Immunodeficiency 91 and hyperinflammation

Summary

Immunodeficiency 91 and hyperinflammation (MONDO:0030491) is a disease caused by ZNFX1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ZNFX1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 18

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 91 and hyperinflammation
Mondo ID	MONDO:0030491
OMIM	619644
DOID	DOID:0061061
UMLS	C5562073
MedGen	1794283
Is cancer (heuristic)	no

Also known as: IMD91 · immunodeficiency, autosomal recessive, due to ZNFX1 deficiency:

Data availability: 18 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › immunodeficiency 91 and hyperinflammation

Related subtypes (94): B cell deficiency, T-cell immunodeficiency, complement deficiency, myalgic encephalomeyelitis/chronic fatigue syndrome, hypoproteinemia, hypercatabolic, X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, autosomal dominant form, immunodeficiency due to CD25 deficiency, immunodeficiency 67, primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency, immunodeficiency 35, pyogenic bacterial infections due to MyD88 deficiency, lymphoproliferative syndrome 1, FADD-related immunodeficiency, immunodeficiency 31B, Wiskott-Aldrich syndrome 2, cryptosporidiosis-chronic cholangitis-liver disease syndrome, idiopathic CD4 lymphocytopenia, immunodeficiency 23, DOCK2 deficiency, immunodeficiency 45, TFRC-related combined immunodeficiency, combined immunodeficiency, autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome, immunodeficiency due to selective anti-polysaccharide antibody deficiency, immunodeficiency 57, immunodeficiency 14b, autosomal recessive, immunodeficiency 98 with autoinflammation, X-linked, immunodeficiency 102, immunodeficiency 74, COVID-19-related, X-linked, immunodeficiency 66, immunodeficiency 80 with or without congenital cardiomyopathy, immunodeficiency 81, immunodeficiency 82 with systemic inflammation, immunodeficiency 84, immunodeficiency 85 and autoimmunity, immunodeficiency 86, immunodeficiency 87 and autoimmunity, immunodeficiency 88, immunodeficiency 89 and autoimmunity, immunodeficiency 92, immunodeficiency 93 and hypertrophic cardiomyopathy, immunodeficiency 95, immunodeficiency 96, immunodeficiency 97 with autoinflammation, immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, immunodeficiency 101 (varicella zoster virus-specific), immunodeficiency 75, immunodeficiency 76, immunodeficiency 106, susceptibility to viral infections, immunodeficiency 78 with autoimmunity and developmental delay, immunodeficiency 77, immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, immunodeficiency 15a, immunodeficiency 60, immunodeficiency 62, immunodeficiency 63 with lymphoproliferation and autoimmunity, immunodeficiency 64, immunodeficiency 65, susceptibility to viral infections, immunodeficiency 69, immunodeficiency 70, immunodeficiency 72 with autoinflammation, GATA2 deficiency with susceptibility to MDS/AML, Shwachman-Diamond syndrome 1, immunodeficiency 53, immunodeficiency 11b with atopic dermatitis, IKBKG-related immunodeficiency with or without ectodermal dysplasia, FNIP1-associated syndrome, FASLG-related immunodeficiency, TNFRSF9-related immunodeficiency, DNAJC21-related Shwachman Diamond syndrome, IRF4-related immune disorder, PTEN harmartoma tumor syndrome with immune disorder, primary immunodeficiency due to calcium channel deficiency, chronic mucocutaneous candidiasis and connective tissue disease due to JNK1 haploinsufficiency, immune deficiency due to impaired neutrophil phagocytosis and migration, hatipoglu immunodeficiency syndrome, immunodeficiency 112, immunodeficiency 113 with autoimmunity and autoinflammation, immunodeficiency 114, folate-responsive, immunodeficiency 115 with autoinflammation, immunodeficiency 117, immunodeficiency 118, immunodeficiency 119, immunodeficiency 121 with autoinflammation, immunodeficiency 122, immunodeficiency 123 with HPV-related verrucosis, immunodeficiency 125, immunodeficiency 126, susceptibility to, immunodeficiency 127, immunodeficiency 128, immunodeficiency 132b, immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, immunodeficiency 134 (Epstein-Barr virus-specific)

