Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency

Summary

Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency (MONDO:0014502) is a disease caused by ISG15 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ISG15 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 150

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency
Mondo ID	MONDO:0014502
OMIM	616126
Orphanet	319563
DOID	DOID:0111934
UMLS	C4015293
MedGen	863730
GARD	0017458
Is cancer (heuristic)	no

Also known as: autosomal recessive mendelian susceptibility to mycobacterial diseases due to a complete deficiency caused by mutation in ISG15 · IMD38 · immunodeficiency 38 with basal ganglia calcification · ISG15 autosomal recessive mendelian susceptibility to mycobacterial diseases due to a complete deficiency · MSMD due to complete ISG15 deficiency

Data availability: 150 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › inherited susceptibility to mycobacterial diseases › Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency

Related subtypes (13): immunodeficiency 27A, Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency, Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency, Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency, Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency, autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency, autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency, autosomal recessive Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency, autosomal dominant mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency, X-linked Mendelian susceptibility to mycobacterial diseases, Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR1 deficiency, Mendelian susceptibility to mycobacterial diseases due to a complete deficiency, Mendelian susceptibility to mycobacterial diseases due to a partial deficiency

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

150 retrieved; paginated sample, class counts are floors:

68 uncertain significance, 58 likely benign, 11 benign, 6 conflicting classifications of pathogenicity, 3 pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1412663	NC_000001.10:g.(?861322)(3768971_?)del	ARHGEF16	Pathogenic	criteria provided, single submitter
1028857	NM_005101.4(ISG15):c.4-1G>A	ISG15	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
161455	NM_005101.4(ISG15):c.339dup (p.Leu114fs)	ISG15	Pathogenic	no assertion criteria provided
183381	NM_005101.4(ISG15):c.163C>T (p.Gln55Ter)	ISG15	Pathogenic	no assertion criteria provided
161454	NM_005101.4(ISG15):c.379G>T (p.Glu127Ter)	ISG15	Likely pathogenic	criteria provided, single submitter
1354468	NM_005101.4(ISG15):c.83T>A (p.Leu28Gln)	ISG15	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1360941	NM_005101.4(ISG15):c.71C>T (p.Ser24Leu)	ISG15	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1644340	NM_005101.4(ISG15):c.151G>T (p.Gly51Cys)	ISG15	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
542076	NM_005101.4(ISG15):c.421G>A (p.Gly141Ser)	ISG15	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
568195	NM_005101.4(ISG15):c.296G>A (p.Arg99Gln)	ISG15	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
