.002	RBPJ
regulation of generation of precursor metabolites and energy	1	2808.7×	0.002	RBPJ
regulation of cell adhesion involved in heart morphogenesis	1	2808.7×	0.002	RBPJ
mitotic telomere maintenance via semi-conservative replication	1	2808.7×	0.002	RTEL1
negative regulation of t-circle formation	1	2808.7×	0.002	RTEL1
pulmonary valve development	1	2106.5×	0.002	RBPJ
regulation of timing of cell differentiation	1	2106.5×	0.002	RBPJ
aortic valve development	1	1685.2×	0.002	RBPJ
epidermal cell fate specification	1	1685.2×	0.002	RBPJ
club cell differentiation	1	1685.2×	0.002	RBPJ
cardiac muscle cell fate commitment	1	1685.2×	0.002	RBPJ
positive regulation of telomere capping	1	1685.2×	0.002	RTEL1
positive regulation of cell proliferation involved in heart morphogenesis	1	1685.2×	0.002	RBPJ
positive regulation of telomere maintenance via telomere lengthening	1	1404.3×	0.002	RTEL1
positive regulation of transcription of Notch receptor target	1	1203.7×	0.002	RBPJ
dorsal aorta morphogenesis	1	1053.2×	0.002	RBPJ
sebaceous gland development	1	1053.2×	0.002	RBPJ
hair follicle maturation	1	1053.2×	0.002	RBPJ
telomere maintenance in response to DNA damage	1	936.2×	0.003	RTEL1
secondary heart field specification	1	766.0×	0.003	RBPJ

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
RBPJ	0	0
RTEL1	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
RBPJ	8	Binding:8

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	RBPJ, RTEL1

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)
RBPJ	8	—
RTEL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.