combined immunodeficiency due to DOCK8 deficiency

Summary

combined immunodeficiency due to DOCK8 deficiency (MONDO:0009478) is a disease caused by DOCK8 (GenCC Strong), with 4 cohort genes and 1 clinical trial. Top therapeutic interventions include busulfan.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DOCK8 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 2,327
• Phenotypes (HPO): 18
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		11	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0000389	Chronic otitis media	Very frequent (80-99%)
HP:0001047	Atopic dermatitis	Very frequent (80-99%)
HP:0002090	Pneumonia	Very frequent (80-99%)
HP:0002099	Asthma	Very frequent (80-99%)
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0003212	Increased circulating IgE level	Very frequent (80-99%)
HP:0004429	Recurrent viral infections	Very frequent (80-99%)
HP:0005401	Recurrent candida infections	Very frequent (80-99%)
HP:0005403	Decreased total T cell count	Very frequent (80-99%)
HP:0005406	Recurrent bacterial skin infections	Very frequent (80-99%)
HP:0010976	Decreased total B cell count	Very frequent (80-99%)
HP:0011108	Recurrent sinusitis	Very frequent (80-99%)
HP:0012203	Onychomycosis	Very frequent (80-99%)
HP:0200042	Skin ulcer	Very frequent (80-99%)
HP:0200043	Verrucae	Very frequent (80-99%)
HP:0002860	Squamous cell carcinoma	Occasional (5-29%)
HP:0006763	Anal canal squamous carcinoma	Occasional (5-29%)
HP:0030417	Squamous cell carcinoma of the vulva	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	combined immunodeficiency due to DOCK8 deficiency
Mondo ID	MONDO:0009478
OMIM	243700
Orphanet	217390
DOID	DOID:0080594
ICD-11	136043326
NCIT	C126343
UMLS	C4722305
MedGen	1648410
GARD	0002816
Is cancer (heuristic)	no

Also known as: AR hyperimmunoglobulin E syndrome · AR-HIES · autosomal recessive hyper IgE syndrome · Cid due to DOCK8 deficiency · combined immunodeficiency due to dedicator of cytokinesis 8 protein deficiency · combined immunodeficiency due to DOCK8 deficiency · dedicator of cytokinesis 8 deficiency · DOCK8 deficiency · DOCK8 immunodeficiency syndrome · HIES autosomal recessive · hyper Ig E syndrome, autosomal recessive · hyperimmunoglobulin E recurrent infection syndrome, autosomal recessive

Data availability: 2,327 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › B cell deficiency › hyperimmunoglobulin syndrome › hyper-IgE syndrome › combined immunodeficiency due to DOCK8 deficiency

Related subtypes (13): hyper-IgE recurrent infection syndrome 1, autosomal dominant, Netherton syndrome, hyper-IgE recurrent infection syndrome 5, autosomal recessive, immunodeficiency 94 with autoinflammation and dysmorphic facies, hyper-IgE recurrent infection syndrome 3, autosomal recessive, hyper-IgE recurrent infection syndrome 4, autosomal recessive, hyper-IgE recurrent infection syndrome 4A, autosomal dominant, hyper-IgE syndrome 6, autosomal dominant, with recurrent infections, autosomal recessive combined immunodeficiency due to complete IL6ST deficiency, autosomal recessive combined immunodeficiency due to partial IL6ST deficiency, autosomal dominant combined immunodeficiency due to partial IL6ST deficiency, autosomal recessive combined immunodeficiency due to IL6R deficiency, autosomal dominant combined immunodeficiency due to ERBIN 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

600 retrieved; paginated sample, class counts are floors:

