Familial isolated congenital asplenia

Summary

Familial isolated congenital asplenia (MONDO:0010066) is a disease caused by RPSA (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: RPSA (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial isolated congenital asplenia
Mondo ID	MONDO:0010066
MeSH	C563028
OMIM	271400
Orphanet	101351
SNOMED CT	726708009
UMLS	C0685889
MedGen	151935
GARD	0016944
Is cancer (heuristic)	no

Also known as: asplenia, isolated congenital · ICAS

Data availability: 16 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › familial isolated congenital asplenia

Related subtypes (40): B cell deficiency, complement deficiency, phagocyte bactericidal dysfunction, trichohepatoenteric syndrome, hepatic veno-occlusive disease-immunodeficiency syndrome, immunodeficiency with defective T-cell response to interleukin 1, Say-Barber-Miller syndrome, X-linked immunoneurologic disorder, ectodermal dysplasia and immune deficiency, immunodeficiency 33, immunodeficiency 47, combined immunodeficiency due to moesin deficiency, immunodeficiency, X-linked, with deficiency of 115,000 Dalton surface glycoprotein, properdin deficiency, X-linked, combined immunodeficiency with faciooculoskeletal anomalies, recurrent infections associated with rare immunoglobulin isotypes deficiency, immunodeficiency 28, autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity, immunodeficiency 37, immunodeficiency 39, BENTA disease, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection, immunodeficiency 49, chronic mucocutaneous candidiasis, hereditary hemophagocytic lymphohistiocytosis, immunoglobulin heavy chain deficiency, immuno-osseous dysplasia, lymphoproliferative syndrome, IL10-related early-onset inflammatory bowel disease, T-cell immunodeficiency with epidermodysplasia verruciformis, Aicardi-Goutieres syndrome, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, inflammatory bowel disease-recurrent sinopulmonary infections syndrome, A20 haploinsufficiency, NK cell deficiency, T cell and NK cell immunodeficiency, dendritic cell deficiency, immunodysregulation with variable immunodeficiency and autoimmunity, immune dysregulation with immunodeficiency due to AIOLOS haploinsufficiency, STAT5 haploinsufficiency

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

16 retrieved; paginated sample, class counts are floors:

6 pathogenic, 3 benign, 3 likely pathogenic, 2 uncertain significance, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
64671	NM_002295.6(RPSA):c.25C>T (p.Gln9Ter)	RPSA	Pathogenic	no assertion criteria provided
64672	NM_002295.6(RPSA):c.590_594dup (p.Pro199fs)	RPSA	Pathogenic	no assertion criteria provided
64673	NM_002295.6(RPSA):c.538C>G (p.Arg180Gly)	RPSA	Pathogenic	no assertion criteria provided
64674	NM_002295.6(RPSA):c.538C>T (p.Arg180Trp)	RPSA	Pathogenic	criteria provided, single submitter
64676	NM_002295.6(RPSA):c.161C>A (p.Thr54Asn)	RPSA	Pathogenic	no assertion criteria provided
64677	NM_002295.6(RPSA):c.172C>T (p.Leu58Phe)	RPSA	Pathogenic	no assertion criteria provided
4795154	NM_002295.6(RPSA):c.659_663del (p.Lys220fs)	RPSA	Likely pathogenic	criteria provided, single submitter
4819200	NM_002295.6(RPSA):c.493A>T (p.Asn165Tyr)	RPSA	Likely pathogenic	criteria provided, single submitter
64675	NM_002295.6(RPSA):c.556C>T (p.Arg186Cys)	RPSA	Likely pathogenic	criteria provided, single submitter
39433	NM_004387.4(NKX2-5):c.707C>A (p.Pro236His)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626159	NM_002295.6(RPSA):c.498+8T>A	RPSA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2412689	NM_002295.6(RPSA):c.491A>T (p.Asn164Ile)	RPSA	Uncertain significance	criteria provided, single submitter
2671652	NM_002295.6(RPSA):c.508T>G (p.Ser170Ala)	RPSA	Uncertain significance	criteria provided, single submitter
1327975	NM_002295.6(RPSA):c.134-32C>T	RPSA	Benign	criteria provided, multiple submitters, no conflicts
403395	NM_002295.6(RPSA):c.-8T>C	RPSA	Benign	criteria provided, multiple submitters, no conflicts
403396	NM_002295.6(RPSA):c.519G>A (p.Leu173=)	RPSA	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 12 · 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
NKX2-5	Definitive	Autosomal dominant	hypothyroidism, congenital, nongoitrous, 5	17
RPSA	Definitive	Autosomal dominant	familial isolated congenital asplenia	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NKX2-5	Orphanet:101351	Familial isolated congenital asplenia
NKX2-5	Orphanet:1479	Atrial septal defect-atrioventricular conduction defects syndrome
NKX2-5	Orphanet:1627	Deletion 5q35 syndrome
NKX2-5	Orphanet:2248	Hypoplastic left heart syndrome
NKX2-5	Orphanet:3303	Tetralogy of Fallot
NKX2-5	Orphanet:334	Hereditary atrial fibrillation
NKX2-5	Orphanet:402075	Familial bicuspid aortic valve
NKX2-5	Orphanet:871	Hereditary progressive cardiac conduction defect
NKX2-5	Orphanet:95712	Thyroid ectopia
NKX2-5	Orphanet:95713	Athyreosis
NKX2-5	Orphanet:99103	Atrial septal defect, ostium secundum type
RPSA	Orphanet:101351	Familial isolated congenital asplenia

