FADD-related immunodeficiency

Summary

FADD-related immunodeficiency (MONDO:0013408) is a disease caused by FADD (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FADD (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 136
• Phenotypes (HPO): 8

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Obligate (100%)
HP:0001298	Encephalopathy	Obligate (100%)
HP:0001410	Decreased liver function	Obligate (100%)
HP:0001395	Hepatic fibrosis	Frequent (30-79%)
HP:0002059	Cerebral atrophy	Frequent (30-79%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0004935	Pulmonary artery atresia	Occasional (5-29%)
HP:0030057	Autoimmune antibody positivity	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	FADD-related immunodeficiency
Mondo ID	MONDO:0013408
OMIM	613759
Orphanet	306550
DOID	DOID:0061060
ICD-11	440676168
SNOMED CT	723334006
UMLS	C3151062
MedGen	462412
GARD	0015004
Is cancer (heuristic)	no

Also known as: FADD-related immunodeficiency · immunodeficiency 90 with encephalopathy, functional hyposplenia, and hepatic dysfunction

Data availability: 136 ClinVar variants · 4 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 › FADD-related immunodeficiency

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, 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 91 and hyperinflammation, 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

136 retrieved; paginated sample, class counts are floors:

76 likely benign, 51 uncertain significance, 4 conflicting classifications of pathogenicity, 2 likely pathogenic, 1 pathogenic, 1 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
242497	NM_003824.4(FADD):c.52_58del (p.Ser17_Ser18insTer)	FADD	Pathogenic	no assertion criteria provided
424777	NM_003824.3(FADD):c.[313T>C];[52_58delAGCGAGC]		Likely pathogenic	criteria provided, single submitter
30267	NM_003824.4(FADD):c.315T>G (p.Cys105Trp)	FADD	Likely pathogenic	criteria provided, single submitter
1128791	NM_003824.4(FADD):c.620C>T (p.Ala207Val)	FADD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1361585	NM_003824.4(FADD):c.584C>T (p.Pro195Leu)	FADD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242496	NM_003824.4(FADD):c.313T>C (p.Cys105Arg)	FADD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
806711	NM_003824.4(FADD):c.350G>A (p.Arg117His)	FADD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2424770	NC_000011.9:g.(?64973914)(70052579_?)dup	ACTN3	Uncertain significance	criteria provided, single submitter
1007395	NM_003824.4(FADD):c.152A>G (p.Glu51Gly)	FADD	Uncertain significance	criteria provided, single submitter
1008211	NM_003824.4(FADD):c.466G>A (p.Ala156Thr)	FADD	Uncertain significance	criteria provided, multiple submitters, no conflicts
1009010	NM_003824.4(FADD):c.304A>C (p.Asn102His)	FADD	Uncertain significance	criteria provided, single submitter
1009886	NM_003824.4(FADD):c.397T>C (p.Tyr133His)	FADD	Uncertain significance	criteria provided, single submitter
1027224	NM_003824.4(FADD):c.419G>A (p.Arg140His)	FADD	Uncertain significance	criteria provided, single submitter
1039740	NM_003824.4(FADD):c.551G>A (p.Arg184His)	FADD	Uncertain significance	criteria provided, single submitter
1047817	NM_003824.4(FADD):c.8C>G (p.Pro3Arg)	FADD	Uncertain significance	criteria provided, single submitter
1050930	NM_003824.4(FADD):c.241G>T (p.Asp81Tyr)	FADD	Uncertain significance	criteria provided, single submitter
1063379	NM_003824.4(FADD):c.89G>C (p.Arg30Pro)	FADD	Uncertain significance	criteria provided, single submitter
1361202	NM_003824.4(FADD):c.52A>G (p.Ser18Gly)	FADD	Uncertain significance	criteria provided, single submitter
1377943	NM_003824.4(FADD):c.604G>A (p.Ala202Thr)	FADD	Uncertain significance	criteria provided, single submitter
1380073	NM_003824.4(FADD):c.330A>C (p.Lys110Asn)	FADD	Uncertain significance	criteria provided, single submitter
1401800	NM_003824.4(FADD):c.547G>T (p.Ala183Ser)	FADD	Uncertain significance	criteria provided, single submitter
1482860	NM_003824.4(FADD):c.623C>T (p.Ser208Phe)	FADD	Uncertain significance	criteria provided, single submitter
1494177	NM_003824.4(FADD):c.310A>G (p.Ile104Val)	FADD	Uncertain significance	criteria provided, single submitter
1502513	NM_003824.4(FADD):c.385A>G (p.Ile129Val)	FADD	Uncertain significance	criteria provided, single submitter
1503264	NM_003824.4(FADD):c.617A>C (p.Glu206Ala)	FADD	Uncertain significance	criteria provided, single submitter
1904081	NM_003824.4(FADD):c.316G>A (p.Asp106Asn)	FADD	Uncertain significance	criteria provided, multiple submitters, no conflicts
1913323	NM_003824.4(FADD):c.578T>C (p.Met193Thr)	FADD	Uncertain significance	criteria provided, multiple submitters, no conflicts
1923265	NM_003824.4(FADD):c.382A>G (p.Ser128Gly)	FADD	Uncertain significance	criteria provided, single submitter
1924615	NM_003824.4(FADD):c.283G>A (p.Glu95Lys)	FADD	Uncertain significance	criteria provided, single submitter
1940096	NM_003824.4(FADD):c.109G>A (p.Glu37Lys)	FADD	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
FADD	Strong	Autosomal recessive	FADD-related immunodeficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FADD	Orphanet:306550	FADD-related immunodeficiency
FADD	Orphanet:99806	Oculootodental syndrome

