Neonatal lupus erythematosus

Summary

Neonatal lupus erythematosus (MONDO:0018360) is a disease with 9 cohort genes (5 GWAS associations across 1 studies) and 6 clinical trials. The dominant Reactome pathway is TNFR2 non-canonical NF-kB pathway (3 cohort genes). Top therapeutic interventions include hydroxychloroquine.

At a glance

• Prevalence: 1-9 / 1 000 000 (United States) [Orphanet-validated]
• Cohort genes: 9
• GWAS associations: 5
• Phenotypes (HPO): 36
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	5	United States	Validated
Prevalence at birth	1-9 / 100 000	5	United States	Validated

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0030057	Autoimmune antibody positivity	Very frequent (80-99%)
HP:0000951	Abnormality of the skin	Frequent (30-79%)
HP:0001392	Abnormality of the liver	Frequent (30-79%)
HP:0001871	Abnormality of blood and blood-forming tissues	Frequent (30-79%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000962	Hyperkeratosis	Occasional (5-29%)
HP:0000988	Skin rash	Occasional (5-29%)
HP:0000992	Cutaneous photosensitivity	Occasional (5-29%)
HP:0001036	Parakeratosis	Occasional (5-29%)
HP:0001644	Dilated cardiomyopathy	Occasional (5-29%)
HP:0001678	Atrioventricular block	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0001875	Decreased total neutrophil count	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002500	Abnormal cerebral white matter morphology	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)
HP:0012722	Heart block	Occasional (5-29%)
HP:0025300	Malar rash	Occasional (5-29%)
HP:0025474	Erythematous plaque	Occasional (5-29%)
HP:0040186	Maculopapular exanthema	Occasional (5-29%)
HP:0001396	Cholestasis	Excluded (0%)
HP:0000256	Macrocephaly	Very rare (<1-4%)
HP:0001399	Hepatic failure	Very rare (<1-4%)
HP:0001627	Abnormal heart morphology	Very rare (<1-4%)
HP:0001657	Prolonged QT interval	Very rare (<1-4%)
HP:0001744	Splenomegaly	Very rare (<1-4%)
HP:0001876	Pancytopenia	Very rare (<1-4%)
HP:0001878	Hemolytic anemia	Very rare (<1-4%)
HP:0001892	Abnormal bleeding	Very rare (<1-4%)
HP:0001915	Aplastic anemia	Very rare (<1-4%)
HP:0002086	Abnormality of the respiratory system	Very rare (<1-4%)
HP:0002135	Basal ganglia calcification	Very rare (<1-4%)
HP:0002652	Skeletal dysplasia	Very rare (<1-4%)
HP:0011702	Abnormal electrophysiology of sinoatrial node origin	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neonatal lupus erythematosus
Mondo ID	MONDO:0018360
EFO	EFO:0004537
MeSH	C536397
Orphanet	398124
ICD-11	213855225
NCIT	C99236
SNOMED CT	95609003
UMLS	C0409979
MedGen	98372
GARD	0021647
NORD	1495
Is cancer (heuristic)	no

Also known as: congenital lupus · congenital lupus erythematosus · Neonatal Lupus · neonatal lupus · neonatal lupus syndrome · neonatal SLE · neonatal systemic lupus erythematosus

Data availability: 5 GWAS associations (1 study) · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › connective tissue disorder › rheumatic disorder › lupus erythematosus › systemic lupus erythematosus › neonatal lupus erythematosus

Related subtypes (11): autosomal systemic lupus erythematosus type 16, pediatric systemic lupus erythematosus, central nervous system lupus, bullous systemic lupus erythematosus, systemic lupus erythematosus related to C4A, systemic lupus erythematosus 17, systemic lupus erythematosus related to C1QA, systemic lupus erythematosus related to C1S, systemic lupus erythematosus 18, systemic lupus erythematosus related to C1QC, systemic lupus erythematosus related to C1QB

Genetics & variants

GWAS landscape

5 GWAS associations across 1 studies. Top hits map to 4 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs3099844	5e-10	HCP5, MICB-DT	?	3.34
rs2403106	3e-06	RPL6P25 - SLC6A15	?	2.48
rs1890645	4e-06	RNU6-983P - LINC01724	?	2.98
rs743446	5e-06	ERG - LINC00114	?	2.4
rs1391511	7e-06	MANCR, LINC00705	?	1.84

