leukocyte adhesion deficiency type II

Summary

leukocyte adhesion deficiency type II (MONDO:0009953) is a disease caused by SLC35C1 (GenCC Definitive), with 4 cohort genes and 1 clinical trial. Top therapeutic interventions include l-fucose.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC35C1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 306
• Phenotypes (HPO): 58
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000280	Coarse facial features	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001903	Anemia	Very frequent (80-99%)
HP:0001974	Leukocytosis	Very frequent (80-99%)
HP:0002719	Recurrent infections	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0011897	Neutrophilia	Very frequent (80-99%)
HP:0410292	Abnormal isohemagglutinin level	Very frequent (80-99%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001518	Small for gestational age	Frequent (30-79%)
HP:0001935	Microcytic anemia	Frequent (30-79%)
HP:0001954	Recurrent fever	Frequent (30-79%)
HP:0002059	Cerebral atrophy	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0000010	Recurrent urinary tract infections	Occasional (5-29%)
HP:0000166	Severe periodontitis	Occasional (5-29%)
HP:0000189	Narrow palate	Occasional (5-29%)
HP:0000212	Gingival overgrowth	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000294	Low anterior hairline	Occasional (5-29%)
HP:0000303	Mandibular prognathia	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000385	Small earlobe	Occasional (5-29%)
HP:0000403	Recurrent otitis media	Occasional (5-29%)
HP:0000405	Conductive hearing impairment	Occasional (5-29%)
HP:0000431	Wide nasal bridge	Occasional (5-29%)
HP:0000457	Depressed nasal ridge	Occasional (5-29%)
HP:0000491	Keratitis	Occasional (5-29%)
HP:0000527	Long eyelashes	Occasional (5-29%)
HP:0001169	Broad palm	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001290	Generalized hypotonia	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0001537	Umbilical hernia	Occasional (5-29%)
HP:0001845	Overlapping toe	Occasional (5-29%)
HP:0002002	Deep philtrum	Occasional (5-29%)
HP:0002028	Chronic diarrhea	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0005280	Depressed nasal bridge	Occasional (5-29%)
HP:0006480	Premature loss of teeth	Occasional (5-29%)
HP:0006532	Recurrent pneumonia	Occasional (5-29%)
HP:0006895	Lower limb hypertonia	Occasional (5-29%)
HP:0007041	Chronic lymphocytic meningitis	Occasional (5-29%)
HP:0007333	Hypoplasia of the frontal lobes	Occasional (5-29%)
HP:0008551	Microtia	Occasional (5-29%)
HP:0009826	Limb undergrowth	Occasional (5-29%)
HP:0010808	Protruding tongue	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	leukocyte adhesion deficiency type II
Mondo ID	MONDO:0009953
MeSH	C535755
OMIM	266265
Orphanet	99843
DOID	DOID:0070255, DOID:0080492
NCIT	C4690
SNOMED CT	234583001
UMLS	C0398739
MedGen	96022
GARD	0004634
Is cancer (heuristic)	no

Also known as: CDG 2C · CDG IIc · CDG syndrome type IIc · CDG-IIc · CDG2C · CDGIIc · congenital disorder of glycosylation type IIC · congenital disorder of glycosylation, type IIc · LAD-II · lad-II · lad-type II · LAD2 · leukocyte adhesion deficiency type 2 · leukocyte adhesion deficiency type II · leukocyte adhesion deficiency, type II · Rambam-Hasharon syndrome · RHS · sialyl-Lewis X defect · SLC35C1-CDG · SLC35C1-CDG (CDG-IIc)

Data availability: 306 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › congenital disorder of glycosylation › congenital disorder of glycosylation type II › leukocyte adhesion deficiency type II

Related subtypes (25): MGAT2-congenital disorder of glycosylation, SLC35A2-congenital disorder of glycosylation, SLC35A1-congenital disorder of glycosylation, MOGS-congenital disorder of glycosylation, B4GALT1-congenital disorder of glycosylation, COG7-congenital disorder of glycosylation, COG8-congenital disorder of glycosylation, COG1-congenital disorder of glycosylation, COG4-congenital disorder of glycosylation, COG5-congenital disorder of glycosylation, COG6-congenital disorder of glycosylation, TMEM165-congenital disorder of glycosylation, SLC39A8-CDG, CCDC115-CDG, TMEM199-CDG, congenital disorder of glycosylation, type IIr, congenital disorder of glycosylation, type iit, congenital disorder of glycosylation, type 2v, congenital disorder of glycosylation, type IIw, congenital disorder of glycosylation, type IIq, congenital disorder of glycosylation, type IIy, congenital disorder of glycosylation, type IIz, congenital disorder of glycosylation, type IIaa, congenital disorder of glycosylation, type IIbb, congenital disorder of glycosylation, type IIcc

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

306 retrieved; paginated sample, class counts are floors:

152 uncertain significance, 111 likely benign, 16 conflicting classifications of pathogenicity, 14 benign, 8 pathogenic, 2 likely pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2426467	NC_000011.9:g.(?45827353)(47804770_?)del	MAPK8IP1	Pathogenic	criteria provided, single submitter
1173063	NM_018389.5(SLC35C1):c.891T>A (p.Asn297Lys)	SLC35C1	Pathogenic	criteria provided, single submitter
1514864	NM_018389.5(SLC35C1):c.778C>T (p.Gln260Ter)	SLC35C1	Pathogenic	criteria provided, single submitter
4293859	NM_018389.5(SLC35C1):c.267del (p.Gly90fs)	SLC35C1	Pathogenic	criteria provided, single submitter
4723157	NM_018389.5(SLC35C1):c.69dup (p.Ala24fs)	SLC35C1	Pathogenic	criteria provided, single submitter
4740	NM_018389.5(SLC35C1):c.923C>G (p.Thr308Arg)	SLC35C1	Pathogenic	no assertion criteria provided
504285	NM_018389.5(SLC35C1):c.942C>G (p.Tyr314Ter)	SLC35C1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
836912	NM_018389.5(SLC35C1):c.367del (p.Val123fs)	SLC35C1	Pathogenic	criteria provided, single submitter
95906	NM_018389.5(SLC35C1):c.91G>T (p.Glu31Ter)	SLC35C1	Pathogenic	criteria provided, single submitter
1184819	NM_018389.5(SLC35C1):c.887A>G (p.His296Arg)	SLC35C1	Likely pathogenic	no assertion criteria provided
4739	NM_018389.5(SLC35C1):c.439C>T (p.Arg147Cys)	SLC35C1	Likely pathogenic	criteria provided, single submitter
144046	NM_018389.5(SLC35C1):c.503_505del (p.Phe168del)	SLC35C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216999	NM_018389.5(SLC35C1):c.872C>T (p.Thr291Ile)	SLC35C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
252721	NM_018389.5(SLC35C1):c.1054C>T (p.Pro352Ser)	SLC35C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304736	NM_018389.5(SLC35C1):c.29G>A (p.Arg10Lys)	SLC35C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304739	NM_018389.5(SLC35C1):c.522C>T (p.Cys174=)	SLC35C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304740	NM_018389.5(SLC35C1):c.666G>A (p.Ala222=)	SLC35C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304741	NM_018389.5(SLC35C1):c.747C>T (p.Leu249=)	SLC35C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304742	NM_018389.5(SLC35C1):c.748G>A (p.Gly250Arg)	SLC35C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304743	NM_018389.5(SLC35C1):c.837C>T (p.Ala279=)	SLC35C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
530701	NM_018389.5(SLC35C1):c.598G>A (p.Val200Ile)	SLC35C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626020	NM_018389.5(SLC35C1):c.402C>T (p.Cys134=)	SLC35C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
657718	NM_018389.5(SLC35C1):c.767G>A (p.Arg256His)	SLC35C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
723737	NM_018389.5(SLC35C1):c.226G>A (p.Val76Ile)	SLC35C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
755027	NM_018389.5(SLC35C1):c.51C>T (p.Thr17=)	SLC35C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880342	NM_018389.5(SLC35C1):c.738C>T (p.Leu246=)	SLC35C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
95904	NM_018389.5(SLC35C1):c.663G>A (p.Pro221=)	SLC35C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
832501	NC_000011.10:g.(?45805782)(45910982_?)dup	FREY1	Uncertain significance	criteria provided, single submitter
304725	NM_018389.5(SLC35C1):c.-569C>T	LOC130005625	Uncertain significance	criteria provided, single submitter
304727	NM_018389.5(SLC35C1):c.-518C>A	LOC130005625	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
SLC35C1	Definitive	Autosomal recessive	leukocyte adhesion deficiency type II	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC35C1	Orphanet:99843	Leukocyte adhesion deficiency type II
NDUFS3	Orphanet:2609	Isolated complex I deficiency

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
SLC35C1	HGNC:20197	ENSG00000181830	Q96A29	GDP-fucose transporter 1	gencc,clinvar
FREY1	HGNC:37213	ENSG00000234776	C9JXX5	Protein Frey 1	clinvar
MAPK8IP1	HGNC:6882	ENSG00000121653	Q9UQF2	C-Jun-amino-terminal kinase-interacting protein 1	clinvar
NDUFS3	HGNC:7710	ENSG00000213619	O75489	NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC35C1	GDP-fucose transporter 1	Antiporter specific for GDP-l-fucose and depending on the concomitant reverse transport of GMP.
FREY1	Protein Frey 1	Key regulator for male fertility expressed transiently in round spermatids where it recruits IZUMO1 at the endoplasmic reticulum (ER) membrane and coordinates the oolemmal binding multimeric complex (IZUMO1 complex) assembly.
MAPK8IP1	C-Jun-amino-terminal kinase-interacting protein 1	The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module.
NDUFS3	NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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
Transporter	1	19.4×	0.151
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC35C1	Transporter	yes		Sugar_P_trans_dom, TPT_transporter
FREY1	Other/Unknown	no		Frey
MAPK8IP1	Scaffold/PPI	no		SH3_domain, PTB/PI_dom, PH-like_dom_sf
NDUFS3	Other/Unknown	no		NADH_UbQ_OxRdtase_30kDa_su, NADH_DH_suC, NADH_UbQ_OxRdtase_CS

