Right atrial isomerism

Summary

Right atrial isomerism (MONDO:0008832) is a disease caused by GDF1 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (France) [Orphanet-validated]
• Causal gene: GDF1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 14
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-5 / 10 000	16.67	France	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	right atrial isomerism
Mondo ID	MONDO:0008832
OMIM	208530
Orphanet	97548
DOID	DOID:0060856
UMLS	C3178806
MedGen	465274
GARD	0006795
MedDRA	10068335
NORD	1305
Is cancer (heuristic)	no

Also known as: asplenia syndrome · asplenia with cardiovascular anomalies · bilateral right-sidedness sequence · Ivemark Syndrome · Ivemark syndrome · RAI · right atrial isomerism · right atrial isomerism (disease) · right atrial isomerism (ivemark) · splenic agenesis syndrome

Data availability: 14 ClinVar variants · 4 GenCC gene-disease records · 1 HPO phenotype.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › visceral heterotaxy › right atrial isomerism

Related subtypes (18): situs inversus, heterotaxy, visceral, 1, X-linked, laterality defects, autosomal dominant, heterotaxy, visceral, 2, autosomal, heterotaxy, visceral, 3, autosomal, heterotaxy, visceral, 4, autosomal, heterotaxy, visceral, 6, autosomal, heterotaxy, visceral, 7, autosomal, heterotaxy, visceral, 8, autosomal, dextrocardia, levocardia, heterotaxy, visceral, 9, autosomal, with male infertility, heterotaxy, visceral, 10, autosomal, with male infertility, heterotaxy, visceral, 11, autosomal, with male infertility, heterotaxy, visceral, 5, autosomal, heterotaxy, visceral, 12, autosomal, heterotaxy, visceral, 13, autosomal, heterotaxy, visceral, 14, autosomal

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

14 retrieved; paginated sample, class counts are floors:

5 pathogenic/likely pathogenic, 4 likely pathogenic, 3 uncertain significance, 2 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
4531712	NM_001492.6(GDF1):c.653dup (p.Leu219fs)	CERS1	Pathogenic	criteria provided, single submitter
522570	NM_001492.6(GDF1):c.1090_1092del (p.Met364del)	CERS1	Pathogenic	no assertion criteria provided
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
985628	NM_001492.6(GDF1):c.608G>A (p.Trp203Ter)	CERS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2663906	NM_001492.6(GDF1):c.[1008C>G];[681C>A]		Likely pathogenic	criteria provided, single submitter
3377285	NM_001492.6(GDF1):c.91_98dup (p.Gly34fs)	CERS1	Likely pathogenic	criteria provided, single submitter
4086170	NM_001492.6(GDF1):c.968_969dup (p.Met324fs)	CERS1	Likely pathogenic	criteria provided, single submitter
418232	NM_001492.6(GDF1):c.776_801del (p.Leu259fs)	CERS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1348662	NM_001492.6(GDF1):c.596T>C (p.Leu199Pro)	CERS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
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

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 recessive	right atrial isomerism	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
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: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04009863	Not specified	COMPLETED	HIFU Ablation vs Fixed-dose RAI-131 Therapy in Moderate-sized Non-toxic MNG