Adams-Oliver syndrome 2

Summary

Adams-Oliver syndrome 2 (MONDO:0013635) is a disease caused by DOCK6 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: DOCK6 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 101

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Adams-Oliver syndrome 2
Mondo ID	MONDO:0013635
OMIM	614219
UMLS	C3280182
MedGen	481812
GARD	0015775
Is cancer (heuristic)	no

Also known as: Adams-Oliver syndrome 2 · Adams-Oliver syndrome caused by mutation in DOCK6 · Adams-Oliver syndrome type 2 · AOS2 · DOCK6 Adams-Oliver syndrome

Data availability: 101 ClinVar variants · 3 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 2

Related subtypes (5): Adams-Oliver syndrome 3, 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

101 retrieved; paginated sample, class counts are floors:

35 uncertain significance, 17 pathogenic, 14 likely pathogenic, 12 benign, 7 conflicting classifications of pathogenicity, 7 pathogenic/likely pathogenic, 4 benign/likely benign, 4 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1206321	NM_020812.4(DOCK6):c.3190_3191del (p.Leu1064fs)	DOCK6	Pathogenic	criteria provided, multiple submitters, no conflicts
1320059	NM_020812.4(DOCK6):c.1396C>T (p.Arg466Ter)	DOCK6	Pathogenic	criteria provided, single submitter
1320060	NM_020812.4(DOCK6):c.1300del (p.Gln434fs)	DOCK6	Pathogenic	criteria provided, single submitter
1322760	NM_020812.4(DOCK6):c.5783_5790del (p.Lys1928fs)	DOCK6	Pathogenic	criteria provided, multiple submitters, no conflicts
1322762	NM_020812.4(DOCK6):c.4106+1G>A	DOCK6	Pathogenic	criteria provided, single submitter
1705622	NM_020812.4(DOCK6):c.550C>T (p.Arg184Ter)	DOCK6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1708249	NM_020812.4(DOCK6):c.5616dup (p.Lys1873Ter)	DOCK6	Pathogenic	criteria provided, single submitter
183335	NM_020812.4(DOCK6):c.1362_1365del (p.Thr455fs)	DOCK6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1939973	NM_020812.4(DOCK6):c.616_617dup (p.Leu207fs)	DOCK6	Pathogenic	criteria provided, multiple submitters, no conflicts
2445975	NM_020812.4(DOCK6):c.3180del (p.Cys1061fs)	DOCK6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
253046	NM_020812.4(DOCK6):c.788T>A (p.Val263Asp)	DOCK6	Pathogenic	no assertion criteria provided
253047	NM_020812.4(DOCK6):c.5939+2T>C	DOCK6	Pathogenic	criteria provided, multiple submitters, no conflicts
31128	NM_020812.4(DOCK6):c.1245dup (p.Asp416Ter)	DOCK6	Pathogenic	no assertion criteria provided
3377288	NM_020812.4(DOCK6):c.4457dup (p.Tyr1486Ter)	DOCK6	Pathogenic	criteria provided, single submitter
3778769	NM_020812.4(DOCK6):c.4196dup (p.Val1400fs)	DOCK6	Pathogenic	criteria provided, single submitter
3893259	NM_020812.4(DOCK6):c.3241-1G>T	DOCK6	Pathogenic	no assertion criteria provided
499282	NM_020812.4(DOCK6):c.705C>G (p.Tyr235Ter)	DOCK6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
504926	NM_020812.4(DOCK6):c.4576C>T (p.Arg1526Ter)	DOCK6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
522950	NM_020812.4(DOCK6):c.4824_4828del (p.Glu1609fs)	DOCK6	Pathogenic	criteria provided, single submitter
55814	NM_020812.4(DOCK6):c.2520dup (p.Arg841fs)	DOCK6	Pathogenic	no assertion criteria provided
55815	NM_020812.4(DOCK6):c.4107-1G>C	DOCK6	Pathogenic	criteria provided, single submitter
620465	NM_020812.4(DOCK6):c.1462C>T (p.Arg488Ter)	DOCK6	Pathogenic	criteria provided, multiple submitters, no conflicts
620466	NM_020812.4(DOCK6):c.387C>G (p.Tyr129Ter)	DOCK6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1319695	NM_020812.4(DOCK6):c.4012C>T (p.Arg1338Ter)	DOCK6-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1028688	NM_020812.4(DOCK6):c.1987C>T (p.Gln663Ter)	DOCK6	Likely pathogenic	criteria provided, single submitter
1676533	NM_020812.4(DOCK6):c.4203+2T>C	DOCK6	Likely pathogenic	criteria provided, single submitter
1810235	NM_020812.4(DOCK6):c.3241-1G>A	DOCK6	Likely pathogenic	criteria provided, single submitter
2429276	NC_000019.9:g.(11315008_11319361)_(11326604_11327589)del	DOCK6	Likely pathogenic	criteria provided, single submitter
2872746	NM_020812.4(DOCK6):c.807-1G>A	DOCK6	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382645	NM_020812.4(DOCK6):c.5062del (p.Glu1688fs)	DOCK6	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
DOCK6	Strong	Autosomal recessive	Adams-Oliver syndrome 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DOCK6	Orphanet:974	Adams-Oliver syndrome
NOTCH1	Orphanet:402075	Familial bicuspid aortic valve
NOTCH1	Orphanet:974	Adams-Oliver syndrome

