Combined immunodeficiency with faciooculoskeletal anomalies

Summary

Combined immunodeficiency with faciooculoskeletal anomalies (MONDO:0013226) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 17
• Phenotypes (HPO): 69

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

69 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0032140	Decreased specific antibody response to vaccination	Frequent (30-79%)
HP:0032218	Decreased proportion of CD4-positive T cells	Frequent (30-79%)
HP:0040022	Clinodactyly of the 2nd finger	Frequent (30-79%)
HP:0040024	Clinodactyly of the 3rd finger	Frequent (30-79%)
HP:0040025	Clinodactyly of the 4th finger	Frequent (30-79%)
HP:0040218	Reduced natural killer cell count	Frequent (30-79%)
HP:0040288	Nasogastric tube feeding	Frequent (30-79%)
HP:0100540	Palpebral edema	Frequent (30-79%)
HP:0410018	Recurrent ear infections	Frequent (30-79%)
HP:0000010	Recurrent urinary tract infections	Frequent (30-79%)
HP:0000122	Unilateral renal agenesis	Frequent (30-79%)
HP:0000306	Abnormality of the chin	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000348	High forehead	Frequent (30-79%)
HP:0000411	Protruding ear	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000455	Broad nasal tip	Frequent (30-79%)
HP:0000463	Anteverted nares	Frequent (30-79%)
HP:0000490	Deeply set eye	Frequent (30-79%)
HP:0000609	Optic nerve hypoplasia	Frequent (30-79%)
HP:0000924	Abnormality of the skeletal system	Frequent (30-79%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0000953	Hyperpigmentation of the skin	Frequent (30-79%)
HP:0000998	Hypertrichosis	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001319	Neonatal hypotonia	Frequent (30-79%)
HP:0001369	Arthritis	Frequent (30-79%)
HP:0001537	Umbilical hernia	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0002058	Myopathic facies	Frequent (30-79%)
HP:0002080	Intention tremor	Frequent (30-79%)
HP:0002100	Recurrent aspiration pneumonia	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002123	Generalized myoclonic seizure	Frequent (30-79%)
HP:0002162	Low posterior hairline	Frequent (30-79%)
HP:0002403	Positive Romberg sign	Frequent (30-79%)
HP:0002643	Neonatal respiratory distress	Frequent (30-79%)
HP:0002718	Recurrent bacterial infections	Frequent (30-79%)
HP:0002841	Recurrent fungal infections	Frequent (30-79%)
HP:0002850	Decreased circulating total IgM	Frequent (30-79%)
HP:0003307	Hyperlordosis	Frequent (30-79%)
HP:0003460	Decreased circulating total IgA	Frequent (30-79%)
HP:0003765	Psoriasiform dermatitis	Frequent (30-79%)
HP:0004313	Decreased circulating antibody level	Frequent (30-79%)
HP:0004429	Recurrent viral infections	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	combined immunodeficiency with faciooculoskeletal anomalies
Mondo ID	MONDO:0013226
MeSH	C567641
OMIM	613328
Orphanet	221139
UMLS	C2750068
MedGen	442377
GARD	0017139
Is cancer (heuristic)	no

Also known as: Roifman-Chitayat syndrome · Roifman-Chitayat syndrome, digenic

Data availability: 17 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › combined immunodeficiency with faciooculoskeletal anomalies

Related subtypes (40): B cell deficiency, complement deficiency, phagocyte bactericidal dysfunction, trichohepatoenteric syndrome, hepatic veno-occlusive disease-immunodeficiency syndrome, immunodeficiency with defective T-cell response to interleukin 1, Say-Barber-Miller syndrome, familial isolated congenital asplenia, X-linked immunoneurologic disorder, ectodermal dysplasia and immune deficiency, immunodeficiency 33, immunodeficiency 47, combined immunodeficiency due to moesin deficiency, immunodeficiency, X-linked, with deficiency of 115,000 Dalton surface glycoprotein, properdin deficiency, X-linked, recurrent infections associated with rare immunoglobulin isotypes deficiency, immunodeficiency 28, autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity, immunodeficiency 37, immunodeficiency 39, BENTA disease, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection, immunodeficiency 49, chronic mucocutaneous candidiasis, hereditary hemophagocytic lymphohistiocytosis, immunoglobulin heavy chain deficiency, immuno-osseous dysplasia, lymphoproliferative syndrome, IL10-related early-onset inflammatory bowel disease, T-cell immunodeficiency with epidermodysplasia verruciformis, Aicardi-Goutieres syndrome, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, inflammatory bowel disease-recurrent sinopulmonary infections syndrome, A20 haploinsufficiency, NK cell deficiency, T cell and NK cell immunodeficiency, dendritic cell deficiency, immunodysregulation with variable immunodeficiency and autoimmunity, immune dysregulation with immunodeficiency due to AIOLOS haploinsufficiency, STAT5 haploinsufficiency

