Adams-Oliver syndrome 6

Summary

Adams-Oliver syndrome 6 (MONDO:0014703) is a disease caused by DLL4 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: DLL4 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 28

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Adams-Oliver syndrome 6
Mondo ID	MONDO:0014703
OMIM	616589
UMLS	C4225271
MedGen	908556
GARD	0016142
Is cancer (heuristic)	no

Also known as: Adams-Oliver syndrome 6 · Adams-Oliver syndrome caused by mutation in DLL4 · Adams-Oliver syndrome type 6 · AOS6 · DLL4 Adams-Oliver syndrome

Data availability: 28 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 6

Related subtypes (5): Adams-Oliver syndrome 2, Adams-Oliver syndrome 3, Adams-Oliver syndrome 4, Adams-Oliver syndrome 5, 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

28 retrieved; paginated sample, class counts are floors:

9 pathogenic, 8 likely pathogenic, 7 uncertain significance, 2 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
204368	NM_019074.4(DLL4):c.1660C>T (p.Gln554Ter)	DLL4	Pathogenic	criteria provided, single submitter
204369	NM_019074.4(DLL4):c.1672C>T (p.Arg558Ter)	DLL4	Pathogenic	criteria provided, single submitter
204371	NM_019074.4(DLL4):c.1169G>A (p.Cys390Tyr)	DLL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204372	NM_019074.4(DLL4):c.1168T>C (p.Cys390Arg)	DLL4	Pathogenic	criteria provided, single submitter
204373	NM_019074.4(DLL4):c.556C>T (p.Arg186Cys)	DLL4	Pathogenic	criteria provided, single submitter
204375	NM_019074.4(DLL4):c.361G>C (p.Ala121Pro)	DLL4	Pathogenic	criteria provided, single submitter
3651482	NM_019074.4(DLL4):c.1750C>T (p.Gln584Ter)	DLL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523582	NM_019074.4(DLL4):c.1825C>T (p.Gln609Ter)	DLL4	Pathogenic	criteria provided, single submitter
523591	NM_019074.4(DLL4):c.1310G>C (p.Cys437Ser)	DLL4	Pathogenic	criteria provided, single submitter
523592	NM_019074.4(DLL4):c.1397G>A (p.Cys466Tyr)	DLL4	Pathogenic	criteria provided, single submitter
929444	NM_019074.4(DLL4):c.1857_1864del (p.Pro621fs)	DLL4	Pathogenic	criteria provided, single submitter
1320129	NM_019074.4(DLL4):c.784G>A (p.Gly262Ser)	DLL4	Likely pathogenic	criteria provided, single submitter
2506498	NM_019074.4(DLL4):c.1396T>C (p.Cys466Arg)	DLL4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3066222	NM_019074.4(DLL4):c.187A>G (p.Lys63Glu)	DLL4	Likely pathogenic	criteria provided, single submitter
3254751	NM_019074.4(DLL4):c.329C>T (p.Thr110Ile)	DLL4	Likely pathogenic	criteria provided, single submitter
3600511	NM_019074.4(DLL4):c.1424G>C (p.Cys475Ser)	DLL4	Likely pathogenic	criteria provided, single submitter
523590	NM_019074.4(DLL4):c.949A>C (p.Thr317Pro)	DLL4	Likely pathogenic	criteria provided, single submitter
800940	NM_019074.4(DLL4):c.1392C>A (p.Cys464Ter)	DLL4	Likely pathogenic	criteria provided, single submitter
992895	NM_019074.4(DLL4):c.82G>C (p.Gly28Arg)	DLL4	Likely pathogenic	no assertion criteria provided
1345645	NM_019074.4(DLL4):c.382G>A (p.Asp128Asn)	DLL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2217867	NM_019074.4(DLL4):c.1102G>A (p.Asp368Asn)	DLL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204374	NM_019074.4(DLL4):c.799C>A (p.Pro267Thr)	DLL4	Uncertain significance	criteria provided, single submitter
2575222	NM_019074.4(DLL4):c.1429G>T (p.Val477Leu)	DLL4	Uncertain significance	criteria provided, single submitter
3065445	NM_019074.4(DLL4):c.1109C>T (p.Pro370Leu)	DLL4	Uncertain significance	criteria provided, single submitter
3602109	NM_019074.4(DLL4):c.1844A>G (p.Tyr615Cys)	DLL4	Uncertain significance	criteria provided, single submitter
523604	NM_019074.4(DLL4):c.265_267del (p.Phe89del)	DLL4	Uncertain significance	criteria provided, single submitter
523605	NM_019074.4(DLL4):c.1240+5G>C	DLL4	Uncertain significance	criteria provided, single submitter
659370	NM_015512.5(DNAH1):c.4670C>T (p.Thr1557Met)	DNAH1	Uncertain significance	criteria provided, multiple submitters, no conflicts

