Congenital heart defects, multiple types, 6
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Also known as CHTD6dextro-looped transposition of the great arteries caused by mutation in GDF1dextro-looped transposition of the great arteries type 3DTGA3GDF1 dextro-looped transposition of the great arteriestransposition of the great arteries, dextro-looped 3transposition of the great arteries, dextro-looped type 3
Summary
Congenital heart defects, multiple types, 6 (MONDO:0013463) is a disease caused by GDF1 (GenCC Strong), with 2 cohort genes.
At a glance
- Causal gene: GDF1 (GenCC Strong)
- Cohort genes: 2
- ClinVar variants: 15
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | congenital heart defects, multiple types, 6 |
| Mondo ID | MONDO:0013463 |
| OMIM | 613854 |
| DOID | DOID:0060772 |
| UMLS | C3151221 |
| MedGen | 462571 |
| GARD | 0024928 |
| Is cancer (heuristic) | no |
Also known as: CHTD6 · congenital heart defects, multiple types, 6 · dextro-looped transposition of the great arteries caused by mutation in GDF1 · dextro-looped transposition of the great arteries type 3 · DTGA3 · GDF1 dextro-looped transposition of the great arteries · transposition of the great arteries, dextro-looped 3 · transposition of the great arteries, dextro-looped type 3
Data availability: 15 ClinVar variants · 3 GenCC gene-disease records.
Disease family
Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › congenital heart disease › congenital heart defects, multiple types › congenital heart defects, multiple types, 6
Related subtypes (7): congenital heart defects, multiple types, 3, congenital heart defects, multiple types, 2, congenital heart defects, multiple types, 4, congenital heart defects, multiple types, 5, MYH-6 related congenital heart defects, congenital heart defects, multiple types, 8, with or without heterotaxy, congenital heart defects, multiple types, 9
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
15 retrieved; paginated sample, class counts are floors:
8 uncertain significance, 4 pathogenic/likely pathogenic, 3 likely pathogenic
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 410641 | NM_001492.6(GDF1):c.1047_1050del (p.Phe349fs) | CERS1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 522571 | NM_001492.6(GDF1):c.1091T>C (p.Met364Thr) | CERS1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 65389 | NM_001492.6(GDF1):c.909dup (p.Val304fs) | CERS1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 6747 | NM_001492.6(GDF1):c.681C>A (p.Cys227Ter) | CERS1 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1301764 | NM_021267.5(CERS1):c.*1120G>A | CERS1 | Likely pathogenic | criteria provided, single submitter |
| 4056383 | NM_001492.6(GDF1):c.822del (p.Ser275fs) | CERS1 | Likely pathogenic | criteria provided, single submitter |
| 977094 | NM_001492.6(GDF1):c.380G>A (p.Trp127Ter) | CERS1 | Likely pathogenic | criteria provided, single submitter |
| 1010796 | NM_001492.6(GDF1):c.649C>G (p.Leu217Val) | CERS1 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 1031988 | NM_001492.6(GDF1):c.997G>A (p.Asp333Asn) | CERS1 | Uncertain significance | criteria provided, single submitter |
| 1348662 | NM_001492.6(GDF1):c.596T>C (p.Leu199Pro) | CERS1 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 2576542 | NM_001492.6(GDF1):c.537del (p.Pro180fs) | CERS1 | Uncertain significance | criteria provided, single submitter |
| 3779691 | NM_001492.6(GDF1):c.1082_1097dup (p.Val366_Asp367insTer) | CERS1 | Uncertain significance | criteria provided, single submitter |
| 410639 | NM_001492.6(GDF1):c.599G>A (p.Gly200Asp) | CERS1 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 930879 | NM_001492.6(GDF1):c.137G>C (p.Arg46Pro) | CERS1 | Uncertain significance | criteria provided, single submitter |
| 966764 | NM_001492.6(GDF1):c.812G>C (p.Arg271Pro) | GDF1 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 8 · 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 |
|---|---|---|---|---|
| GDF1 | Strong | Autosomal dominant | congenital heart defects, multiple types, 6 | 8 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| GDF1 | Orphanet:216718 | Isolated congenitally uncorrected transposition of the great arteries |
| GDF1 | Orphanet:3303 | Tetralogy of Fallot |
| GDF1 | Orphanet:97548 | Right isomerism |
| CERS1 | Orphanet:424027 | Progressive myoclonic epilepsy type 8 |
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 |
|---|---|---|---|---|---|
| GDF1 | HGNC:4214 | ENSG00000130283 | P27539 | Embryonic growth/differentiation factor 1 | gencc,clinvar |
| CERS1 | HGNC:14253 | ENSG00000223802 | P27544 | Ceramide synthase 1 | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| GDF1 | Embryonic growth/differentiation factor 1 | May mediate cell differentiation events during embryonic development. |
| CERS1 | Ceramide synthase 1 | Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward stearoyl-CoA (octadecanoyl-CoA; C18:0-CoA). |
Protein-family classification
Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5
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) | 1 | 6.0× | 0.320 |
| Other/Unknown | 1 | 0.9× | 0.805 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| GDF1 | Other/Unknown | no | TGF-b_C, TGF-beta-like, TGFb_CS | |
| CERS1 | Enzyme (other) | yes | 2.3.1.299 | TLC-dom, Lag1/Lac1-like |
Expression context
Cohort genes with no expression data: 0.
