Leukocyte adhesion deficiency 3

Summary

Leukocyte adhesion deficiency 3 (MONDO:0013016) is a disease caused by FERMT3 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FERMT3 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 553

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		40	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	leukocyte adhesion deficiency 3
Mondo ID	MONDO:0013016
MeSH	C567555
OMIM	612840
Orphanet	99844
DOID	DOID:0110912
UMLS	C2748536
MedGen	411605
GARD	0016915
Is cancer (heuristic)	no

Also known as: FERMT3 leukocyte adhesion deficiency · IADD · integrin activation deficiency disease · lad-1 variant · LAD-III · lad-III · LAD1V · LAD3 · leukocyte adhesion deficiency 1 variant · leukocyte adhesion deficiency 3 · leukocyte adhesion deficiency caused by mutation in FERMT3 · leukocyte adhesion deficiency type 3 · leukocyte adhesion deficiency type III · leukocyte adhesion deficiency, type III · leukocyte adhesion deficiency-1 variant

Data availability: 553 ClinVar variants · 5 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › leukocyte adhesion deficiency › leukocyte adhesion deficiency 3

Related subtypes (2): leukocyte adhesion deficiency 1, leukocyte adhesion deficiency type II

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

553 retrieved; paginated sample, class counts are floors:

278 likely benign, 204 uncertain significance, 24 benign, 17 pathogenic, 11 conflicting classifications of pathogenicity, 10 benign/likely benign, 7 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1453537	NM_031471.6(FERMT3):c.540del (p.Met181fs)	FERMT3	Pathogenic	criteria provided, single submitter
1686803	NM_031471.6(FERMT3):c.921del (p.Ser307fs)	FERMT3	Pathogenic	no assertion criteria provided
2023047	NM_031471.6(FERMT3):c.847_853del (p.Glu283fs)	FERMT3	Pathogenic	criteria provided, single submitter
2584467	NM_031471.6(FERMT3):c.1601_1602del (p.Glu534fs)	FERMT3	Pathogenic	criteria provided, single submitter
2708	NM_031471.6(FERMT3):c.1671-2A>G	FERMT3	Pathogenic	no assertion criteria provided
2709	NM_031471.6(FERMT3):c.48G>A (p.Trp16Ter)	FERMT3	Pathogenic	criteria provided, single submitter
2710	NM_031471.6(FERMT3):c.1717C>T (p.Arg573Ter)	FERMT3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2711	NM_031471.6(FERMT3):c.687G>A (p.Trp229Ter)	FERMT3	Pathogenic	no assertion criteria provided
2712	NM_031471.6(FERMT3):c.1525C>T (p.Arg509Ter)	FERMT3	Pathogenic	no assertion criteria provided
30687	NM_031471.6(FERMT3):c.1275del (p.Glu426fs)	FERMT3	Pathogenic	no assertion criteria provided
31528	NM_031471.6(FERMT3):c.161-2A>C	FERMT3	Pathogenic	no assertion criteria provided
3721047	NM_031471.6(FERMT3):c.1426C>T (p.Gln476Ter)	FERMT3	Pathogenic	criteria provided, single submitter
4707843	NM_031471.6(FERMT3):c.1462del (p.His488fs)	FERMT3	Pathogenic	criteria provided, single submitter
4726349	NM_031471.6(FERMT3):c.224del (p.Gln75fs)	FERMT3	Pathogenic	criteria provided, single submitter
4732996	NM_031471.6(FERMT3):c.1295_1296insACTGCGGTGCCAGGATGTGAGTGAGATCTA (p.Tyr432Ter)	FERMT3	Pathogenic	criteria provided, single submitter
643472	NM_031471.6(FERMT3):c.664_665del (p.Lys222fs)	FERMT3	Pathogenic	criteria provided, single submitter
646802	NM_031471.6(FERMT3):c.1029+2T>C	FERMT3	Pathogenic	criteria provided, single submitter
652864	NM_031471.6(FERMT3):c.814dup (p.Tyr272fs)	FERMT3	Pathogenic	criteria provided, single submitter
2585527	NM_000211.5(ITGB2):c.120del (p.Gly42fs)	ITGB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2068172	NM_031471.6(FERMT3):c.684-1G>A	FERMT3	Likely pathogenic	criteria provided, single submitter
2800615	NM_031471.6(FERMT3):c.1671-4_1671del	FERMT3	Likely pathogenic	criteria provided, single submitter
3004277	NM_031471.6(FERMT3):c.786+1G>T	FERMT3	Likely pathogenic	criteria provided, single submitter
3660341	NM_031471.6(FERMT3):c.1204+1G>T	FERMT3	Likely pathogenic	criteria provided, single submitter
3680800	NM_031471.6(FERMT3):c.787-14_788del	FERMT3	Likely pathogenic	criteria provided, single submitter
947116	NM_031471.6(FERMT3):c.1312-2A>C	FERMT3	Likely pathogenic	criteria provided, single submitter
2585219	NM_000211.5(ITGB2):c.393T>A (p.Tyr131Ter)	ITGB2	Likely pathogenic	criteria provided, single submitter
1166763	NM_031471.6(FERMT3):c.1430G>A (p.Arg477His)	FERMT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193746	NM_031471.6(FERMT3):c.1188G>A (p.Gln396=)	FERMT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194564	NM_031471.6(FERMT3):c.1893C>T (p.Ile631=)	FERMT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
198272	NM_031471.6(FERMT3):c.708C>T (p.Leu236=)	FERMT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
FERMT3	Definitive	Autosomal recessive	leukocyte adhesion deficiency 3	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FERMT3	Orphanet:99844	Leukocyte adhesion deficiency type III
ITGB2	Orphanet:99842	Leukocyte adhesion deficiency type I

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
FERMT3	HGNC:23151	ENSG00000149781	Q86UX7	Fermitin family homolog 3	gencc,clinvar
AHNAK	HGNC:347	ENSG00000124942	Q09666	Neuroblast differentiation-associated protein AHNAK	clinvar
ITGB2	HGNC:6155	ENSG00000160255	P05107	Integrin beta-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FERMT3	Fermitin family homolog 3	Plays a central role in cell adhesion in hematopoietic cells.
AHNAK	Neuroblast differentiation-associated protein AHNAK	May be required for neuronal cell differentiation.
ITGB2	Integrin beta-2	Integrin ITGAL:ITGB2 is a receptor for ICAM1, ICAM2 and ICAM3.