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST000738	Clancy RM	2010	116	3,351	Identification of candidate loci at 6p21 and 21q22 in a genome-wide association study of cardiac manifestations of neonatal lupus.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	5

MAF distribution

Bucket	Variants
common (>=0.05)	5
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intergenic_variant	3
non_coding_transcript_exon_variant	1
intron_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs3099844	6	31481199	C>A,G	0.11	non_coding_transcript_exon_variant	HCP5, MICB-DT	5e-10	Tier 4: intronic/intergenic
rs2403106	12	83614496	A>C,G,T	0.07	intergenic_variant	RPL6P25 - SLC6A15	3e-06	Tier 4: intronic/intergenic
rs1890645	1	195562293	T>C	0.3	intergenic_variant	RNU6-983P - LINC01724	4e-06	Tier 4: intronic/intergenic
rs743446	21	38684499	A>C,G,T	0.49	intergenic_variant	ERG - LINC00114	5e-06	Tier 4: intronic/intergenic
rs1391511	10	4677604	A>C,G,T	0.36	intron_variant	MANCR, LINC00705	7e-06	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERG	Orphanet:319	Skeletal Ewing sarcoma
ERG	Orphanet:370334	Extraskeletal Ewing sarcoma

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNF	HGNC:11892	ENSG00000232810	P01375	Tumor necrosis factor	gwas
LINC00114	HGNC:1265	ENSG00000223806	Q6XXX2	Putative uncharacterized protein encoded by LINC00114	gwas
AKR1E2	HGNC:23437	ENSG00000165568	Q96JD6	1,5-anhydro-D-fructose reductase	gwas
TMTC2	HGNC:25440	ENSG00000179104	Q8N394	Protein O-mannosyl-transferase TMTC2	gwas
ERG	HGNC:3446	ENSG00000157554	P11308	Transcriptional regulator ERG	gwas
AIF1	HGNC:352	ENSG00000204472	P55008	Allograft inflammatory factor 1	gwas
LTA	HGNC:6709	ENSG00000226979	P01374	Lymphotoxin-alpha	gwas
LTB	HGNC:6711	ENSG00000227507	Q06643	Lymphotoxin-beta	gwas
NFKBIL1	HGNC:7800	ENSG00000204498	Q9UBC1	NF-kappa-B inhibitor-like protein 1	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNF	Tumor necrosis factor	Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR.
AKR1E2	1,5-anhydro-D-fructose reductase	Catalyzes the NADPH-dependent reduction of 1,5-anhydro-D-fructose (AF) to 1,5-anhydro-D-glucitol.
TMTC2	Protein O-mannosyl-transferase TMTC2	Transfers mannosyl residues to the hydroxyl group of serine or threonine residues.
ERG	Transcriptional regulator ERG	Transcriptional regulator.
AIF1	Allograft inflammatory factor 1	Actin-binding protein that enhances membrane ruffling and RAC activation.
LTA	Lymphotoxin-alpha	Cytokine that in its homotrimeric form binds to TNFRSF1A/TNFR1, TNFRSF1B/TNFBR and TNFRSF14/HVEM.
LTB	Lymphotoxin-beta	Cytokine that binds to LTBR/TNFRSF3.
NFKBIL1	NF-kappa-B inhibitor-like protein 1	Involved in the regulation of innate immune response.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 8 · 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
Other/Unknown	8	1.6×	0.085
Scaffold/PPI	1	1.9×	0.415

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNF	Other/Unknown	no		TNF_alpha, TNF_dom, TNF
LINC00114	Other/Unknown	no
AKR1E2	Other/Unknown	no		Aldo/ket_reductase_CS, AKR, NADP_OxRdtase_dom
TMTC2	Other/Unknown	no		TPR-like_helical_dom_sf, TMTC_DUF1736, TPR_rpt
ERG	Other/Unknown	no		Ets_dom, Pointed_dom, SAM/pointed_sf
AIF1	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, AIF1/AIF1L
LTA	Other/Unknown	no		TNF_beta, TNF_dom, TNF
LTB	Other/Unknown	no		TNF_C, TNF_dom, TNF
NFKBIL1	Scaffold/PPI	no		Ankyrin_rpt-contain_sf, NFKBIL1