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
esophagus mucosa	1
lower esophagus mucosa	1
right lobe of liver	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1
C1 segment of cervical spinal cord	1
adenohypophysis	1
right frontal lobe	1
apex of heart	1
mucosa of transverse colon	1
putamen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC35C1	245	ubiquitous	marker	lower esophagus mucosa, right lobe of liver, esophagus mucosa
FREY1	149	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, left testis, right testis
MAPK8IP1	179	broad	marker	C1 segment of cervical spinal cord, right frontal lobe, adenohypophysis
NDUFS3	140	ubiquitous	marker	putamen, mucosa of transverse colon, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDUFS3	5,461
MAPK8IP1	1,724
SLC35C1	910
FREY1	186

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MAPK8IP1	Q9UQF2	27
NDUFS3	O75489	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC35C1	Q96A29	82.38
FREY1	C9JXX5	70.16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. 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
Defective SLC35C1 causes congenital disorder of glycosylation 2C (CDG2C)	1	5710.0×	0.002	SLC35C1
GDP-fucose biosynthesis	1	951.7×	0.007	SLC35C1
Transport of nucleotide sugars	1	571.0×	0.008	SLC35C1
Complex I biogenesis	1	82.8×	0.038	NDUFS3
RHOG GTPase cycle	1	74.2×	0.038	NDUFS3
Mitochondrial protein degradation	1	57.1×	0.039	NDUFS3
Respiratory electron transport	1	47.6×	0.039	NDUFS3
Aerobic respiration and respiratory electron transport	1	44.3×	0.039	NDUFS3
RHO GTPase cycle	1	30.1×	0.051	NDUFS3
Signaling by Rho GTPases	1	17.1×	0.075	NDUFS3
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.075	NDUFS3
Metabolism of proteins	1	6.2×	0.177	NDUFS3
Metabolism	1	5.8×	0.177	NDUFS3
Signal Transduction	1	5.1×	0.187	NDUFS3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
GDP-fucose import into Golgi lumen	1	4213.0×	0.005	SLC35C1
protein localization involved in acrosome reaction	1	2106.5×	0.005	FREY1
‘de novo’ GDP-L-fucose biosynthetic process	1	1404.3×	0.005	SLC35C1
regulation of CD8-positive, alpha-beta T cell proliferation	1	1404.3×	0.005	MAPK8IP1
GDP-L-fucose biosynthetic process	1	1053.2×	0.005	SLC35C1
GDP-L-fucose salvage	1	1053.2×	0.005	SLC35C1
maintenance of protein localization in endoplasmic reticulum	1	842.6×	0.005	FREY1
negative regulation of JUN kinase activity	1	601.9×	0.006	MAPK8IP1
sperm-egg recognition	1	280.9×	0.012	FREY1
regulation of JNK cascade	1	221.7×	0.014	MAPK8IP1
negative regulation of intrinsic apoptotic signaling pathway	1	191.5×	0.014	MAPK8IP1
fusion of sperm to egg plasma membrane involved in single fertilization	1	140.4×	0.018	FREY1
reactive oxygen species metabolic process	1	117.0×	0.019	NDUFS3
negative regulation of Notch signaling pathway	1	108.0×	0.019	SLC35C1
mitochondrial respiratory chain complex I assembly	1	102.8×	0.019	NDUFS3
substantia nigra development	1	91.6×	0.020	NDUFS3
mitochondrial electron transport, NADH to ubiquinone	1	89.6×	0.020	NDUFS3
JNK cascade	1	68.0×	0.023	MAPK8IP1
protein N-linked glycosylation	1	65.8×	0.023	FREY1
proton motive force-driven mitochondrial ATP synthesis	1	65.8×	0.023	NDUFS3
aerobic respiration	1	62.0×	0.023	NDUFS3
positive regulation of JNK cascade	1	40.9×	0.033	MAPK8IP1
intracellular calcium ion homeostasis	1	36.3×	0.034	FREY1
spermatid development	1	36.3×	0.034	FREY1
protein-containing complex assembly	1	28.5×	0.042	FREY1
vesicle-mediated transport	1	24.1×	0.047	MAPK8IP1
gene expression	1	20.0×	0.055	FREY1
protein stabilization	1	16.7×	0.063	FREY1
protein ubiquitination	1	10.3×	0.096	FREY1
regulation of DNA-templated transcription	1	7.9×	0.121	MAPK8IP1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC35C1	0	0
FREY1	0	0
MAPK8IP1	0	0
NDUFS3	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
NDUFS3	5	Binding:5

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	SLC35C1
E	Difficult family or no structure, no drug	3	FREY1, MAPK8IP1, NDUFS3

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)
SLC35C1	0	—
FREY1	0	—
MAPK8IP1	0	—
NDUFS3	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03354533	PHASE1/PHASE2	COMPLETED	Study of ORL-1F (L-fucose) in Patients With Leukocyte Adhesion Deficiency Type II

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
L-FUCOSE	3	1
CHEMBL1230861	0	1