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
DLL4	Definitive	Autosomal dominant	Adams-Oliver syndrome 6	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DLL4	Orphanet:1114	Aplasia cutis congenita
DLL4	Orphanet:974	Adams-Oliver syndrome
DNAH1	Orphanet:244	Primary ciliary dyskinesia
DNAH1	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder

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
DLL4	HGNC:2910	ENSG00000128917	Q9NR61	Delta-like protein 4	gencc,clinvar
DNAH1	HGNC:2940	ENSG00000114841	Q9P2D7	Dynein axonemal heavy chain 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DLL4	Delta-like protein 4	Involved in the Notch signaling pathway as Notch ligand.
DNAH1	Dynein axonemal heavy chain 1	Force generating protein of cilia required for sperm flagellum motility.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DLL4	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, DSL
DNAH1	Other/Unknown	no		Dhc_D6_P-loop, Dhc_linker, Dhc_D4

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
apex of heart	1
body of tongue	1
vena cava	1
bronchial epithelial cell	1
bronchus	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DLL4	188	broad	marker	vena cava, apex of heart, body of tongue
DNAH1	183	tissue_specific	marker	right uterine tube, bronchial epithelial cell, bronchus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DLL4	2,749
DNAH1	1,699

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNAH1	Q9P2D7	2
DLL4	Q9NR61	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	1631.4×	0.004	DLL4
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	1038.2×	0.004	DLL4
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	761.3×	0.004	DLL4
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	475.8×	0.004	DLL4
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	439.2×	0.004	DLL4
Activated NOTCH1 Transmits Signal to the Nucleus	1	356.9×	0.004	DLL4
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	196.9×	0.005	DLL4
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	196.9×	0.005	DLL4

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
blood vessel lumenization	1	4213.0×	0.004	DLL4
ventral spinal cord interneuron fate commitment	1	2808.7×	0.004	DLL4
regulation of neural retina development	1	2808.7×	0.004	DLL4
cardiac atrium morphogenesis	1	1404.3×	0.005	DLL4
pericardium morphogenesis	1	1053.2×	0.005	DLL4
dorsal aorta morphogenesis	1	1053.2×	0.005	DLL4
negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1	1053.2×	0.005	DLL4
cardiac ventricle morphogenesis	1	936.2×	0.005	DLL4
cilium-dependent cell motility	1	702.2×	0.005	DNAH1
ventricular trabecula myocardium morphogenesis	1	526.6×	0.006	DLL4
negative regulation of cell migration involved in sprouting angiogenesis	1	495.6×	0.006	DLL4
inner dynein arm assembly	1	443.5×	0.006	DNAH1
epithelial cilium movement involved in extracellular fluid movement	1	383.0×	0.006	DNAH1
negative regulation of endothelial cell migration	1	383.0×	0.006	DLL4
positive regulation of neural precursor cell proliferation	1	383.0×	0.006	DLL4
cellular response to vascular endothelial growth factor stimulus	1	280.9×	0.007	DLL4
cellular response to fibroblast growth factor stimulus	1	271.8×	0.007	DLL4
branching involved in blood vessel morphogenesis	1	263.3×	0.007	DLL4
sperm axoneme assembly	1	234.1×	0.007	DNAH1
aortic valve morphogenesis	1	216.1×	0.007	DLL4
negative regulation of Notch signaling pathway	1	216.1×	0.007	DLL4
regulation of neurogenesis	1	200.6×	0.007	DLL4
blood vessel remodeling	1	191.5×	0.007	DLL4
T cell differentiation	1	191.5×	0.007	DLL4
positive regulation of Notch signaling pathway	1	175.5×	0.008	DLL4
Notch signaling pathway	1	70.8×	0.018	DLL4
flagellated sperm motility	1	58.5×	0.021	DNAH1
visual perception	1	39.8×	0.030	DLL4
negative regulation of gene expression	1	34.5×	0.034	DLL4
angiogenesis	1	31.2×	0.036	DLL4

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
DLL4	0	0
DNAH1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	DLL4, DNAH1

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)
DLL4	0	—
DNAH1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.