652606	NM_005101.4(ISG15):c.158C>T (p.Ala53Val)	ISG15	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2425297	NC_000001.10:g.(?861322)(948976_?)dup	HES4	Uncertain significance	criteria provided, single submitter
1011331	NM_005101.4(ISG15):c.358G>A (p.Asp120Asn)	ISG15	Uncertain significance	criteria provided, multiple submitters, no conflicts
1017805	NM_005101.4(ISG15):c.491G>A (p.Arg164Gln)	ISG15	Uncertain significance	criteria provided, single submitter
1020899	NM_005101.4(ISG15):c.463dup (p.Arg155fs)	ISG15	Uncertain significance	criteria provided, multiple submitters, no conflicts
1021524	NM_005101.4(ISG15):c.383G>A (p.Gly128Glu)	ISG15	Uncertain significance	criteria provided, single submitter
1023883	NM_005101.4(ISG15):c.310G>A (p.Val104Met)	ISG15	Uncertain significance	criteria provided, single submitter
1035971	NM_005101.4(ISG15):c.17C>A (p.Thr6Lys)	ISG15	Uncertain significance	criteria provided, single submitter
1036426	NM_005101.4(ISG15):c.355G>A (p.Asp119Asn)	ISG15	Uncertain significance	criteria provided, single submitter
1038082	NM_005101.4(ISG15):c.482_483insCGTGCC (p.Pro161_Gly162insValPro)	ISG15	Uncertain significance	criteria provided, single submitter
1039103	NM_005101.4(ISG15):c.400C>T (p.Gln134Ter)	ISG15	Uncertain significance	criteria provided, single submitter
1042671	NM_005101.4(ISG15):c.73G>T (p.Val25Leu)	ISG15	Uncertain significance	criteria provided, single submitter
1042776	NM_005101.4(ISG15):c.347G>T (p.Gly116Val)	ISG15	Uncertain significance	criteria provided, single submitter
1047697	NM_005101.4(ISG15):c.313G>A (p.Ala105Thr)	ISG15	Uncertain significance	criteria provided, single submitter
1055760	NM_005101.4(ISG15):c.415del (p.Glu139fs)	ISG15	Uncertain significance	criteria provided, single submitter
1061485	NM_005101.4(ISG15):c.352C>T (p.Gln118Ter)	ISG15	Uncertain significance	criteria provided, single submitter
1162796	NM_005101.4(ISG15):c.95T>A (p.Ile32Asn)	ISG15	Uncertain significance	criteria provided, multiple submitters, no conflicts
1396122	NM_005101.4(ISG15):c.256G>A (p.Val86Met)	ISG15	Uncertain significance	criteria provided, single submitter
1403707	NM_005101.4(ISG15):c.65C>T (p.Ser22Phe)	ISG15	Uncertain significance	criteria provided, multiple submitters, no conflicts
1440345	NM_005101.4(ISG15):c.490C>T (p.Arg164Trp)	ISG15	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
ISG15	Strong	Autosomal recessive	Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ISG15	Orphanet:319563	Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ISG15	HGNC:4053	ENSG00000187608	P05161	Ubiquitin-like protein ISG15	gencc,clinvar
ARHGEF16	HGNC:15515	ENSG00000130762	Q5VV41	Rho guanine nucleotide exchange factor 16	clinvar
HES4	HGNC:24149	ENSG00000188290	Q9HCC6	Transcription factor HES-4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ISG15	Ubiquitin-like protein ISG15	Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein.
ARHGEF16	Rho guanine nucleotide exchange factor 16	Guanyl-nucleotide exchange factor of the RHOG GTPase stimulating the exchange of RHOG-associated GDP for GTP.
HES4	Transcription factor HES-4	Transcriptional repressor.

