Familial atrioventricular septal defect

Summary

Familial atrioventricular septal defect (MONDO:0020290) is a disease (an umbrella term covering 6 Mondo subtypes) with 7 cohort genes and 9 clinical trials. Top therapeutic interventions include prednisolone, l-citrulline, and plasmalyte a.

At a glance

• Umbrella term: 6 Mondo subtypes
• Cohort genes: 7
• ClinVar variants: 8
• Clinical trials: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial atrioventricular septal defect
Mondo ID	MONDO:0020290
OMIM	606215
Orphanet	98722
DOID	DOID:0050651
ICD-10-CM	Q21.2
NCIT	C101029
SNOMED CT	15459006
GARD	0000802
NORD	821
Anatomy (UBERON)	UBERON:0005989
Is cancer (heuristic)	no

Also known as: atrioventricular canal defect · Atrioventricular Septal Defect · atrioventricular septal defect · AV septal defect · AVCD · AVSD · common atrioventricular canal · common AV canal · ECD · endocardial cushion defect

Data availability: 8 ClinVar variants · 3 cell lines.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › congenital heart disease › heart septal defect › familial atrioventricular septal defect

Related subtypes (2): ventricular septal defect, atrial septal defect

Subtypes (6): atrioventricular septal defect 4, atrioventricular septal defect 5, congenital heart defects, multiple types, 4, complete atrioventricular canal, partial atrioventricular canal, atrioventricular septal defect

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

8 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 conflicting classifications of pathogenicity, 2 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
997064	GRCh37/hg19 16p11.2(chr16:28615644-29042118)	ATP2A1	Pathogenic	criteria provided, single submitter
374208	NM_014140.4(SMARCAL1):c.723C>A (p.Cys241Ter)	SMARCAL1	Pathogenic	criteria provided, multiple submitters, no conflicts
4171	NM_014140.4(SMARCAL1):c.2542G>T (p.Glu848Ter)	SMARCAL1	Pathogenic	criteria provided, multiple submitters, no conflicts
690345	NM_005126.5(NR1D2):c.523C>T (p.Arg175Trp)	NR1D2	Likely pathogenic	no assertion criteria provided
375289	NM_181486.4(TBX5):c.404T>G (p.Leu135Arg)	TBX5	Likely pathogenic	criteria provided, single submitter
800492	NM_017780.4(CHD7):c.6088G>A (p.Val2030Ile)	CHD7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360636	NM_000501.4(ELN):c.328G>A (p.Ala110Thr)	ELN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
55847	NM_001349338.3(FOXP1):c.1702C>T (p.Pro568Ser)	FOXP1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 15 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMARCAL1	Orphanet:1830	Schimke immuno-osseous dysplasia
TBX5	Orphanet:101016	Romano-Ward syndrome
TBX5	Orphanet:392	Holt-Oram syndrome
CHD7	Orphanet:138	CHARGE syndrome
CHD7	Orphanet:39041	Omenn syndrome
CHD7	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
CHD7	Orphanet:478	Kallmann syndrome
ELN	Orphanet:3193	Supravalvular aortic stenosis
ELN	Orphanet:90348	Autosomal dominant cutis laxa
ELN	Orphanet:904	Williams syndrome
ELN	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
FOXP1	Orphanet:391372	FOXP1 Syndrome
FOXP1	Orphanet:52417	MALT lymphoma
FOXP1	Orphanet:585877	B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormality
ATP2A1	Orphanet:53347	Brody myopathy

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMARCAL1	HGNC:11102	ENSG00000138375	Q9NZC9	SNF2 related chromatin remodeling annealing helicase 1	clinvar
TBX5	HGNC:11604	ENSG00000089225	Q99593	T-box transcription factor TBX5	clinvar
CHD7	HGNC:20626	ENSG00000171316	Q9P2D1	ATP-dependent chromatin remodeler CHD7	clinvar
ELN	HGNC:3327	ENSG00000049540	P15502	Elastin	clinvar
FOXP1	HGNC:3823	ENSG00000114861	Q9H334	Forkhead box protein P1	clinvar
NR1D2	HGNC:7963	ENSG00000174738	Q14995	Nuclear receptor subfamily 1 group D member 2	clinvar
ATP2A1	HGNC:811	ENSG00000196296	O14983	Sarcoplasmic/endoplasmic reticulum calcium ATPase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMARCAL1	SNF2 related chromatin remodeling annealing helicase 1	ATP-dependent annealing helicase that binds selectively to fork DNA relative to ssDNA or dsDNA and catalyzes the rewinding of the stably unwound DNA.
TBX5	T-box transcription factor TBX5	DNA-binding protein that regulates the transcription of several genes and is involved in heart development and limb pattern formation.
CHD7	ATP-dependent chromatin remodeler CHD7	ATP-dependent chromatin-remodeling factor, slides nucleosomes along DNA; nucleosome sliding requires ATP.
ELN	Elastin	Major structural protein of tissues such as aorta and nuchal ligament, which must expand rapidly and recover completely.
FOXP1	Forkhead box protein P1	Transcriptional repressor.
NR1D2	Nuclear receptor subfamily 1 group D member 2	Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner.
ATP2A1	Sarcoplasmic/endoplasmic reticulum calcium ATPase 1	Key regulator of striated muscle performance by acting as the major Ca(2+) ATPase responsible for the reuptake of cytosolic Ca(2+) into the sarcoplasmic reticulum.

