Lymphoproliferative syndrome 2

Summary

Lymphoproliferative syndrome 2 (MONDO:0014054) is a disease caused by CD27 (GenCC Strong), with 5 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CD27 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 226

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		18	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	lymphoproliferative syndrome 2
Mondo ID	MONDO:0014054
OMIM	615122
Orphanet	238505
DOID	DOID:0060708
UMLS	C3554540
MedGen	767454
GARD	0024968
Is cancer (heuristic)	no

Also known as: CD27 lymphoproliferative syndrome · LPFS2 · lymphoproliferative syndrome 2 · lymphoproliferative syndrome caused by mutation in CD27 · lymphoproliferative syndrome type 2

Data availability: 226 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › lymphoproliferative syndrome › lymphoproliferative syndrome 2

Related subtypes (7): X-linked lymphoproliferative syndrome, Dianzani autoimmune lymphoproliferative disease, lymphoproliferative syndrome 1, Castleman disease, autoimmune lymphoproliferative syndrome, severe combined immunodeficiency due to CD70 deficiency, atypical lymphoproliferative disorder

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

226 retrieved; paginated sample, class counts are floors:

110 uncertain significance, 86 likely benign, 11 pathogenic, 7 benign, 5 conflicting classifications of pathogenicity, 4 likely pathogenic, 2 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1163933	NM_001242.5(CD27):c.406_407del (p.Leu136fs)	CD27	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1961237	NM_001242.5(CD27):c.441T>A (p.Tyr147Ter)	CD27	Pathogenic	criteria provided, single submitter
2126450	NM_001242.5(CD27):c.256del (p.His86fs)	CD27	Pathogenic	criteria provided, single submitter
3244333	NC_000012.11:g.(?6554691)(6560069_?)dup	CD27	Pathogenic	criteria provided, single submitter
3657123	NM_001242.5(CD27):c.399del (p.Gln134fs)	CD27	Pathogenic	criteria provided, single submitter
3690987	NM_001242.5(CD27):c.410del (p.Ser137fs)	CD27	Pathogenic	criteria provided, single submitter
3696331	NM_001242.5(CD27):c.421C>T (p.Gln141Ter)	CD27	Pathogenic	criteria provided, single submitter
578414	NM_001242.5(CD27):c.239dup (p.His80fs)	CD27	Pathogenic	criteria provided, single submitter
871276	NM_001242.5(CD27):c.154del (p.Asp52fs)	CD27	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2825285	NM_001242.5(CD27):c.479del (p.Met160fs)	CD27-AS1	Pathogenic	criteria provided, single submitter
40889	NM_001242.5(CD27):c.24G>A (p.Trp8Ter)	CD27-AS1	Pathogenic	no assertion criteria provided
40890	NM_001242.5(CD27):c.158G>A (p.Cys53Tyr)	CD27-AS1	Pathogenic	criteria provided, multiple submitters, no conflicts
973578	NM_001167.4(XIAP):c.-10_977+11del	XIAP	Pathogenic	criteria provided, single submitter
1339535	NM_001242.5(CD27):c.98G>A (p.Trp33Ter)	CD27	Likely pathogenic	criteria provided, single submitter
3244332	NC_000012.11:g.(?6559440)(6560401_?)del	CD27	Likely pathogenic	criteria provided, single submitter
4701655	NM_001242.5(CD27):c.538+1G>C	CD27	Likely pathogenic	criteria provided, single submitter
4770039	NM_001242.5(CD27):c.538+1G>A	CD27	Likely pathogenic	criteria provided, single submitter
1059188	NM_001242.5(CD27):c.31G>A (p.Val11Ile)	CD27	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1439434	NM_001242.5(CD27):c.388G>A (p.Ala130Thr)	CD27	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
540910	NM_001242.5(CD27):c.541C>T (p.Gln181Ter)	CD27	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
724198	NM_001242.5(CD27):c.539-6T>C	CD27	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
827695	NM_001242.5(CD27):c.319C>T (p.Arg107Cys)	CD27	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3244331	NC_000012.11:g.(?6438478)(6950528_?)dup	ACRBP	Uncertain significance	criteria provided, single submitter
2423987	NC_000012.11:g.(?4368352)(9027607_?)dup	CD163L1	Uncertain significance	criteria provided, single submitter
1003118	NM_001242.5(CD27):c.763G>C (p.Glu255Gln)	CD27	Uncertain significance	criteria provided, multiple submitters, no conflicts
1010640	NM_001242.5(CD27):c.586T>C (p.Phe196Leu)	CD27	Uncertain significance	criteria provided, single submitter
1021457	NM_001242.5(CD27):c.685G>A (p.Ala229Thr)	CD27	Uncertain significance	criteria provided, multiple submitters, no conflicts
1022183	NM_001242.5(CD27):c.148G>A (p.Val50Met)	CD27	Uncertain significance	criteria provided, multiple submitters, no conflicts
1022722	NC_000012.11:g.(?6554242)(6560578_?)dup	CD27	Uncertain significance	criteria provided, single submitter
1041352	NM_001242.5(CD27):c.143T>A (p.Phe48Tyr)	CD27	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
CD27	Strong	Autosomal recessive	lymphoproliferative syndrome 2	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CD27	Orphanet:238505	Combined immunodeficiency due to CD27 deficiency
XIAP	Orphanet:538934	X-linked lymphoproliferative disease due to XIAP deficiency