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

18 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 6 pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1327517	NM_021035.3(ZNFX1):c.4815_4818del (p.Glu1606fs)	ZNFX1	Pathogenic	no assertion criteria provided
1327518	NM_021035.3(ZNFX1):c.2876C>G (p.Ser959Ter)	ZNFX1	Pathogenic	no assertion criteria provided
1327519	NM_021035.3(ZNFX1):c.495_496insT (p.Thr166fs)	ZNFX1	Pathogenic	no assertion criteria provided
1327520	NM_021035.3(ZNFX1):c.2698_2699insT (p.Arg900fs)	ZNFX1	Pathogenic	no assertion criteria provided
1327521	NM_021035.3(ZNFX1):c.1623_1624del (p.His542fs)	ZNFX1	Pathogenic	no assertion criteria provided
1327522	NM_021035.3(ZNFX1):c.397A>T (p.Lys133Ter)	ZNFX1	Pathogenic	criteria provided, single submitter
3778725	NM_021035.3(ZNFX1):c.4966_4969delinsTC (p.Glu1656fs)	ZNFX1	Likely pathogenic	criteria provided, single submitter
4077754	NM_021035.3(ZNFX1):c.561_562del (p.Ile187fs)	ZNFX1	Likely pathogenic	criteria provided, single submitter
2431448	NM_021035.3(ZNFX1):c.2003-121C>T	ZNFX1	Uncertain significance	criteria provided, single submitter
2431749	NM_021035.3(ZNFX1):c.3557A>G (p.Lys1186Arg)	ZNFX1	Uncertain significance	criteria provided, single submitter
2579719	NM_021035.3(ZNFX1):c.4880G>A (p.Arg1627His)	ZNFX1	Uncertain significance	criteria provided, single submitter
2579720	NM_021035.3(ZNFX1):c.872C>T (p.Thr291Met)	ZNFX1	Uncertain significance	criteria provided, single submitter
3064944	NM_021035.3(ZNFX1):c.3292_3302del (p.Leu1098fs)	ZNFX1	Uncertain significance	criteria provided, single submitter
3068301	NM_021035.3(ZNFX1):c.3469C>G (p.Leu1157Val)	ZNFX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3587319	NM_021035.3(ZNFX1):c.3152T>C (p.Leu1051Pro)	ZNFX1	Uncertain significance	criteria provided, single submitter
3776169	NM_021035.3(ZNFX1):c.1997T>A (p.Leu666Gln)	ZNFX1	Uncertain significance	criteria provided, single submitter
3823411	NM_021035.3(ZNFX1):c.4367G>A (p.Arg1456His)	ZNFX1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4813297	NM_021035.3(ZNFX1):c.1120C>T (p.Arg374Trp)	ZNFX1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · 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
ZNFX1	Strong	Autosomal recessive	immunodeficiency 91 and hyperinflammation	3

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
ZNFX1	HGNC:29271	ENSG00000124201	Q9P2E3	NFX1-type zinc finger-containing protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZNFX1	NFX1-type zinc finger-containing protein 1	RNA-binding protein that initiates the antiviral response and is required to restrict the replication of RNA viruses.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZNFX1	Transcription factor	no		Znf_NFX1, ARM-type_fold, P-loop_NTPase

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
cardiac muscle of right atrium	1
cartilage tissue	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZNFX1	253	ubiquitous	marker	cardiac muscle of right atrium, left ventricle myocardium, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ZNFX1	1,011

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ZNFX1	Q9P2E3	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
regulatory ncRNA-mediated heterochromatin formation	1	1872.4×	0.003	ZNFX1
activation of innate immune response	1	481.5×	0.005	ZNFX1
negative regulation of viral genome replication	1	374.5×	0.005	ZNFX1
defense response to bacterium	1	108.0×	0.014	ZNFX1
defense response to virus	1	69.3×	0.017	ZNFX1
innate immune response	1	33.6×	0.030	ZNFX1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ZNFX1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ZNFX1

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)
ZNFX1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.