Protein-family classification

Druggable: 0 · Difficult: 2 · 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
Scaffold/PPI	1	5.8×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ISG15	Other/Unknown	no		Ubiquitin-like_dom, Ubiquilin, Ubiquitin_dom
ARHGEF16	Scaffold/PPI	no		DH_dom, SH3_domain, PH_domain
HES4	Transcription factor	no		Orange_dom, bHLH_dom, HLH_DNA-bd_sf

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
decidua	1
male germ line stem cell (sensu Vertebrata) in testis	1
periodontal ligament	1
ileal mucosa	1
metanephros cortex	1
mucosa of transverse colon	1
popliteal artery	1
tibial artery	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ISG15	286	ubiquitous	marker	decidua, periodontal ligament, male germ line stem cell (sensu Vertebrata) in testis
ARHGEF16	199	broad	marker	mucosa of transverse colon, metanephros cortex, ileal mucosa
HES4	223	ubiquitous	marker	ventricular zone, popliteal artery, tibial artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ISG15	6,273
ARHGEF16	1,269
HES4	751

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ISG15	P05161	22
ARHGEF16	Q5VV41	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HES4	Q9HCC6	73.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 39. Enrichment computed across 3 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
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	1	1142.0×	0.017	ISG15
DNA Damage Bypass	1	1142.0×	0.017	ISG15
Modulation of host responses by IFN-stimulated genes	1	300.5×	0.028	ISG15
Termination of translesion DNA synthesis	1	173.0×	0.028	ISG15
Negative regulators of DDX58/IFIH1 signaling	1	163.1×	0.028	ISG15
NS1 Mediated Effects on Host Pathways	1	142.8×	0.028	ISG15
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1	126.9×	0.028	ISG15
Cell death signalling via NRAGE, NRIF and NADE	1	109.8×	0.028	ARHGEF16
Antimicrobial mechanism of IFN-stimulated genes	1	98.5×	0.028	ISG15
Respiratory Syncytial Virus Infection Pathway	1	98.5×	0.028	ISG15
p75 NTR receptor-mediated signalling	1	93.6×	0.028	ARHGEF16
NRAGE signals death through JNK	1	92.1×	0.028	ARHGEF16
Influenza Infection	1	87.8×	0.028	ISG15
RSV-host interactions	1	78.2×	0.028	ISG15
Interferon alpha/beta signaling	1	76.1×	0.028	ISG15
ISG15 antiviral mechanism	1	75.1×	0.028	ISG15
RHOG GTPase cycle	1	74.2×	0.028	ARHGEF16
PKR-mediated signaling	1	70.5×	0.028	ISG15
Death Receptor Signaling	1	69.6×	0.028	ARHGEF16
G alpha (12/13) signalling events	1	68.8×	0.028	ARHGEF16
Interferon Signaling	1	60.1×	0.030	ISG15
SARS-CoV-2-host interactions	1	59.5×	0.030	ISG15
DNA Repair	1	49.2×	0.034	ISG15
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	44.6×	0.036	ISG15
SARS-CoV-2 Infection	1	40.2×	0.039	ISG15
CDC42 GTPase cycle	1	36.1×	0.041	ARHGEF16
RHO GTPase cycle	1	30.1×	0.048	ARHGEF16
SARS-CoV Infections	1	27.7×	0.050	ISG15
GPCR downstream signalling	1	21.7×	0.061	ARHGEF16
Cytokine Signaling in Immune system	1	20.4×	0.062	ISG15

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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 protein oligomerization	1	1872.4×	0.009	ISG15
ISG15-protein conjugation	1	936.2×	0.009	ISG15
modification-dependent protein catabolic process	1	702.2×	0.009	ISG15
regulation of type II interferon production	1	702.2×	0.009	ISG15
response to type I interferon	1	624.1×	0.009	ISG15
regulation of Cdc42 protein signal transduction	1	468.1×	0.009	ARHGEF16
protein localization to mitochondrion	1	432.1×	0.009	ISG15
negative regulation of type I interferon-mediated signaling pathway	1	255.3×	0.013	ISG15
activation of GTPase activity	1	244.2×	0.013	ARHGEF16
positive regulation of erythrocyte differentiation	1	170.2×	0.016	ISG15
positive regulation of interleukin-10 production	1	133.8×	0.016	ISG15
positive regulation of bone mineralization	1	130.6×	0.016	ISG15
positive regulation of interferon-beta production	1	130.6×	0.016	ISG15
negative regulation of viral genome replication	1	124.8×	0.016	ISG15
negative regulation of protein ubiquitination	1	95.2×	0.019	ISG15
positive regulation of protein localization to plasma membrane	1	90.6×	0.019	ARHGEF16
positive regulation of type II interferon production	1	74.9×	0.022	ISG15
cell chemotaxis	1	61.7×	0.024	ARHGEF16
anterior/posterior pattern specification	1	60.4×	0.024	HES4
integrin-mediated signaling pathway	1	53.5×	0.025	ISG15
regulation of actin cytoskeleton organization	1	52.5×	0.025	ARHGEF16
response to virus	1	48.0×	0.026	ISG15
defense response to bacterium	1	36.0×	0.033	ISG15
defense response to virus	1	23.1×	0.050	ISG15
nervous system development	1	15.3×	0.072	HES4
innate immune response	1	11.2×	0.093	ISG15
cell differentiation	1	9.7×	0.103	HES4
regulation of transcription by RNA polymerase II	1	3.9×	0.236	HES4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ISG15	0	0
ARHGEF16	0	0
HES4	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
ISG15	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	ISG15, ARHGEF16, HES4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ISG15	1	—
ARHGEF16	0	—
HES4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.