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CD27	HGNC:11922	ENSG00000139193	P26842	CD27 antigen	gencc,clinvar
ACRBP	HGNC:17195	ENSG00000111644	Q8NEB7	Acrosin-binding protein	clinvar
CD163L1	HGNC:30375	ENSG00000177675	Q9NR16	Scavenger receptor cysteine-rich type 1 protein M160	clinvar
CD27-AS1	HGNC:43896	ENSG00000215039		CD27 antisense RNA 1	clinvar
XIAP	HGNC:592	ENSG00000101966	P98170	E3 ubiquitin-protein ligase XIAP	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CD27	CD27 antigen	Costimulatory immune-checkpoint receptor expressed at the surface of T-cells, NK-cells and B-cells which binds to and is activated by its ligand CD70/CD27L expressed by B-cells.
ACRBP	Acrosin-binding protein	Acrosomal protein that maintains proacrosin (pro-ACR) as an enzymatically inactive zymogen in the acrosome.
XIAP	E3 ubiquitin-protein ligase XIAP	Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 4 · 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
Transcription factor	1	1.6×	0.476
Other/Unknown	4	1.4×	0.476

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CD27	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_7, TNFRSF7_N
ACRBP	Other/Unknown	no		Proacrosin-bd, Kazal_dom_sf
CD163L1	Other/Unknown	no		SRCR, SRCR-like_dom_sf
CD27-AS1	Other/Unknown	no
XIAP	Transcription factor	no		BIR_rpt, Znf_RING, DEATH-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
spleen	2
ileal mucosa	2
lymph node	1
vermiform appendix	1
left testis	1
monocyte	1
right testis	1
rectum	1
C1 segment of cervical spinal cord	1
spinal cord	1
thymus	1
buccal mucosa cell	1
kidney epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CD27	132	tissue_specific	marker	lymph node, spleen, vermiform appendix
ACRBP	177	broad	marker	left testis, right testis, monocyte
CD163L1	176	broad	marker	rectum, spleen, ileal mucosa
CD27-AS1	137	ubiquitous	marker	thymus, spinal cord, C1 segment of cervical spinal cord
XIAP	256	ubiquitous	marker	kidney epithelium, ileal mucosa, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
XIAP	5,252
CD27	2,452
ACRBP	1,029
CD163L1	703
CD27-AS1	0