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 |
|---|---|
| primary visual cortex | 1 |
| superior frontal gyrus | 1 |
| sural nerve | 1 |
| C1 segment of cervical spinal cord | 1 |
| right frontal lobe | 1 |
| spinal cord | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| GDF1 | 34 | ubiquitous | yes | primary visual cortex, sural nerve, superior frontal gyrus |
| CERS1 | 177 | broad | yes | C1 segment of cervical spinal cord, right frontal lobe, spinal cord |
Protein interactions among cohort
Intra-cohort edges: 0.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| GDF1 | 1,066 |
| CERS1 | 76 |
Structural data
PDB: 0 · AlphaFold-only: 2 · No structure: 0
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| CERS1 | P27544 | 88.95 |
| GDF1 | P27539 | 74.44 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 2. 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 |
|---|---|---|---|---|
| Signaling by NODAL | 1 | 248.3× | 0.007 | GDF1 |
| Sphingolipid de novo biosynthesis | 1 | 142.8× | 0.007 | CERS1 |
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 |
|---|---|---|---|---|
| cellular response to dithiothreitol | 1 | 8426.0× | 9e-04 | CERS1 |
| regulation of transmembrane receptor protein serine/threonine kinase signaling pathway | 1 | 8426.0× | 9e-04 | GDF1 |
| cellular response to mycotoxin | 1 | 4213.0× | 0.001 | CERS1 |
| cellular response to UV-A | 1 | 702.2× | 0.004 | CERS1 |
| negative regulation of D-glucose import across plasma membrane | 1 | 601.9× | 0.004 | CERS1 |
| negative regulation of cardiac muscle hypertrophy | 1 | 561.7× | 0.004 | CERS1 |
| positive regulation of mitophagy | 1 | 561.7× | 0.004 | CERS1 |
| endoderm development | 1 | 312.1× | 0.006 | GDF1 |
| mesoderm development | 1 | 263.3× | 0.006 | GDF1 |
| ceramide biosynthetic process | 1 | 210.7× | 0.007 | CERS1 |
| sphingolipid biosynthetic process | 1 | 179.3× | 0.008 | CERS1 |
| cellular response to xenobiotic stimulus | 1 | 120.4× | 0.010 | CERS1 |
| BMP signaling pathway | 1 | 100.3× | 0.011 | GDF1 |
| brain development | 1 | 39.8× | 0.027 | CERS1 |
| in utero embryonic development | 1 | 36.0× | 0.028 | GDF1 |
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 |
|---|---|---|
| GDF1 | 0 | 0 |
| CERS1 | 0 | 0 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 1.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| CERS1 | 2 | Binding:2 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| CERS1 | 2.3.1.299 | sphingoid base N-stearoyltransferase |
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 | 1 | CERS1 |
| E | Difficult family or no structure, no drug | 1 | GDF1 |
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) |
|---|---|---|
| GDF1 | 0 | — |
| CERS1 | 2 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 0.