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
DOCK6	HGNC:19189	ENSG00000130158	Q96HP0	Dedicator of cytokinesis protein 6	gencc,clinvar
DOCK6-AS1	HGNC:56684	ENSG00000267082		DOCK6 antisense RNA 1	clinvar
NOTCH1	HGNC:7881	ENSG00000148400	P46531	Neurogenic locus notch homolog protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DOCK6	Dedicator of cytokinesis protein 6	Acts as a guanine nucleotide exchange factor (GEF) for CDC42 and RAC1 small GTPases.
NOTCH1	Neurogenic locus notch homolog protein 1	Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DOCK6	Other/Unknown	no		DOCK_C/D_N, DOCK, C2_DOCK-type_domain
DOCK6-AS1	Other/Unknown	no
NOTCH1	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic epithelium	2
right lung	2
apex of heart	1
male germ line stem cell (sensu Vertebrata) in testis	1
upper lobe of left lung	1
ventricular zone	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DOCK6	254	ubiquitous	marker	colonic epithelium, right lung, apex of heart
DOCK6-AS1	129		yes	right lung, upper lobe of left lung, male germ line stem cell (sensu Vertebrata) in testis
NOTCH1	272	ubiquitous	marker	ventricular zone, colonic epithelium, visceral pleura

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOTCH1	7,411
DOCK6	1,018
DOCK6-AS1	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOTCH1	P46531	29
DOCK6	Q96HP0	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 3 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
Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling	1	1142.0×	0.007	NOTCH1
Defective LFNG causes SCDO3	1	1142.0×	0.007	NOTCH1
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	951.7×	0.007	NOTCH1
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	815.7×	0.007	NOTCH1
Regulation of NFE2L2 gene expression	1	713.8×	0.007	NOTCH1
NFE2L2 regulating tumorigenic genes	1	475.8×	0.008	NOTCH1
RUNX3 regulates NOTCH signaling	1	407.9×	0.008	NOTCH1
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	380.7×	0.008	NOTCH1
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	356.9×	0.008	NOTCH1
Pre-NOTCH Processing in Golgi	1	317.2×	0.008	NOTCH1
MECP2 regulates neuronal receptors and channels	1	300.5×	0.008	NOTCH1
NOTCH4 Intracellular Domain Regulates Transcription	1	285.5×	0.008	NOTCH1
NOTCH3 Intracellular Domain Regulates Transcription	1	219.6×	0.008	NOTCH1
Notch-HLH transcription pathway	1	203.9×	0.008	NOTCH1
Formation of paraxial mesoderm	1	203.9×	0.008	NOTCH1
Activated NOTCH1 Transmits Signal to the Nucleus	1	178.4×	0.009	NOTCH1
Nuclear events stimulated by ALK signaling in cancer	1	163.1×	0.009	NOTCH1
NOTCH1 Intracellular Domain Regulates Transcription	1	119.0×	0.012	NOTCH1
Somitogenesis	1	116.5×	0.012	NOTCH1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	98.5×	0.013	NOTCH1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	98.5×	0.013	NOTCH1
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	73.2×	0.016	NOTCH1
Pre-NOTCH Transcription and Translation	1	61.4×	0.018	NOTCH1
CDC42 GTPase cycle	1	36.1×	0.030	DOCK6
Factors involved in megakaryocyte development and platelet production	1	33.2×	0.031	DOCK6
RAC1 GTPase cycle	1	30.5×	0.032	DOCK6