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
NKX2-5	HGNC:2488	ENSG00000183072	P52952	Homeobox protein Nkx-2.5	gencc,clinvar
RPSA	HGNC:6502	ENSG00000168028	P08865	Small ribosomal subunit protein uS2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NKX2-5	Homeobox protein Nkx-2.5	Transcription factor required for the development of the heart and the spleen.
RPSA	Small ribosomal subunit protein uS2	Required for the assembly and/or stability of the 40S ribosomal subunit.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NKX2-5	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
RPSA	Other/Unknown	no		Ribosomal_uS2, Ribosomal_uS2_euk_arc, Ribosomal_uS2_CS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
cardiac atrium	1
right atrium auricular region	1
cortical plate	1
primordial germ cell in gonad	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NKX2-5	98	broad	yes	apex of heart, right atrium auricular region, cardiac atrium
RPSA	157	ubiquitous	marker	primordial germ cell in gonad, right uterine tube, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RPSA	6,855
NKX2-5	2,355

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RPSA	P08865	209
NKX2-5	P52952	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 54. 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
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	380.7×	0.029	NKX2-5
Physiological factors	1	335.9×	0.029	NKX2-5
Cardiogenesis	1	211.5×	0.029	NKX2-5
Eukaryotic Translation Initiation	1	154.3×	0.029	RPSA
Cap-dependent Translation Initiation	1	154.3×	0.029	RPSA
SARS-CoV-1 modulates host translation machinery	1	154.3×	0.029	RPSA
Eukaryotic Translation Elongation	1	139.3×	0.029	RPSA
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	1	135.9×	0.029	RPSA
Dengue Virus Attachment and Entry	1	129.8×	0.029	RPSA
Nonsense-Mediated Decay (NMD)	1	116.5×	0.029	RPSA
SARS-CoV-2 modulates host translation machinery	1	112.0×	0.029	RPSA
Influenza Viral RNA Transcription and Replication	1	107.7×	0.029	RPSA
Formation of the ternary complex, and subsequently, the 43S complex	1	107.7×	0.029	RPSA
Selenoamino acid metabolism	1	98.5×	0.029	RPSA
Translation initiation complex formation	1	95.2×	0.029	RPSA
Ribosomal scanning and start codon recognition	1	95.2×	0.029	RPSA
Influenza Infection	1	87.8×	0.029	RPSA
SARS-CoV-1-host interactions	1	87.8×	0.029	RPSA
Cellular response to starvation	1	82.8×	0.029	RPSA
rRNA processing in the nucleus and cytosol	1	80.4×	0.029	RPSA
rRNA processing	1	73.2×	0.029	RPSA
SARS-CoV-1 Infection	1	71.4×	0.029	RPSA
Peptide chain elongation	1	63.4×	0.029	RPSA
Viral mRNA Translation	1	63.4×	0.029	RPSA
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	1	62.8×	0.029	RPSA
Signaling by ROBO receptors	1	62.1×	0.029	RPSA
Selenocysteine synthesis	1	60.1×	0.029	RPSA
Eukaryotic Translation Termination	1	60.1×	0.029	RPSA
SARS-CoV-2-host interactions	1	59.5×	0.029	RPSA
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	1	58.9×	0.029	RPSA