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)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	4
male germ line stem cell (sensu Vertebrata) in testis	4
lymph node	2
bone marrow	1
mucosa of transverse colon	1
sural nerve	1
cardiac muscle of right atrium	1
kidney epithelium	1
left ventricle myocardium	1
corpus callosum	1
mucosa of paranasal sinus	1
ventricular zone	1
descending thoracic aorta	1
tendon of biceps brachii	1
thoracic aorta	1
leukocyte	1
monocyte	1
spleen	1
body of pancreas	1
body of stomach	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNF	119	broad	marker	granulocyte, male germ line stem cell (sensu Vertebrata) in testis, bone marrow
LINC00114	116		marker	male germ line stem cell (sensu Vertebrata) in testis, sural nerve, mucosa of transverse colon
AKR1E2	184	ubiquitous	yes	kidney epithelium, cardiac muscle of right atrium, left ventricle myocardium
TMTC2	237	ubiquitous	marker	ventricular zone, corpus callosum, mucosa of paranasal sinus
ERG	247	broad	marker	tendon of biceps brachii, descending thoracic aorta, thoracic aorta
AIF1	159	broad	marker	monocyte, leukocyte, granulocyte
LTA	119	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, granulocyte, lymph node
LTB	130	broad	marker	granulocyte, spleen, lymph node
NFKBIL1	133	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, body of pancreas, body of stomach

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TNF	11,116
AIF1	4,440
LTA	1,807
TMTC2	1,795
ERG	1,223
NFKBIL1	1,128
AKR1E2	1,013
LTB	12
LINC00114	2

Intra-cohort edges

A	B	Sources
AIF1	NFKBIL1	string_interaction
AIF1	TNF	string_interaction
LTA	LTB	biogrid_interaction
LTA	NFKBIL1	string_interaction
NFKBIL1	TNF	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNF	P01375	52
ERG	P11308	8
LTA	P01374	3
AIF1	P55008	2
LTB	Q06643	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AKR1E2	Q96JD6	93.51
TMTC2	Q8N394	90.57
NFKBIL1	Q9UBC1	77.75
LINC00114	Q6XXX2	40.12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 9 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TNFR2 non-canonical NF-kB pathway	3	135.9×	8e-06	TNF, LTA, LTB
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	2	335.9×	8e-05	LTA, LTB
TNFR1-mediated ceramide production	1	475.8×	0.009	TNF
Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)	1	219.6×	0.014	TNF
Glycogen breakdown (glycogenolysis)	1	190.3×	0.014	AKR1E2
TNFR1-induced proapoptotic signaling	1	109.8×	0.016	TNF
TNF signaling	1	105.7×	0.016	TNF
TNFs bind their physiological receptors	1	98.5×	0.016	LTA
TNFR1-induced NF-kappa-B signaling pathway	1	84.0×	0.017	TNF
Interleukin-10 signaling	1	58.3×	0.021	TNF
Regulation of TNFR1 signaling	1	56.0×	0.021	TNF
Transcriptional regulation of white adipocyte differentiation	1	32.4×	0.033	TNF
Interleukin-4 and Interleukin-13 signaling	1	25.7×	0.038	TNF