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
coronary sinus valve morphogenesis	1	8426.0×	0.002	NOTCH1
Notch signaling pathway involved in regulation of secondary heart field cardioblast proliferation	1	8426.0×	0.002	NOTCH1
foregut morphogenesis	1	8426.0×	0.002	NOTCH1
regulation of epithelial cell proliferation involved in prostate gland development	1	8426.0×	0.002	NOTCH1
venous endothelial cell differentiation	1	8426.0×	0.002	NOTCH1
endocardium morphogenesis	1	4213.0×	0.002	NOTCH1
coronary vein morphogenesis	1	4213.0×	0.002	NOTCH1
cardiac right atrium morphogenesis	1	4213.0×	0.002	NOTCH1
growth involved in heart morphogenesis	1	4213.0×	0.002	NOTCH1
obsolete negative regulation of cell proliferation involved in heart valve morphogenesis	1	4213.0×	0.002	NOTCH1
cell differentiation in spinal cord	1	4213.0×	0.002	NOTCH1
positive regulation of aorta morphogenesis	1	4213.0×	0.002	NOTCH1
mitral valve formation	1	2808.7×	0.002	NOTCH1
cardiac chamber formation	1	2808.7×	0.002	NOTCH1
auditory receptor cell fate commitment	1	2808.7×	0.002	NOTCH1
retinal cone cell differentiation	1	2808.7×	0.002	NOTCH1
secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development	1	2808.7×	0.002	NOTCH1
cardiac vascular smooth muscle cell development	1	2808.7×	0.002	NOTCH1
vasculogenesis involved in coronary vascular morphogenesis	1	2808.7×	0.002	NOTCH1
regulation of cell adhesion involved in heart morphogenesis	1	2808.7×	0.002	NOTCH1
distal tubule development	1	2808.7×	0.002	NOTCH1
chemical synaptic transmission, postsynaptic	1	2808.7×	0.002	NOTCH1
apoptotic process involved in embryonic digit morphogenesis	1	2808.7×	0.002	NOTCH1
positive regulation of apoptotic process involved in morphogenesis	1	2808.7×	0.002	NOTCH1
negative regulation of pro-B cell differentiation	1	2808.7×	0.002	NOTCH1
negative regulation of endothelial cell chemotaxis	1	2808.7×	0.002	NOTCH1
inhibition of neuroepithelial cell differentiation	1	2106.5×	0.002	NOTCH1
cardiac right ventricle formation	1	2106.5×	0.002	NOTCH1
cell migration involved in endocardial cushion formation	1	2106.5×	0.002	NOTCH1
negative regulation of extracellular matrix constituent secretion	1	2106.5×	0.002	NOTCH1

Therapeutics

Drug target analysis

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

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
NOTCH1	1	2
DOCK6	0	0
DOCK6-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VAREGACESTAT	2	NOTCH1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NOTCH1	23	Binding:19, ADMET: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

1 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.

Compound	Max phase	Cohort target (bioactivity)
VAREGACESTAT	2	NOTCH1

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	1	NOTCH1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	DOCK6, DOCK6-AS1

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)
DOCK6	0	—
DOCK6-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.