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
Purkinje myocyte differentiation	1	8426.0×	0.002	NKX2-5
septum secundum development	1	8426.0×	0.002	NKX2-5
right ventricular cardiac muscle tissue morphogenesis	1	4213.0×	0.002	NKX2-5
atrioventricular node cell fate commitment	1	4213.0×	0.002	NKX2-5
cardiac ventricle formation	1	2808.7×	0.002	NKX2-5
apoptotic process involved in heart morphogenesis	1	2808.7×	0.002	NKX2-5
proepicardium development	1	2808.7×	0.002	NKX2-5
pulmonary myocardium development	1	2808.7×	0.002	NKX2-5
ventricular cardiac myofibril assembly	1	2808.7×	0.002	NKX2-5
atrial cardiac muscle cell development	1	2808.7×	0.002	NKX2-5
bundle of His development	1	2106.5×	0.002	NKX2-5
atrial cardiac muscle tissue development	1	2106.5×	0.002	NKX2-5
positive regulation of cardioblast differentiation	1	2106.5×	0.002	NKX2-5
atrioventricular node cell development	1	2106.5×	0.002	NKX2-5
regulation of cardiac muscle cell proliferation	1	1685.2×	0.003	NKX2-5
atrioventricular node development	1	1404.3×	0.003	NKX2-5
embryonic heart tube left/right pattern formation	1	1404.3×	0.003	NKX2-5
positive regulation of heart contraction	1	1053.2×	0.004	NKX2-5
ventricular cardiac muscle cell development	1	766.0×	0.005	NKX2-5
ribosomal small subunit assembly	1	702.2×	0.005	RPSA
cardiac muscle tissue morphogenesis	1	702.2×	0.005	NKX2-5
atrial septum morphogenesis	1	648.1×	0.005	NKX2-5
adult heart development	1	601.9×	0.005	NKX2-5
cardiac septum morphogenesis	1	601.9×	0.005	NKX2-5
negative regulation of epithelial cell apoptotic process	1	601.9×	0.005	NKX2-5
negative regulation of myotube differentiation	1	561.7×	0.005	NKX2-5
heart trabecula formation	1	561.7×	0.005	NKX2-5
cardiac conduction system development	1	526.6×	0.005	NKX2-5
ventricular trabecula myocardium morphogenesis	1	526.6×	0.005	NKX2-5
regulation of cardiac muscle contraction	1	443.5×	0.005	NKX2-5

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
RPSA	GENTAMICIN SULFATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RPSA	3	4
NKX2-5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GENTAMICIN SULFATE	4	RPSA
EPIGALOCATECHIN GALLATE	3	RPSA
MOLIBRESIB	2	RPSA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RPSA	103	Binding:103

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
RPSA	103

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

3 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.

Compound	Max phase	Cohort target (bioactivity)
GENTAMICIN SULFATE	4	RPSA
EPIGALOCATECHIN GALLATE	3	RPSA
MOLIBRESIB	2	RPSA

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RPSA
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	1	NKX2-5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NKX2-5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.