Klinefelter syndrome

Summary

Klinefelter syndrome (MONDO:0006823) is a disease with 5 cohort genes and 36 clinical trials. Top therapeutic interventions include gonadotropin, chorionic, testosterone cypionate, and alitretinoin.

At a glance

• Cohort genes: 5
• ClinVar variants: 5
• Clinical trials: 36

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Klinefelter syndrome
Mondo ID	MONDO:0006823
EFO	EFO:1001006
MeSH	D007713
DOID	DOID:1921
ICD-11	1937385304
NCIT	C34752
SNOMED CT	405769009
UMLS	C0022735
MedGen	44033
MedDRA	10023463
Is cancer (heuristic)	no

Also known as: 47,XXY syndrome · Klinefelter syndrome · Klinefelter’s syndrome · Klinefelter’s syndrome, XXY · XXY syndrome · XXY syndrome (Klinefelter syndrome)

Data availability: 5 ClinVar variants · 59 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › disorder of sexual differentiation › sex chromosome disorder of sex development › Klinefelter syndrome

Related subtypes (6): 48,XXYY syndrome, 45,X/46,XY mixed gonadal dysgenesis, tetragametic chimerism, Turner syndrome, 48,XXXY syndrome, 49,XXXXY syndrome

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

5 retrieved; paginated sample, class counts are floors:

5 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2506546	GRCh37/hg19 Xp22.33-q28(chrX:200855-155240074)	ABCB7	Pathogenic	criteria provided, single submitter
1708270	GRCh37/hg19 Yp11.31-11.2(chrY:2650140-9651417)x1	AMELY	Pathogenic	no assertion criteria provided
1708269	GRCh37/hg19 Xp22.33(chrX:2696691-3666623)x1	ARSD	Pathogenic	no assertion criteria provided
1704345	GRCh37/hg19 Xp22.33-q28(chrX:61545-155226048)x2	PORCN	Pathogenic	no assertion criteria provided
3242589	GRCh38/hg38 Xp22.33-q28(chrX:2757837-156030895)x2	SYN1	Pathogenic	criteria provided, single submitter

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
SYN1	Orphanet:85294	X-linked epilepsy-learning disabilities-behavior disorders syndrome
PORCN	Orphanet:2092	Focal dermal hypoplasia
PORCN	Orphanet:98938	Colobomatous microphthalmia
ABCB7	Orphanet:2802	X-linked sideroblastic anemia and spinocerebellar ataxia

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SYN1	HGNC:11494	ENSG00000008056	P17600	Synapsin-1	clinvar
PORCN	HGNC:17652	ENSG00000102312	Q9H237	Protein-serine O-palmitoleoyltransferase porcupine	clinvar
AMELY	HGNC:462	ENSG00000099721	Q99218	Amelogenin, Y isoform	clinvar
ABCB7	HGNC:48	ENSG00000131269	O75027	Iron-sulfur clusters transporter ABCB7, mitochondrial	clinvar
ARSD	HGNC:717	ENSG00000006756	P51689	Arylsulfatase D	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SYN1	Synapsin-1	Neuronal phosphoprotein that coats synaptic vesicles, and binds to the cytoskeleton.
PORCN	Protein-serine O-palmitoleoyltransferase porcupine	Protein-serine O-palmitoleoyltransferase that acts as a key regulator of the Wnt signaling pathway by mediating the attachment of palmitoleate, a 16-carbon monounsaturated fatty acid (C16:1(9Z)), to Wnt proteins.
AMELY	Amelogenin, Y isoform	Plays a role in biomineralization.
ABCB7	Iron-sulfur clusters transporter ABCB7, mitochondrial	Exports glutathione-coordinated iron-sulfur clusters such as [2Fe-2S]-(GS)4 cluster from the mitochondria to the cytosol in an ATP-dependent manner allowing the assembly of the cytosolic iron-sulfur (Fe/S) cluster-containing proteins and p…

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.6

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
Phosphatase	1	16.8×	0.125
Transporter	1	15.6×	0.125
Enzyme (other)	1	2.4×	0.471
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SYN1	Other/Unknown	no		Synapsin, ATP_grasp_subdomain_1, PreATP-grasp_dom_sf
PORCN	Enzyme (other)	yes	2.3.1.250	MBOAT_fam, LPLAT_7/PORCN-like
AMELY	Other/Unknown	no		Amelogenin
ABCB7	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom
ARSD	Phosphatase	yes		Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS

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)	1
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
triceps brachii	2
prefrontal cortex	1
right frontal lobe	1
right hemisphere of cerebellum	1
lower esophagus mucosa	1
right adrenal gland	1
right adrenal gland cortex	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
biceps brachii	1
gluteal muscle	1
cardia of stomach	1
pylorus	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SYN1	190	broad	marker	right frontal lobe, right hemisphere of cerebellum, prefrontal cortex
PORCN	184	ubiquitous	marker	lower esophagus mucosa, right adrenal gland cortex, right adrenal gland
AMELY	20		yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, triceps brachii
ABCB7	273	ubiquitous	marker	biceps brachii, gluteal muscle, triceps brachii
ARSD	263	ubiquitous	marker	renal medulla, cardia of stomach, pylorus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SYN1	3,188
ABCB7	1,838
ARSD	956
PORCN	802
AMELY	568