Protein-family classification

Druggable: 1 · Difficult: 3 · Unknown: 3 · Druggable fraction: 0.14

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
Nuclear receptor	1	55.1×	0.054
Transcription factor	3	3.5×	0.064
Other/Unknown	3	0.8×	0.858

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMARCAL1	Other/Unknown	no		SNF2_N, Helicase_C-like, HARP_dom
TBX5	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
CHD7	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
ELN	Other/Unknown	no		Tropoelastin
FOXP1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_2, FOXP-CC
NR1D2	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
ATP2A1	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIA

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	2
primordial germ cell in gonad	1
stromal cell of endometrium	1
buccal mucosa cell	1
cardiac muscle of right atrium	1
tendon of biceps brachii	1
cerebellar vermis	1
secondary oocyte	1
ascending aorta	1
descending thoracic aorta	1
thoracic aorta	1
cardia of stomach	1
oviduct epithelium	1
pancreatic ductal cell	1
biceps brachii	1
calcaneal tendon	1
skeletal muscle tissue of biceps brachii	1
diaphragm	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMARCAL1	264	ubiquitous	marker	primordial germ cell in gonad, stromal cell of endometrium, sural nerve
TBX5	129	broad	marker	tendon of biceps brachii, cardiac muscle of right atrium, buccal mucosa cell
CHD7	269	ubiquitous	marker	secondary oocyte, cerebellar vermis, sural nerve
ELN	227	broad	marker	descending thoracic aorta, ascending aorta, thoracic aorta
FOXP1	256	ubiquitous	marker	pancreatic ductal cell, oviduct epithelium, cardia of stomach
NR1D2	294	ubiquitous	marker	calcaneal tendon, biceps brachii, skeletal muscle tissue of biceps brachii
ATP2A1	185	tissue_specific	marker	hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis, diaphragm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CHD7	4,819
FOXP1	2,939
SMARCAL1	2,899
ATP2A1	2,809
ELN	2,692
TBX5	2,250
NR1D2	1,106