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of chronic inflammatory response to antigenic stimulus	2	2106.5×	4e-05	TNF, LTA
positive regulation of extrinsic apoptotic signaling pathway	3	170.8×	6e-05	TNF, LTA, LTB
positive regulation of humoral immune response mediated by circulating immunoglobulin	2	842.6×	1e-04	TNF, LTA
positive regulation of mononuclear cell migration	2	842.6×	1e-04	TNF, AIF1
lymph node development	2	200.6×	0.002	LTA, LTB
positive regulation of glial cell proliferation	2	175.5×	0.002	TNF, LTA
microglial cell activation	2	156.0×	0.002	TNF, AIF1
positive regulation of canonical NF-kappaB signal transduction	3	27.2×	0.004	TNF, LTA, LTB
positive regulation of chemokine production	2	93.6×	0.005	TNF, AIF1
positive regulation of smooth muscle cell proliferation	2	82.6×	0.005	TNF, AIF1
positive regulation of translational initiation by iron	1	2106.5×	0.006	TNF
negative regulation of branching involved in lung morphogenesis	1	2106.5×	0.006	TNF
negative regulation of bile acid secretion	1	2106.5×	0.006	TNF
response to Gram-negative bacterium	1	2106.5×	0.006	TNF
positive regulation of interleukin-33 production	1	2106.5×	0.006	TNF
response to 3,3’,5-triiodo-L-thyronine	1	2106.5×	0.006	TNF
humoral immune response	2	70.2×	0.006	TNF, LTA
immune response	3	17.6×	0.006	TNF, LTA, LTB
positive regulation of type II interferon production	2	56.2×	0.006	TNF, LTA
negative regulation of L-glutamate import across plasma membrane	1	1053.2×	0.007	TNF
chronic inflammatory response to antigenic stimulus	1	1053.2×	0.007	TNF
positive regulation of fractalkine production	1	1053.2×	0.007	TNF
positive regulation of protein transport	1	1053.2×	0.007	TNF
positive regulation of vitamin D biosynthetic process	1	1053.2×	0.007	TNF
response to hydrogen sulfide	1	1053.2×	0.007	TNF
response to quercetin	1	1053.2×	0.007	TNF
response to gold nanoparticle	1	1053.2×	0.007	TNF
positive regulation of blood microparticle formation	1	1053.2×	0.007	TNF
regulation of endothelial cell apoptotic process	1	1053.2×	0.007	TNF
cellular response to type II interferon	2	52.0×	0.007	TNF, AIF1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 8

Druggability breadth: 4 of 9 evidence-associated genes (44%) 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
TNF	PREDNISOLONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TNF	12	4
LINC00114	0	0
AKR1E2	0	0
TMTC2	0	0
ERG	0	0
AIF1	0	0
LTA	0	0
LTB	0	0
NFKBIL1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PREDNISOLONE	4	TNF
POMALIDOMIDE	4	TNF
PENTOXIFYLLINE	4	TNF
MESALAMINE	4	TNF
LENALIDOMIDE	4	TNF
MARIMASTAT	3	TNF
IBERDOMIDE	3	TNF
DORAMAPIMOD	2	TNF
AVADOMIDE	2	TNF
MIZACORAT	2	TNF
LINPERLISIB	2	TNF
ROLIPRAM	2	TNF

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TNF	193	Binding:162, Functional:31
ERG	14	Binding:10, Functional:3, ADMET:1
LTA	3	Binding:3
LTB	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TNF	193

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

12 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)
PREDNISOLONE	4	TNF
POMALIDOMIDE	4	TNF
PENTOXIFYLLINE	4	TNF
MESALAMINE	4	TNF
LENALIDOMIDE	4	TNF
MARIMASTAT	3	TNF
IBERDOMIDE	3	TNF
DORAMAPIMOD	2	TNF
AVADOMIDE	2	TNF
MIZACORAT	2	TNF
LINPERLISIB	2	TNF
ROLIPRAM	2	TNF

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TNF
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	8	LINC00114, AKR1E2, TMTC2, ERG, AIF1, LTA, LTB, NFKBIL1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AIF1	0	TNF
LINC00114	0	—
AKR1E2	0	—
TMTC2	0	—
ERG	14	—
LTA	3	—
LTB	1	—
NFKBIL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01379573	PHASE2	COMPLETED	Preventive Approach to Congenital Heart Block With Hydroxychloroquine
NCT00460928	EARLY_PHASE1	COMPLETED	Preventive IVIG Therapy for Congenital Heart Block
NCT00007358	Not specified	COMPLETED	Dexamethasone Treatment for Congenital Heart Block (CHB) in Newborns With Lupus
NCT00074373	Not specified	COMPLETED	The Research Registry for Neonatal Lupus
NCT02920346	Not specified	COMPLETED	Prospective Maternal Surveillance of SSA (Sjögren Syndrome A) Positive Pregnancies Using a Hand-held Fetal Heart Rate Monitor
NCT05958446	Not specified	UNKNOWN	Fetal-Hope Study: Home Monitoring of Fetal Heart Rate in SSA+ Pregnant Women

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
HYDROXYCHLOROQUINE	4	1