Neonatal intrahepatic cholestasis due to citrin deficiency

Summary

Neonatal intrahepatic cholestasis due to citrin deficiency (MONDO:0011601) is a disease caused by SLC25A13 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: SLC25A13 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 92
• Phenotypes (HPO): 41

Clinical features

Signs & symptoms

Clinical features (HPO)

41 HPO clinical features (Orphanet curated; top 41 by frequency):

HPO ID	Term	Frequency
HP:0000952	Jaundice	Very frequent (80-99%)
HP:0001396	Cholestasis	Very frequent (80-99%)
HP:0002155	Hypertriglyceridemia	Very frequent (80-99%)
HP:0002904	Hyperbilirubinemia	Very frequent (80-99%)
HP:0003073	Hypoalbuminemia	Very frequent (80-99%)
HP:0003119	Abnormal circulating lipid concentration	Very frequent (80-99%)
HP:0003128	Lactic acidosis	Very frequent (80-99%)
HP:0003155	Elevated circulating alkaline phosphatase concentration	Very frequent (80-99%)
HP:0004313	Decreased circulating antibody level	Very frequent (80-99%)
HP:0006254	Elevated alpha-fetoprotein	Very frequent (80-99%)
HP:0008151	Prolonged prothrombin time	Very frequent (80-99%)
HP:0011966	Elevated plasma citrulline	Very frequent (80-99%)
HP:0012024	Hypergalactosemia	Very frequent (80-99%)
HP:0025435	Increased circulating lactate dehydrogenase concentration	Very frequent (80-99%)
HP:0030948	Elevated gamma-glutamyltransferase level	Very frequent (80-99%)
HP:0001397	Hepatic steatosis	Frequent (30-79%)
HP:0001433	Hepatosplenomegaly	Frequent (30-79%)
HP:0001531	Failure to thrive in infancy	Frequent (30-79%)
HP:0001987	Hyperammonemia	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002161	Hyperlysinemia	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0003231	Hypertyrosinemia	Frequent (30-79%)
HP:0010903	Abnormality of glutamine metabolism	Frequent (30-79%)
HP:0010909	Abnormality of arginine metabolism	Frequent (30-79%)
HP:0010916	Abnormal circulating alanine concentration	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0002919	Ketonuria	Occasional (5-29%)
HP:0003124	Hypercholesterolemia	Occasional (5-29%)
HP:0003141	Increased LDL cholesterol concentration	Occasional (5-29%)
HP:0003233	Decreased HDL cholesterol concentration	Occasional (5-29%)
HP:0003235	Hypermethioninemia	Occasional (5-29%)
HP:0003354	Hyperthreoninemia	Occasional (5-29%)
HP:0004396	Poor appetite	Occasional (5-29%)
HP:0012278	Abnormality of serine metabolism	Occasional (5-29%)
HP:0040301	Increased urinary glycerol	Occasional (5-29%)
HP:0000518	Cataract	Very rare (<1-4%)
HP:0001892	Abnormal bleeding	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neonatal intrahepatic cholestasis due to citrin deficiency
Mondo ID	MONDO:0011601
MeSH	C536398
OMIM	605814
Orphanet	247598
DOID	DOID:0070341
SNOMED CT	717155003
UMLS	C1853942
MedGen	340091
GARD	0010214
Is cancer (heuristic)	no

Also known as: citrullinemia, type II, neonatal-onset, with or without failure to thrive and dyslipidaemia · neonatal intrahepatic cholestasis caused by citrin deficiency · neonatal intrahepatic cholestasis due to citrin deficiency · neonatal-onset citrullinemia type 2 · neonatal-onset citrullinemia type II · NICCD

Data availability: 92 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › urea cycle disorder › citrullinemia › citrin deficiency › neonatal intrahepatic cholestasis due to citrin deficiency

Related subtypes (1): citrullinemia type II

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

92 retrieved; paginated sample, class counts are floors:

27 pathogenic, 19 likely pathogenic, 15 conflicting classifications of pathogenicity, 14 pathogenic/likely pathogenic, 14 uncertain significance, 2 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1695398	NM_014251.3(SLC25A13):c.[1956C>A;1962del]		Pathogenic	criteria provided, single submitter
21510	NM_014251.3(SLC25A13):c.15G>A (p.Lys5=)	LOC129998833	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074032	NM_014251.3(SLC25A13):c.276del (p.Phe92fs)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1361947	NM_014251.3(SLC25A13):c.127C>T (p.Arg43Ter)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1388183	NM_014251.3(SLC25A13):c.1453-2A>T	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
1450311	NM_014251.3(SLC25A13):c.970C>T (p.Gln324Ter)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451917	NM_014251.3(SLC25A13):c.1095del (p.Phe365fs)	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
1451920	NM_014251.3(SLC25A13):c.754G>A (p.Glu252Lys)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458046	NM_014251.3(SLC25A13):c.605_608dup (p.Val204fs)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1695399	NM_014251.3(SLC25A13):c.70-63_132del	SLC25A13	Pathogenic	no assertion criteria provided
1695400	NM_014251.3(SLC25A13):c.1751-5_1751-4insGATTTCTCCA	SLC25A13	Pathogenic	criteria provided, single submitter
1929400	NM_014251.3(SLC25A13):c.1769C>A (p.Ser590Ter)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2075890	NM_014251.3(SLC25A13):c.1311+1G>C	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
21508	NM_014251.3(SLC25A13):c.1078C>T (p.Arg360Ter)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21513	NM_014251.3(SLC25A13):c.1801G>T (p.Glu601Ter)	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
21514	NM_014251.3(SLC25A13):c.1813C>T (p.Arg605Ter)	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21515	NM_014251.3(SLC25A13):c.550C>T (p.Arg184Ter)	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
21517	NM_014251.3(SLC25A13):c.615+5G>A	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
225472	NM_014251.3(SLC25A13):c.852_855del (p.Met285fs)	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
252920	NM_014251.3(SLC25A13):c.775C>T (p.Gln259Ter)	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
252924	NM_014251.3(SLC25A13):c.495del (p.Ala166fs)	SLC25A13	Pathogenic	no assertion criteria provided
2678819	NM_014251.3(SLC25A13):c.1610_1612delinsAT (p.Leu537fs)	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
3336478	NM_014251.3(SLC25A13):c.1793T>G (p.Leu598Arg)	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
3764701	NM_014251.3(SLC25A13):c.1230+1G>C	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
449394	NM_014251.3(SLC25A13):c.1063C>T (p.Arg355Ter)	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
590803	NM_014251.3(SLC25A13):c.1664_1665insAGATTACAGGTGGCTGCCCGGGG (p.Gln556fs)	SLC25A13	Pathogenic	no assertion criteria provided
590804	NM_014251.3(SLC25A13):c.493C>T (p.Gln165Ter)	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
593512	NM_014251.3(SLC25A13):c.70-1G>A	SLC25A13	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6002	NM_014251.3(SLC25A13):c.1177+1G>A	SLC25A13	Pathogenic	criteria provided, multiple submitters, no conflicts
6003	NM_014251.3(SLC25A13):c.1638_1660dup (p.Ala554fs)	SLC25A13	Pathogenic	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
SLC25A13	Strong	Autosomal recessive	neonatal intrahepatic cholestasis due to citrin deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC25A13	Orphanet:247585	Citrullinemia type II
SLC25A13	Orphanet:247598	Neonatal intrahepatic cholestasis due to citrin deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC25A13	HGNC:10983	ENSG00000004864	Q9UJS0	Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC25A13	Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial	Mitochondrial electrogenic aspartate/glutamate antiporter that favors efflux of aspartate and entry of glutamate and proton within the mitochondria as part of the malate-aspartate shuttle.

Protein-family classification

Druggable: 1 · 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
Transporter	1	77.8×	0.013

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC25A13	Transporter	yes		EF_hand_dom, MCP, EF-hand-dom_pair

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
right lobe of liver	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC25A13	283	ubiquitous	marker	right lobe of liver, liver, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC25A13	1,895

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC25A13	Q9UJS0	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Malate-aspartate shuttle	1	1268.9×	0.004	SLC25A13
Aspartate and asparagine metabolism	1	1038.2×	0.004	SLC25A13
Protein localization	1	190.3×	0.012	SLC25A13
Mitochondrial protein import	1	167.9×	0.012	SLC25A13
Respiratory electron transport	1	95.2×	0.015	SLC25A13
Aerobic respiration and respiratory electron transport	1	88.5×	0.015	SLC25A13
Metabolism of amino acids and derivatives	1	67.6×	0.017	SLC25A13
Metabolism	1	11.6×	0.086	SLC25A13

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
malate-aspartate shuttle	1	1872.4×	0.002	SLC25A13
aspartate transmembrane transport	1	1404.3×	0.002	SLC25A13
mitochondrial transport	1	1203.7×	0.002	SLC25A13
ATP biosynthetic process	1	991.3×	0.002	SLC25A13
L-glutamate transmembrane transport	1	802.5×	0.002	SLC25A13
cellular respiration	1	432.1×	0.003	SLC25A13
gluconeogenesis	1	324.1×	0.003	SLC25A13
response to calcium ion	1	318.0×	0.003	SLC25A13

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC25A13	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
SLC25A13	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	SLC25A13
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
SLC25A13	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.