Vertebral, cardiac, renal, and limb defects syndrome 1

Summary

Vertebral, cardiac, renal, and limb defects syndrome 1 (MONDO:0060554) is a disease caused by HAAO (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: HAAO (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	vertebral, cardiac, renal, and limb defects syndrome 1
Mondo ID	MONDO:0060554
OMIM	617660
UMLS	C4540004
MedGen	1621146
GARD	0018508
Is cancer (heuristic)	no

Also known as: VCRL1 · vertebral, cardiac, renal, and limb defects syndrome 1

Data availability: 20 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 › autosomal genetic disease › autosomal recessive disease › congenital vertebral-cardiac-renal anomalies syndrome › vertebral, cardiac, renal, and limb defects syndrome 1

Related subtypes (2): vertebral, cardiac, renal, and limb defects syndrome 3, vertebral, cardiac, renal, and limb defects syndrome 2

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

20 retrieved; paginated sample, class counts are floors:

6 likely pathogenic, 5 benign, 4 pathogenic, 3 uncertain significance, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
403727	NM_012205.3(HAAO):c.483dup (p.Asp162Ter)	HAAO	Pathogenic	criteria provided, multiple submitters, no conflicts
403728	NM_012205.3(HAAO):c.558G>A (p.Trp186Ter)	HAAO	Pathogenic	criteria provided, multiple submitters, no conflicts
4532199	NM_012205.3(HAAO):c.382_385del (p.Phe128fs)	HAAO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
988085	NM_012205.3(HAAO):c.141C>A (p.His47Gln)	HAAO	Pathogenic	no assertion criteria provided
988086	NM_012205.3(HAAO):c.43del (p.Arg15fs)	HAAO	Pathogenic	no assertion criteria provided
1683650	NM_012205.3(HAAO):c.21del (p.Arg8fs)	HAAO	Likely pathogenic	criteria provided, single submitter
3065740	NM_012205.3(HAAO):c.251T>C (p.Leu84Pro)	HAAO	Likely pathogenic	criteria provided, single submitter
4849493	NM_012205.3(HAAO):c.80+2T>C	HAAO	Likely pathogenic	criteria provided, single submitter
804383	NM_012205.3(HAAO):c.243+1G>A	HAAO	Likely pathogenic	criteria provided, single submitter
988087	NM_012205.3(HAAO):c.301G>T (p.Gly101Trp)	HAAO	Likely pathogenic	criteria provided, single submitter
988088	NM_012205.3(HAAO):c.323G>A (p.Arg108Gln)	HAAO	Likely pathogenic	criteria provided, single submitter
988084	NM_012205.3(HAAO):c.128G>A (p.Arg43Lys)	HAAO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1707511	NM_012205.3(HAAO):c.524G>C (p.Arg175Pro)	HAAO	Uncertain significance	criteria provided, multiple submitters, no conflicts
1707517	NM_012205.3(HAAO):c.431T>C (p.Ile144Thr)	HAAO	Uncertain significance	criteria provided, single submitter
2444014	NM_018161.5(NADSYN1):c.799-2A>G	NADSYN1	Uncertain significance	no assertion criteria provided
1285319	NM_012205.3(HAAO):c.630+34C>T	HAAO	Benign	criteria provided, multiple submitters, no conflicts
1285320	NM_012205.3(HAAO):c.440+19C>T	HAAO	Benign	criteria provided, multiple submitters, no conflicts
1285321	NM_012205.3(HAAO):c.124A>T (p.Thr42Ser)	HAAO	Benign	criteria provided, multiple submitters, no conflicts
1285322	NM_012205.3(HAAO):c.109A>G (p.Ile37Val)	HAAO	Benign	criteria provided, multiple submitters, no conflicts
1285323	NM_012205.3(HAAO):c.81-10C>T	HAAO	Benign	criteria provided, multiple submitters, no conflicts

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
HAAO	Strong	Autosomal recessive	vertebral, cardiac, renal, and limb defects syndrome 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HAAO	Orphanet:521438	Congenital vertebral-cardiac-renal anomalies syndrome
NADSYN1	Orphanet:521438	Congenital vertebral-cardiac-renal anomalies 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
HAAO	HGNC:4796	ENSG00000162882	P46952	3-hydroxyanthranilate 3,4-dioxygenase	gencc,clinvar
NADSYN1	HGNC:29832	ENSG00000172890	Q6IA69	Glutamine-dependent NAD(+) synthetase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HAAO	3-hydroxyanthranilate 3,4-dioxygenase	Catalyzes the oxidative ring opening of 3-hydroxyanthranilate to 2-amino-3-carboxymuconate semialdehyde, which spontaneously cyclizes to quinolinate.
NADSYN1	Glutamine-dependent NAD(+) synthetase	Catalyzes the final step of the nicotinamide adenine dinucleotide (NAD) de novo synthesis pathway, the ATP-dependent amidation of deamido-NAD using L-glutamine as a nitrogen source.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	2	12.0×	0.007

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HAAO	Enzyme (other)	yes	1.13.11.6	3hydroanth_dOase, RmlC_Cupin_sf, RmlC-like_jellyroll
NADSYN1	Enzyme (other)	yes	6.3.5.1	C-N_Hydrolase, NAD_synthase, Gln-dep_NAD_synthase

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
descending thoracic aorta	1
liver	1
right lobe of liver	1
granulocyte	1
mucosa of transverse colon	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HAAO	178	broad	marker	right lobe of liver, liver, descending thoracic aorta
NADSYN1	258	ubiquitous	marker	right uterine tube, granulocyte, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NADSYN1	2,114
HAAO	1,072

Intra-cohort edges

A	B	Sources
HAAO	NADSYN1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HAAO	P46952	3
NADSYN1	Q6IA69	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Tryptophan catabolism	1	380.7×	0.015	HAAO
Nicotinate metabolism	1	196.9×	0.015	NADSYN1
Metabolism	2	11.6×	0.015	HAAO, NADSYN1
Metabolism of water-soluble vitamins and cofactors	1	90.6×	0.017	NADSYN1
Metabolism of vitamins and cofactors	1	58.3×	0.021	NADSYN1
Metabolism of amino acids and derivatives	1	33.8×	0.029	HAAO

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
NAD+ biosynthetic process	2	1872.4×	1e-06	HAAO, NADSYN1
‘de novo’ NAD+ biosynthetic process from L-tryptophan	2	1872.4×	1e-06	HAAO, NADSYN1
quinolinate metabolic process	1	8426.0×	4e-04	HAAO
obsolete anthranilate metabolic process	1	2808.7×	9e-04	HAAO
L-tryptophan catabolic process	1	1404.3×	0.001	HAAO
NAD+ biosynthetic process via the salvage pathway	1	936.2×	0.002	NADSYN1
quinolinate biosynthetic process	1	766.0×	0.002	HAAO
response to cadmium ion	1	366.4×	0.003	HAAO
response to zinc ion	1	312.1×	0.004	HAAO
neuron cellular homeostasis	1	227.7×	0.004	HAAO

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
HAAO	0	0
NADSYN1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
HAAO	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HAAO	1.13.11.6	3-hydroxyanthranilate 3,4-dioxygenase
NADSYN1	6.3.5.1	NAD+ synthase (glutamine-hydrolysing)

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	2	HAAO, NADSYN1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
HAAO	4	—
NADSYN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.