267 uncertain significance, 253 likely benign, 35 benign, 20 benign/likely benign, 12 pathogenic, 7 conflicting classifications of pathogenicity, 6 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027955	NM_203447.4(DOCK8):c.5442del (p.Val1813_Tyr1814insTer)	DOCK8	Pathogenic	criteria provided, single submitter
1069888	NM_203447.4(DOCK8):c.1498C>T (p.Arg500Ter)	DOCK8	Pathogenic	criteria provided, multiple submitters, no conflicts
1071622	NM_203447.4(DOCK8):c.5161C>T (p.Gln1721Ter)	DOCK8	Pathogenic	criteria provided, single submitter
1071623	NM_203447.4(DOCK8):c.5481dup (p.Arg1828Ter)	DOCK8	Pathogenic	criteria provided, single submitter
1301836	NM_203447.4(DOCK8):c.4241+1G>A	DOCK8	Pathogenic	criteria provided, single submitter
1367934	NM_203447.4(DOCK8):c.6115C>T (p.Gln2039Ter)	DOCK8	Pathogenic	criteria provided, single submitter
1390481	NM_203447.4(DOCK8):c.760del (p.Arg254fs)	DOCK8	Pathogenic	criteria provided, single submitter
1421481	NM_203447.4(DOCK8):c.1271_1274dup (p.Ser426fs)	DOCK8	Pathogenic	criteria provided, single submitter
1451221	NM_203447.4(DOCK8):c.4163del (p.Arg1388fs)	DOCK8	Pathogenic	criteria provided, single submitter
1451629	NM_203447.4(DOCK8):c.851del (p.Leu284fs)	DOCK8	Pathogenic	criteria provided, single submitter
1451794	NM_203447.4(DOCK8):c.2464G>T (p.Glu822Ter)	DOCK8	Pathogenic	criteria provided, single submitter
1076364	NC_000009.11:g.(?214977)(464219_?)del	DOCK8-AS1	Pathogenic	criteria provided, single submitter
1066408	NM_203447.4(DOCK8):c.3841-1G>T	DOCK8	Likely pathogenic	criteria provided, single submitter
1067654	NC_000009.11:g.(?271607)(399279_?)dup	DOCK8	Likely pathogenic	criteria provided, single submitter
1327988	NM_203447.4(DOCK8):c.3670_3671insTCAAATTTTGG (p.Asp1224fs)	DOCK8	Likely pathogenic	criteria provided, single submitter
1339151	NM_203447.4(DOCK8):c.560_561insAGCGA (p.Asp187fs)	DOCK8	Likely pathogenic	criteria provided, single submitter
1502020	NM_203447.4(DOCK8):c.53+1G>A	DOCK8	Likely pathogenic	criteria provided, single submitter
1509921	NM_203447.4(DOCK8):c.5223+1del	DOCK8	Likely pathogenic	criteria provided, single submitter
1006702	NM_203447.4(DOCK8):c.4527C>G (p.His1509Gln)	DOCK8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1043674	NM_203447.4(DOCK8):c.4850A>G (p.Gln1617Arg)	DOCK8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1091055	NM_203447.4(DOCK8):c.36C>G (p.Phe12Leu)	DOCK8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1176280	NM_203447.4(DOCK8):c.1798-4A>G	DOCK8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1337529	NM_203447.4(DOCK8):c.5799C>T (p.Ser1933=)	DOCK8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1337938	NM_203447.4(DOCK8):c.4533C>G (p.Val1511=)	DOCK8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1434225	NM_203447.4(DOCK8):c.5620G>A (p.Glu1874Lys)	DOCK8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001299	NM_203447.4(DOCK8):c.4786G>T (p.Val1596Leu)	DOCK8	Uncertain significance	criteria provided, single submitter
1001378	NM_203447.4(DOCK8):c.860G>T (p.Ser287Ile)	DOCK8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1001501	NM_203447.4(DOCK8):c.4742C>T (p.Ser1581Leu)	DOCK8	Uncertain significance	criteria provided, single submitter
1001997	NM_203447.4(DOCK8):c.1325C>T (p.Ser442Phe)	DOCK8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1003726	NM_203447.4(DOCK8):c.2830G>T (p.Asp944Tyr)	DOCK8	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 4 · 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
DOCK8	Strong	Autosomal recessive	combined immunodeficiency due to DOCK8 deficiency	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DOCK8	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DOCK8	Orphanet:217390	Combined immunodeficiency due to DOCK8 deficiency
KANK1	Orphanet:210141	Inherited congenital spastic tetraplegia
CCDC40	Orphanet:244	Primary ciliary dyskinesia

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DOCK8	HGNC:19191	ENSG00000107099	Q8NF50	Dedicator of cytokinesis protein 8	gencc,clinvar
KANK1	HGNC:19309	ENSG00000107104	Q14678	KN motif and ankyrin repeat domain-containing protein 1	clinvar
CCDC40	HGNC:26090	ENSG00000141519	Q4G0X9	Coiled-coil domain-containing protein 40	clinvar
DOCK8-AS1	HGNC:26436	ENSG00000183784	Q5T8R8	Uncharacterized protein DOCK8-AS1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DOCK8	Dedicator of cytokinesis protein 8	Guanine nucleotide exchange factor (GEF) which specifically activates small GTPase CDC42 by exchanging bound GDP for free GTP.
KANK1	KN motif and ankyrin repeat domain-containing protein 1	Adapter protein that links structural and signaling protein complexes positioned to guide microtubule and actin cytoskeleton dynamics during cell morphogenesis.
CCDC40	Coiled-coil domain-containing protein 40	Required for assembly of dynein regulatory complex (DRC) and inner dynein arm (IDA) complexes, which are responsible for ciliary beat regulation, thereby playing a central role in motility in cilia and flagella.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 3 · 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	4.3×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DOCK8	Other/Unknown	no		ARM-type_fold, DOCK_C/D_N, DOCK
KANK1	Scaffold/PPI	no		Ankyrin_rpt, KN_motif, Ankyrin_rpt-contain_sf
CCDC40	Other/Unknown	no		CCDC40
DOCK8-AS1	Other/Unknown	no		DUF5555