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
XIAP	P98170	74
CD27	P26842	5
CD163L1	Q9NR16	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACRBP	Q8NEB7	64.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 5 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
Activation of caspases through apoptosome-mediated cleavage	1	951.7×	0.006	XIAP
SMAC (DIABLO) binds to IAPs	1	815.7×	0.006	XIAP
SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes	1	815.7×	0.006	XIAP
SMAC, XIAP-regulated apoptotic response	1	815.7×	0.006	XIAP
Regulation of PTEN localization	1	519.1×	0.006	XIAP
Regulation of the apoptosome activity	1	519.1×	0.006	XIAP
RIPK1-mediated regulated necrosis	1	228.4×	0.009	XIAP
TNFR1-induced proapoptotic signaling	1	219.6×	0.009	XIAP
Regulation of necroptotic cell death	1	219.6×	0.009	XIAP
TNFs bind their physiological receptors	1	196.9×	0.009	CD27
TNFR1-induced NF-kappa-B signaling pathway	1	167.9×	0.010	XIAP
Deactivation of the beta-catenin transactivating complex	1	116.5×	0.012	XIAP
Regulation of TNFR1 signaling	1	112.0×	0.012	XIAP
Regulation of PTEN stability and activity	1	92.1×	0.013	XIAP
TNFR2 non-canonical NF-kB pathway	1	90.6×	0.013	CD27
Activation of STAT3 by cadherin engagement	1	81.6×	0.014	XIAP
Cytokine Signaling in Immune system	1	20.4×	0.051	CD27
Immune System	1	6.5×	0.148	CD27

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
positive regulation of JNK cascade	2	109.1×	0.004	CD27, XIAP
positive regulation of protein linear polyubiquitination	1	2808.7×	0.004	XIAP
regulation of apoptosis involved in tissue homeostasis	1	1872.4×	0.004	XIAP
adaptive immune memory response involving T cells and B cells	1	1872.4×	0.004	CD27
copper ion homeostasis	1	1404.3×	0.004	XIAP
regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	1	1123.5×	0.004	XIAP
nucleotide-binding oligomerization domain containing 1 signaling pathway	1	1123.5×	0.004	XIAP
CD27 signaling pathway	1	1123.5×	0.004	CD27
negative regulation of T cell apoptotic process	1	561.7×	0.007	CD27
quinolinate biosynthetic process	1	510.7×	0.007	XIAP
nucleotide-binding oligomerization domain containing 2 signaling pathway	1	510.7×	0.007	XIAP
regulation of BMP signaling pathway	1	401.2×	0.007	XIAP
positive regulation of B cell differentiation	1	374.5×	0.007	CD27
negative regulation of apoptotic process	2	23.2×	0.007	CD27, XIAP
immunoglobulin mediated immune response	1	234.1×	0.011	CD27
regulation of innate immune response	1	216.1×	0.011	XIAP
acrosome assembly	1	151.8×	0.013	ACRBP
negative regulation of tumor necrosis factor-mediated signaling pathway	1	151.8×	0.013	XIAP
positive regulation of T cell differentiation	1	151.8×	0.013	CD27
positive regulation of type I interferon production	1	140.4×	0.014	XIAP
fertilization	1	104.0×	0.017	ACRBP
extrinsic apoptotic signaling pathway	1	102.1×	0.017	CD27
protein K63-linked ubiquitination	1	89.2×	0.018	XIAP
T cell activation	1	86.4×	0.018	CD27
positive regulation of non-canonical NF-kappaB signal transduction	1	85.1×	0.018	CD27
positive regulation of protein ubiquitination	1	71.1×	0.021	XIAP
neuron apoptotic process	1	61.7×	0.023	XIAP
regulation of inflammatory response	1	56.2×	0.025	XIAP
positive regulation of canonical Wnt signaling pathway	1	51.5×	0.026	XIAP
response to ethanol	1	48.9×	0.026	CD27

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
XIAP	6	3
CD27	0	0
ACRBP	0	0
CD163L1	0	0
CD27-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
XEVINAPANT	3	XIAP
PHENYLALANINE	3	XIAP
LCL-161	2	XIAP
BIRINAPANT	2	XIAP
GDC-0152	1	XIAP
ASTX-660	1	XIAP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
XIAP	499	Binding:468, Functional:24, ADMET:7
CD27	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
XIAP	499

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

6 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)
XEVINAPANT	3	XIAP
PHENYLALANINE	3	XIAP
LCL-161	2	XIAP
BIRINAPANT	2	XIAP
GDC-0152	1	XIAP
ASTX-660	1	XIAP

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	1	XIAP
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	CD27, ACRBP, CD163L1, CD27-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)
CD27	1	—
ACRBP	0	—
CD163L1	0	—
CD27-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.