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
FADD	HGNC:3573	ENSG00000168040	Q13158	FAS-associated death domain protein	gencc,clinvar
ACTN3	HGNC:165	ENSG00000248746	Q08043	Alpha-actinin-3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FADD	FAS-associated death domain protein	Apoptotic adapter molecule that recruits caspases CASP8 or CASP10 to the activated FAS/CD95 or TNFRSF1A/TNFR-1 receptors.
ACTN3	Alpha-actinin-3	F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FADD	Other/Unknown	no		Death_dom, DED_dom, DEATH-like_dom_sf
ACTN3	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat

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
endometrium epithelium	1
granulocyte	1
tendon of biceps brachii	1
diaphragm	1
skeletal muscle tissue of biceps brachii	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FADD	261	ubiquitous	yes	endometrium epithelium, granulocyte, tendon of biceps brachii
ACTN3	146	tissue_specific	marker	skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii, diaphragm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FADD	3,997
ACTN3	1,772

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FADD	Q13158	18
ACTN3	Q08043	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. 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
FasL/ CD95L signaling	1	1142.0×	0.004	FADD
TLR3-mediated TICAM1-dependent programmed cell death	1	951.7×	0.004	FADD
Defective RIPK1-mediated regulated necrosis	1	951.7×	0.004	FADD
TRAIL signaling	1	713.8×	0.004	FADD
TRIF-mediated programmed cell death	1	634.4×	0.004	FADD
Regulation by c-FLIP	1	519.1×	0.004	FADD
CASP8 activity is inhibited	1	519.1×	0.004	FADD
Dimerization of procaspase-8	1	519.1×	0.004	FADD
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	1	439.2×	0.005	FADD
Caspase activation via Death Receptors in the presence of ligand	1	380.7×	0.005	FADD
Nephrin family interactions	1	237.9×	0.006	ACTN3
RIPK1-mediated regulated necrosis	1	228.4×	0.006	FADD
TNFR1-induced proapoptotic signaling	1	219.6×	0.006	FADD
Regulation of necroptotic cell death	1	219.6×	0.006	FADD
Striated Muscle Contraction	1	154.3×	0.008	ACTN3
Regulation of TNFR1 signaling	1	112.0×	0.010	FADD
Cell-Cell communication	1	68.8×	0.015	ACTN3
Muscle contraction	1	38.6×	0.026	ACTN3

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
positive regulation of glucose catabolic process to lactate via pyruvate	1	8426.0×	0.003	ACTN3
positive regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation	1	8426.0×	0.003	FADD
positive regulation of fast-twitch skeletal muscle fiber contraction	1	4213.0×	0.003	ACTN3
death-inducing signaling complex assembly	1	4213.0×	0.003	FADD
regulation of the force of skeletal muscle contraction	1	2808.7×	0.003	ACTN3
negative regulation of activation-induced cell death of T cells	1	2808.7×	0.003	FADD
positive regulation of bone mineralization involved in bone maturation	1	2808.7×	0.003	ACTN3
negative regulation of relaxation of muscle	1	2106.5×	0.003	ACTN3
skeletal muscle atrophy	1	1685.2×	0.003	ACTN3
positive regulation of skeletal muscle tissue growth	1	1685.2×	0.003	ACTN3
transition between fast and slow fiber	1	1203.7×	0.003	ACTN3
response to denervation involved in regulation of muscle adaptation	1	1203.7×	0.003	ACTN3
negative regulation of oxidative phosphorylation	1	1203.7×	0.003	ACTN3
positive regulation of adaptive immune response	1	1053.2×	0.003	FADD
positive regulation of skeletal muscle fiber development	1	1053.2×	0.003	ACTN3
necroptotic signaling pathway	1	1053.2×	0.003	FADD
regulation of aerobic respiration	1	1053.2×	0.003	ACTN3
TRAIL-activated apoptotic signaling pathway	1	936.2×	0.003	FADD
positive regulation of macrophage differentiation	1	601.9×	0.005	FADD
motor neuron apoptotic process	1	561.7×	0.005	FADD
negative regulation of glycolytic process	1	526.6×	0.005	ACTN3
negative regulation of necroptotic process	1	495.6×	0.005	FADD
muscle cell development	1	468.1×	0.005	ACTN3
negative regulation of calcineurin-NFAT signaling cascade	1	468.1×	0.005	ACTN3
behavioral response to cocaine	1	421.3×	0.005	FADD
positive regulation of type I interferon-mediated signaling pathway	1	421.3×	0.005	FADD
positive regulation of execution phase of apoptosis	1	421.3×	0.005	FADD
positive regulation of proteolysis	1	401.2×	0.005	FADD
lymph node development	1	401.2×	0.005	FADD
positive regulation of activated T cell proliferation	1	337.0×	0.006	FADD

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
FADD	0	0
ACTN3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	2	FADD, ACTN3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FADD	0	—
ACTN3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.