Structural data

PDB: 5 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NR1D2	Q14995	6
TBX5	Q99593	4
CHD7	Q9P2D1	3
SMARCAL1	Q9NZC9	1
FOXP1	Q9H334	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP2A1	O14983	88.65
ELN	P15502	36.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 7 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cardiac conduction	2	36.2×	0.033	TBX5, ATP2A1
Muscle contraction	2	25.7×	0.033	TBX5, ATP2A1
Reduction of cytosolic Ca++ levels	1	158.6×	0.036	ATP2A1
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	126.9×	0.036	TBX5
Platelet calcium homeostasis	1	119.0×	0.036	ATP2A1
Physiological factors	1	112.0×	0.036	TBX5
Pre-NOTCH Processing in Golgi	1	105.7×	0.036	ATP2A1
Transcriptional regulation of pluripotent stem cells	1	90.6×	0.037	FOXP1
Cardiogenesis	1	70.5×	0.042	TBX5
Pre-NOTCH Expression and Processing	1	61.4×	0.043	ATP2A1
Elastic fibre formation	1	56.0×	0.043	ELN
Molecules associated with elastic fibres	1	51.4×	0.043	ELN
Platelet homeostasis	1	46.4×	0.044	ATP2A1
Ion transport by P-type ATPases	1	34.6×	0.050	ATP2A1
Ion homeostasis	1	34.0×	0.050	ATP2A1
Nuclear Receptor transcription pathway	1	33.4×	0.050	NR1D2
Signaling by NOTCH	1	29.3×	0.053	ATP2A1
CHD6, CHD7, CHD8, CHD9 subfamily	1	24.7×	0.060	CHD7
Degradation of the extracellular matrix	1	19.6×	0.071	ELN
Ion channel transport	1	16.0×	0.082	ATP2A1
Hemostasis	1	6.0×	0.200	ATP2A1
Transport of small molecules	1	4.2×	0.265	ATP2A1
RNA Polymerase II Transcription	1	3.8×	0.280	TBX5
Gene expression (Transcription)	1	3.0×	0.329	TBX5
Generic Transcription Pathway	1	2.5×	0.363	TBX5
Developmental Biology	1	2.4×	0.363	TBX5
Signal Transduction	1	1.7×	0.463	ATP2A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
right ventricular compact myocardium morphogenesis	1	2407.4×	0.007	CHD7
maintenance of mitochondrion location	1	2407.4×	0.007	ATP2A1
cell migration involved in coronary vasculogenesis	1	2407.4×	0.007	TBX5
regulation of macrophage colony-stimulating factor production	1	2407.4×	0.007	FOXP1
positive regulation of cardiac conduction	1	2407.4×	0.007	TBX5
cardiac left ventricle formation	1	1203.7×	0.007	TBX5
positive regulation of fast-twitch skeletal muscle fiber contraction	1	1203.7×	0.007	ATP2A1
regulation of monocyte differentiation	1	1203.7×	0.007	FOXP1
atrioventricular node cell fate commitment	1	1203.7×	0.007	TBX5
bundle of His cell to Purkinje myocyte communication by electrical coupling	1	1203.7×	0.007	TBX5
regulation of defense response to bacterium	1	1203.7×	0.007	FOXP1
positive regulation of cell communication by electrical coupling involved in cardiac conduction	1	1203.7×	0.007	TBX5
positive regulation of ATPase-coupled calcium transmembrane transporter activity	1	1203.7×	0.007	ATP2A1
positive regulation of calcium ion import into sarcoplasmic reticulum	1	1203.7×	0.007	ATP2A1
atrioventricular bundle cell differentiation	1	802.5×	0.007	TBX5
cranial nerve development	1	802.5×	0.007	CHD7
olfactory nerve development	1	802.5×	0.007	CHD7
positive regulation of endoplasmic reticulum calcium ion concentration	1	802.5×	0.007	ATP2A1
positive regulation of interleukin-21 production	1	802.5×	0.007	FOXP1
negative regulation of striated muscle contraction	1	802.5×	0.007	ATP2A1
regulation of growth hormone secretion	1	802.5×	0.007	CHD7
positive regulation of secondary heart field cardioblast proliferation	1	802.5×	0.007	TBX5
relaxation of skeletal muscle	1	802.5×	0.007	ATP2A1
positive regulation of cardiac muscle cell contraction	1	802.5×	0.007	ATP2A1
calcium ion import into sarcoplasmic reticulum	1	802.5×	0.007	ATP2A1
regulation of chemokine (C-X-C motif) ligand 2 production	1	802.5×	0.007	FOXP1
blood circulation	2	145.9×	0.007	CHD7, ELN
regulation of inflammatory response	2	48.1×	0.007	FOXP1, NR1D2
bundle of His development	1	601.9×	0.008	TBX5
regulation of interleukin-12 production	1	601.9×	0.008	FOXP1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 7

Druggability breadth: 4 of 7 evidence-associated genes (57%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMARCAL1	0	0
TBX5	0	0
CHD7	0	0
ELN	0	0
FOXP1	0	0
NR1D2	0	0
ATP2A1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NR1D2	12	Binding:10, Functional:2
ATP2A1	6	Binding:6
TBX5	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; 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	1	NR1D2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	SMARCAL1, TBX5, CHD7, ELN, FOXP1, ATP2A1

Undrugged target profiles

7 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SMARCAL1	0	—
TBX5	1	—
CHD7	0	—
ELN	0	—
FOXP1	0	—
NR1D2	12	—
ATP2A1	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 9.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE3	2
PHASE2	2
PHASE1/PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02314312	PHASE3	UNKNOWN	Efficacy and Safety of Everolimus in de Novo Kidney Transplant Recipients of ECD or AKI Donors
NCT05253209	PHASE3	TERMINATED	A Study Evaluating the Efficacy and Safety of IV L-Citrulline for the Prevention of Clinical Sequelae of Acute Lung Injury Induced by Cardiopulmonary Bypass in Pediatric Patients Undergoing Surgery for Congenital Heart Defects
NCT00199771	PHASE2	COMPLETED	Hypertonic Saline Dextran in Pediatric Cardiac Surgery
NCT01120964	PHASE1/PHASE2	COMPLETED	Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery : Revised Protocol
NCT05092815	PHASE2	UNKNOWN	The Efficacy and Safety of HLX208 in Adult Langerhans Cell Histiocytosis (LCH) and Erdheim-Chester Disease (ECD) With BRAF V600E Mutation
NCT01825369	PHASE1	WITHDRAWN	Aberrations in Carnitine Homeostasis in Congenital Heart Disease With Increased Pulmonary Blood Flow
NCT00005322	Not specified	COMPLETED	Molecular Genetic Epidemiology of Endocardial Cushion Defects - SCOR in Pediatric Cardiovascular Disease
NCT00005546	Not specified	COMPLETED	Molecular Genetic Epidemiology of Three Cardiac Defects -SCOR in Pediatric Cardiovascular Disease
NCT00229827	Not specified	TERMINATED	Optimal Timing for Repair of Left to Right Shunt Lesions

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PREDNISOLONE	4	1
L-CITRULLINE	3	2
PLASMALYTE A	3	1