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow cell	1
leukocyte	1
monocyte	1
blood vessel layer	1
cartilage tissue	1
descending thoracic aorta	1
bronchial epithelial cell	1
right uterine tube	1
sural nerve	1
adult mammalian kidney	1
cortex of kidney	1
kidney	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DOCK8	236	ubiquitous	marker	bone marrow cell, leukocyte, monocyte
KANK1	291	ubiquitous	marker	blood vessel layer, cartilage tissue, descending thoracic aorta
CCDC40	184	ubiquitous	marker	right uterine tube, bronchial epithelial cell, sural nerve
DOCK8-AS1	138	tissue_specific	marker	adult mammalian kidney, kidney, cortex of kidney

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DOCK8	2,036
KANK1	1,931
CCDC40	1,527
DOCK8-AS1	0

Intra-cohort edges

A	B	Sources
DOCK8	KANK1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KANK1	Q14678	5
CCDC40	Q4G0X9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DOCK8	Q8NF50	75.17
DOCK8-AS1	Q5T8R8	47.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 4 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
Signaling by membrane-tethered fusions of PDGFRA or PDGFRB	1	1142.0×	0.007	KANK1
Signaling by PDGFR in disease	1	815.7×	0.007	KANK1
RHOJ GTPase cycle	1	100.2×	0.040	DOCK8
ESR-mediated signaling	1	64.2×	0.042	KANK1
Signaling by Nuclear Receptors	1	51.0×	0.042	KANK1
Estrogen-dependent gene expression	1	37.8×	0.042	KANK1
CDC42 GTPase cycle	1	36.1×	0.042	DOCK8
Factors involved in megakaryocyte development and platelet production	1	33.2×	0.042	DOCK8
RAC1 GTPase cycle	1	30.5×	0.042	DOCK8
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.042	KANK1
Disease	1	6.5×	0.160	KANK1
Signal Transduction	1	5.1×	0.187	KANK1

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
regulation of Rho protein signal transduction	2	340.4×	5e-04	DOCK8, KANK1
memory T cell proliferation	1	5617.3×	0.004	DOCK8
negative regulation of lamellipodium morphogenesis	1	2808.7×	0.005	KANK1
positive regulation of establishment of T cell polarity	1	1404.3×	0.006	DOCK8
determination of pancreatic left/right asymmetry	1	1123.5×	0.006	CCDC40
determination of digestive tract left/right asymmetry	1	936.2×	0.006	CCDC40
determination of liver left/right asymmetry	1	936.2×	0.006	CCDC40
podocyte cell migration	1	802.5×	0.006	KANK1
negative regulation of ruffle assembly	1	802.5×	0.006	KANK1
regulation of cilium beat frequency	1	702.2×	0.006	CCDC40
dendritic cell migration	1	624.1×	0.006	DOCK8
cortical microtubule organization	1	624.1×	0.006	KANK1
negative regulation of T cell apoptotic process	1	561.7×	0.006	DOCK8
immunological synapse formation	1	432.1×	0.007	DOCK8
epithelial cilium movement involved in determination of left/right asymmetry	1	432.1×	0.007	CCDC40
negative regulation of substrate adhesion-dependent cell spreading	1	374.5×	0.007	KANK1
axonemal dynein complex assembly	1	351.1×	0.007	CCDC40
cellular response to chemokine	1	330.4×	0.007	DOCK8
negative regulation of actin filament polymerization	1	312.1×	0.007	KANK1
regulation of establishment of cell polarity	1	312.1×	0.007	KANK1
inner dynein arm assembly	1	295.6×	0.007	CCDC40
epithelial cilium movement involved in extracellular fluid movement	1	255.3×	0.007	CCDC40
negative regulation of Rho protein signal transduction	1	255.3×	0.007	KANK1
positive regulation of T cell migration	1	244.2×	0.007	DOCK8
cilium organization	1	200.6×	0.009	CCDC40
motile cilium assembly	1	193.7×	0.009	CCDC40
axoneme assembly	1	181.2×	0.009	CCDC40
positive regulation of wound healing	1	175.5×	0.009	KANK1
protein localization to cilium	1	133.8×	0.011	CCDC40
cilium movement	1	130.6×	0.011	CCDC40

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 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
DOCK8	0	0
KANK1	0	0
CCDC40	0	0
DOCK8-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	4	DOCK8, KANK1, CCDC40, DOCK8-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DOCK8	0	—
KANK1	0	—
CCDC40	0	—
DOCK8-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01176006	PHASE2	ACTIVE_NOT_RECRUITING	Pilot Study of Reduced-Intensity Hematopoietic Stem Cell Transplant of DOCK8 Deficiency

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BUSULFAN	4	1