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

17 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 4 benign, 4 likely benign, 3 pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064712	NM_033286.4(KNSTRN):c.629del (p.Leu210fs)	KNSTRN	Pathogenic	no assertion criteria provided
1064709	NM_005026.5(PIK3CD):c.2161C>T (p.Gln721Ter)	PIK3CD	Pathogenic	no assertion criteria provided
88675	NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys)	PIK3CD	Pathogenic	reviewed by expert panel
651966	NM_005026.5(PIK3CD):c.1242G>A (p.Ala414=)	LOC126805612	Uncertain significance	criteria provided, multiple submitters, no conflicts
1359338	NM_005026.5(PIK3CD):c.58G>A (p.Val20Ile)	PIK3CD	Uncertain significance	criteria provided, multiple submitters, no conflicts
373411	NM_005026.5(PIK3CD):c.3029A>C (p.Glu1010Ala)	PIK3CD	Uncertain significance	criteria provided, multiple submitters, no conflicts
643256	NM_005026.5(PIK3CD):c.1955+5C>T	PIK3CD	Uncertain significance	criteria provided, multiple submitters, no conflicts
969000	NM_005026.5(PIK3CD):c.1339+4G>A	PIK3CD	Uncertain significance	criteria provided, multiple submitters, no conflicts
709503	NM_005026.5(PIK3CD):c.1394C>T (p.Thr465Met)	LOC126805612	Benign	reviewed by expert panel
941354	NM_005026.5(PIK3CD):c.1459G>A (p.Ala487Thr)	LOC126805612	Likely benign	reviewed by expert panel
1227097	NM_005026.5(PIK3CD):c.2348-30C>T	PIK3CD	Benign	criteria provided, multiple submitters, no conflicts
424409	NM_005026.5(PIK3CD):c.1777G>C (p.Gly593Arg)	PIK3CD	Likely benign	reviewed by expert panel
474022	NM_005026.5(PIK3CD):c.1005C>T (p.Ala335=)	PIK3CD	Benign	criteria provided, multiple submitters, no conflicts
474028	NM_005026.5(PIK3CD):c.2919C>T (p.Leu973=)	PIK3CD	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
642308	NM_005026.5(PIK3CD):c.598G>A (p.Glu200Lys)	PIK3CD	Likely benign	reviewed by expert panel
736478	NM_005026.5(PIK3CD):c.2997+10G>A	PIK3CD	Likely benign	criteria provided, multiple submitters, no conflicts
811566	NM_005026.5(PIK3CD):c.2808C>T (p.Tyr936=)	PIK3CD	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KNSTRN	Orphanet:221139	Combined immunodeficiency with facio-oculo-skeletal anomalies
PIK3CD	Orphanet:221139	Combined immunodeficiency with facio-oculo-skeletal anomalies
PIK3CD	Orphanet:33110	Autosomal non-syndromic agammaglobulinemia
PIK3CD	Orphanet:693661	Activated PI3K-delta syndrome 1

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
KNSTRN	HGNC:30767	ENSG00000128944	Q9Y448	Small kinetochore-associated protein	clinvar
PIK3CD	HGNC:8977	ENSG00000171608	O00329	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KNSTRN	Small kinetochore-associated protein	Essential component of the mitotic spindle required for faithful chromosome segregation and progression into anaphase.
PIK3CD	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform	Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KNSTRN	Other/Unknown	no		SKAP
PIK3CD	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of thyroid gland	1
sperm	1
ventricular zone	1
blood	1
granulocyte	1
lymph node	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KNSTRN	233	ubiquitous	marker	ventricular zone, right lobe of thyroid gland, sperm
PIK3CD	253	ubiquitous	marker	granulocyte, blood, lymph node

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIK3CD	2,059
KNSTRN	1,346

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIK3CD	O00329	18

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KNSTRN	Q9Y448	68.55

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Co-stimulation by ICOS	1	1038.2×	0.006	PIK3CD
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	1	951.7×	0.006	PIK3CD
Regulation of signaling by CBL	1	496.5×	0.006	PIK3CD
Interleukin receptor SHC signaling	1	407.9×	0.006	PIK3CD
CD28 dependent PI3K/Akt signaling	1	393.8×	0.006	PIK3CD
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	356.9×	0.006	PIK3CD
Signaling by CSF1 (M-CSF) in myeloid cells	1	346.1×	0.006	PIK3CD
Interleukin-3, Interleukin-5 and GM-CSF signaling	1	317.2×	0.006	PIK3CD
RET signaling	1	259.6×	0.006	PIK3CD
Synthesis of PIPs at the plasma membrane	1	211.5×	0.007	PIK3CD
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	160.8×	0.008	PIK3CD
Constitutive Signaling by Aberrant PI3K in Cancer	1	126.9×	0.009	PIK3CD
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	96.8×	0.011	PIK3CD
PIP3 activates AKT signaling	1	66.8×	0.015	PIK3CD