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	2	11.5×	0.019
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FERMT3	Scaffold/PPI	no		PH_domain, PH-like_dom_sf, FERM_central
AHNAK	Scaffold/PPI	no		PDZ, PDZ_sf, Myelin_sheath_structural
ITGB2	Other/Unknown	no		Integrin_bsu_VWA, Integrin_bsu_tail, Integrin_bsu_cyt_dom

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
granulocyte	2
leukocyte	2
monocyte	2
calcaneal tendon	1
olfactory bulb	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FERMT3	189	broad	marker	granulocyte, monocyte, leukocyte
AHNAK	297	ubiquitous	marker	olfactory bulb, calcaneal tendon, tendon of biceps brachii
ITGB2	249	broad	marker	granulocyte, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AHNAK	4,006
ITGB2	3,884
FERMT3	1,600

Intra-cohort edges

A	B	Sources
FERMT3	ITGB2	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ITGB2	P05107	29
FERMT3	Q86UX7	4
AHNAK	Q09666	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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
Integrin cell surface interactions	1	67.2×	0.049	ITGB2
Toll Like Receptor 4 (TLR4) Cascade	1	65.6×	0.049	ITGB2
Toll-like Receptor Cascades	1	62.1×	0.049	ITGB2
Interleukin-4 and Interleukin-13 signaling	1	51.4×	0.049	ITGB2
Cell surface interactions at the vascular wall	1	47.6×	0.049	ITGB2
Platelet degranulation	1	43.9×	0.049	FERMT3
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	43.6×	0.049	ITGB2
Signaling by Interleukins	1	32.1×	0.052	ITGB2
Extracellular matrix organization	1	31.6×	0.052	ITGB2
Cytokine Signaling in Immune system	1	20.4×	0.073	ITGB2
Hemostasis	1	18.0×	0.075	ITGB2
Adaptive Immune System	1	14.9×	0.082	ITGB2
Innate Immune System	1	12.8×	0.089	ITGB2
Neutrophil degranulation	1	11.5×	0.091	ITGB2
Immune System	1	6.5×	0.148	ITGB2

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
leukocyte cell-cell adhesion	2	312.1×	5e-04	FERMT3, ITGB2
cell-matrix adhesion	2	109.1×	0.002	FERMT3, ITGB2
integrin-mediated signaling pathway	2	107.0×	0.002	FERMT3, ITGB2
regulation of cell-cell adhesion mediated by integrin	1	1872.4×	0.004	FERMT3
positive regulation of neutrophil degranulation	1	1872.4×	0.004	ITGB2
negative regulation of dopamine metabolic process	1	1872.4×	0.004	ITGB2
cellular extravasation	1	1404.3×	0.004	ITGB2
positive regulation of plasma membrane repair	1	1404.3×	0.004	AHNAK
regulation of peptidyl-tyrosine phosphorylation	1	1123.5×	0.004	ITGB2
integrin activation	1	468.1×	0.007	FERMT3
positive regulation of leukocyte adhesion to vascular endothelial cell	1	468.1×	0.007	ITGB2
neutrophil migration	1	468.1×	0.007	ITGB2
leukocyte migration involved in inflammatory response	1	401.2×	0.008	ITGB2
obsolete cell-cell adhesion via plasma-membrane adhesion molecules	1	374.5×	0.008	ITGB2
amyloid-beta clearance	1	312.1×	0.008	ITGB2
positive regulation of superoxide anion generation	1	295.6×	0.008	ITGB2
cellular response to low-density lipoprotein particle stimulus	1	295.6×	0.008	ITGB2
phagocytosis, engulfment	1	224.7×	0.009	ITGB2
cell adhesion mediated by integrin	1	224.7×	0.009	ITGB2
microglial cell activation	1	208.1×	0.009	ITGB2
receptor clustering	1	208.1×	0.009	ITGB2
heterotypic cell-cell adhesion	1	193.7×	0.009	ITGB2
positive regulation of protein targeting to membrane	1	187.2×	0.009	ITGB2
endodermal cell differentiation	1	165.2×	0.010	ITGB2
positive regulation of nitric oxide biosynthetic process	1	151.8×	0.011	ITGB2
endothelial cell migration	1	137.0×	0.011	ITGB2
substrate adhesion-dependent cell spreading	1	114.6×	0.013	FERMT3
platelet aggregation	1	112.3×	0.013	FERMT3
receptor internalization	1	108.0×	0.013	ITGB2
neutrophil chemotaxis	1	95.2×	0.014	ITGB2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
ITGB2	LIFITEGRAST

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ITGB2	2	4
FERMT3	0	0
AHNAK	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LIFITEGRAST	4	ITGB2
LOVASTATIN	4	ITGB2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ITGB2	109	Binding:73, Functional:36
AHNAK	2	Binding:2

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
ITGB2	109

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

2 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)
LIFITEGRAST	4	ITGB2
LOVASTATIN	4	ITGB2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ITGB2
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	FERMT3, AHNAK

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)
FERMT3	0	ITGB2
AHNAK	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.