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
natural killer cell chemotaxis	1	4213.0×	0.003	PIK3CD
mast cell chemotaxis	1	2106.5×	0.003	PIK3CD
respiratory burst involved in defense response	1	2106.5×	0.003	PIK3CD
mast cell differentiation	1	2106.5×	0.003	PIK3CD
positive regulation of neutrophil apoptotic process	1	1685.2×	0.003	PIK3CD
B cell chemotaxis	1	1404.3×	0.003	PIK3CD
neutrophil extravasation	1	1404.3×	0.003	PIK3CD
positive regulation of epithelial tube formation	1	1404.3×	0.003	PIK3CD
cell migration	2	61.5×	0.003	KNSTRN, PIK3CD
regulation of attachment of spindle microtubules to kinetochore	1	842.6×	0.005	KNSTRN
phosphatidylinositol-3-phosphate biosynthetic process	1	648.1×	0.006	PIK3CD
T cell chemotaxis	1	561.7×	0.006	PIK3CD
vascular endothelial growth factor signaling pathway	1	526.6×	0.006	PIK3CD
spindle organization	1	495.6×	0.006	KNSTRN
natural killer cell differentiation	1	443.5×	0.007	PIK3CD
phosphatidylinositol-mediated signaling	1	351.1×	0.008	PIK3CD
mast cell degranulation	1	312.1×	0.008	PIK3CD
natural killer cell activation	1	290.6×	0.008	PIK3CD
mitotic sister chromatid segregation	1	240.7×	0.010	KNSTRN
B cell activation	1	227.7×	0.010	PIK3CD
B cell receptor signaling pathway	1	200.6×	0.010	PIK3CD
T cell differentiation	1	191.5×	0.010	PIK3CD
T cell costimulation	1	187.2×	0.010	PIK3CD
cellular response to epidermal growth factor stimulus	1	159.0×	0.012	KNSTRN
neutrophil chemotaxis	1	142.8×	0.012	PIK3CD
positive regulation of cytokine production	1	135.9×	0.012	PIK3CD
T cell activation	1	129.6×	0.012	PIK3CD
positive regulation of endothelial cell migration	1	125.8×	0.012	PIK3CD
positive regulation of endothelial cell proliferation	1	115.4×	0.013	PIK3CD
B cell differentiation	1	109.4×	0.013	PIK3CD

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
PIK3CD	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIK3CD	66	4
KNSTRN	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDELALISIB	4	PIK3CD
ALPELISIB	4	PIK3CD
DUVELISIB	4	PIK3CD
COPANLISIB	4	PIK3CD
UMBRALISIB	4	PIK3CD
CAFFEINE	4	PIK3CD
THEOPHYLLINE	4	PIK3CD
COPANLISIB HYDROCHLORIDE	4	PIK3CD
LENIOLISIB	4	PIK3CD
INAVOLISIB	4	PIK3CD
SUNITINIB	4	PIK3CD
DASATINIB	4	PIK3CD
DACTOLISIB	3	PIK3CD
BUPARLISIB	3	PIK3CD
TASELISIB	3	PIK3CD
PARSACLISIB	3	PIK3CD
POVORCITINIB	3	PIK3CD
GEDATOLISIB	3	PIK3CD
LESTAURTINIB	3	PIK3CD
OMIPALISIB	2	PIK3CD
GSK-2636771	2	PIK3CD
FIMEPINOSTAT	2	PIK3CD
EGANELISIB	2	PIK3CD
AMDIZALISIB	2	PIK3CD
RISOVALISIB	2	PIK3CD
PICTILISIB	2	PIK3CD
ZSTK-474	2	PIK3CD
PF-04691502	2	PIK3CD
IZORLISIB	2	PIK3CD
APITOLISIB	2	PIK3CD

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PIK3CD	1,111	Binding:1094, ADMET:8, Functional:8, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PIK3CD	2.7.1.137, 2.7.1.153, 2.7.11.1	phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PIK3CD	1,111

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

30 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)
IDELALISIB	4	PIK3CD
ALPELISIB	4	PIK3CD
DUVELISIB	4	PIK3CD
COPANLISIB	4	PIK3CD
UMBRALISIB	4	PIK3CD
CAFFEINE	4	PIK3CD
THEOPHYLLINE	4	PIK3CD
COPANLISIB HYDROCHLORIDE	4	PIK3CD
LENIOLISIB	4	PIK3CD
INAVOLISIB	4	PIK3CD
SUNITINIB	4	PIK3CD
DASATINIB	4	PIK3CD
DACTOLISIB	3	PIK3CD
BUPARLISIB	3	PIK3CD
TASELISIB	3	PIK3CD
PARSACLISIB	3	PIK3CD
POVORCITINIB	3	PIK3CD
GEDATOLISIB	3	PIK3CD
LESTAURTINIB	3	PIK3CD
OMIPALISIB	2	PIK3CD
GSK-2636771	2	PIK3CD
FIMEPINOSTAT	2	PIK3CD
EGANELISIB	2	PIK3CD
AMDIZALISIB	2	PIK3CD
RISOVALISIB	2	PIK3CD
PICTILISIB	2	PIK3CD
ZSTK-474	2	PIK3CD
PF-04691502	2	PIK3CD
IZORLISIB	2	PIK3CD
APITOLISIB	2	PIK3CD

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PIK3CD
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	KNSTRN

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)
KNSTRN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.