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PORCN	Q9H237	7
ABCB7	O75027	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARSD	P51689	92.71
SYN1	P17600	69.86
AMELY	Q99218	57.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
LGK974 inhibits PORCN	1	1427.5×	0.016	PORCN
Mitochondrial ABC transporters	1	713.8×	0.016	ABCB7
The activation of arylsulfatases	1	219.6×	0.024	ARSD
Cytosolic iron-sulfur cluster assembly	1	190.3×	0.024	ABCB7
Serotonin Neurotransmitter Release Cycle	1	158.6×	0.024	SYN1
Dopamine Neurotransmitter Release Cycle	1	124.1×	0.024	SYN1
Neurotransmitter release cycle	1	109.8×	0.024	SYN1
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1	105.7×	0.024	ARSD
WNT ligand biogenesis and trafficking	1	105.7×	0.024	PORCN
Sensory processing of sound	1	77.2×	0.026	SYN1
Glycosphingolipid metabolism	1	75.1×	0.026	ARSD
Glycosphingolipid catabolism	1	73.2×	0.026	ARSD
Sphingolipid metabolism	1	42.0×	0.040	ARSD
Sensory processing of sound by inner hair cells of the cochlea	1	40.8×	0.040	SYN1
ABC-family protein mediated transport	1	30.4×	0.050	ABCB7
Sensory Perception	1	23.8×	0.056	SYN1
Metabolism	2	5.8×	0.056	ABCB7, ARSD
Transmission across Chemical Synapses	1	19.0×	0.066	SYN1
Neuronal System	1	11.1×	0.106	SYN1
Metabolism of lipids	1	7.9×	0.139	ARSD
Transport of small molecules	1	6.3×	0.164	ABCB7
Post-translational protein modification	1	4.8×	0.201	ARSD
Metabolism of proteins	1	3.1×	0.286	ARSD

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
iron-sulfur cluster export from the mitochondrion	1	4213.0×	0.003	ABCB7
positive regulation of iron-sulfur cluster assembly	1	4213.0×	0.003	ABCB7
protein palmitoleylation	1	2106.5×	0.003	PORCN
Wnt protein secretion	1	1404.3×	0.003	PORCN
positive regulation of heme biosynthetic process	1	1404.3×	0.003	ABCB7
protein lipidation	1	842.6×	0.005	PORCN
iron ion transmembrane transport	1	601.9×	0.006	ABCB7
lipid modification	1	468.1×	0.006	PORCN
synaptic vesicle clustering	1	351.1×	0.007	SYN1
enamel mineralization	1	300.9×	0.007	AMELY
glycoprotein metabolic process	1	280.9×	0.007	PORCN
regulation of synaptic vesicle cycle	1	280.9×	0.007	SYN1
negative regulation of reactive oxygen species biosynthetic process	1	247.8×	0.007	ABCB7
regulation of neurotransmitter secretion	1	191.5×	0.009	SYN1
neurotransmitter secretion	1	175.5×	0.009	SYN1
iron-sulfur cluster assembly	1	150.5×	0.010	ABCB7
regulation of postsynaptic membrane neurotransmitter receptor levels	1	123.9×	0.011	PORCN
regulation of synaptic vesicle exocytosis	1	113.9×	0.012	SYN1
synapse organization	1	70.2×	0.018	SYN1
neuron development	1	63.8×	0.019	SYN1
intracellular iron ion homeostasis	1	61.1×	0.019	ABCB7
transmembrane transport	1	42.1×	0.026	ABCB7
Wnt signaling pathway	1	24.9×	0.041	PORCN
chemical synaptic transmission	1	19.3×	0.051	SYN1

Therapeutics

Drugs indicated for this disease

2 approved, 3 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Testosterone	Approved (phase 4)
Testosterone Undecanoate	Approved (phase 4)
Anastrozole	Phase 3 (in late-stage trials)
Gonadotropin, Chorionic	Phase 3 (in late-stage trials)
Semaglutide	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Calcitriol, Isotretinoin, Oxandrolone.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · 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
PORCN	2	2
SYN1	0	0
AMELY	0	0
ABCB7	0	0
ARSD	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
WNT-974	2	PORCN
ETC-159	1	PORCN

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PORCN	31	Binding:31
ABCB7	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PORCN	2.3.1.250	[Wnt protein] O-palmitoleoyl transferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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)
WNT-974	2	PORCN
ETC-159	1	PORCN

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	PORCN
C	Druggable family + PDB, no drug	1	ABCB7
D	Druggable family + AlphaFold only, no drug	1	ARSD
E	Difficult family or no structure, no drug	2	SYN1, AMELY

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)
SYN1	0	—
AMELY	0	—
ABCB7	1	—
ARSD	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 36.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	28
PHASE4	4
PHASE2	2
PHASE2/PHASE3	1
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06294990	PHASE4	RECRUITING	Klinefelter Syndrome and Testosterone Treatment in Puberty
NCT02408445	PHASE4	COMPLETED	Body Composition in Infants With Klinefelter Syndrome and Effects of Testosterone Treatment
NCT03325647	PHASE4	COMPLETED	TESTO: Testosterone Effects on Short-Term Outcomes in Infants With XXY
NCT05498090	PHASE4	UNKNOWN	Interrogating Fatty Acid Metabolism Impairment and Clinical Correlates in Males with Klinefelter Syndrome
NCT05586802	PHASE3	RECRUITING	Sex Steroids Balance for Metabolic and Reproductive Health in Klinefelter Syndrome
NCT01206270	PHASE2/PHASE3	COMPLETED	Androgen for Leydig Cell Proliferation
NCT00348946	PHASE2	COMPLETED	Androgen Effect on Klinefelter Syndrome Motor Outcome
NCT02061384	PHASE2	COMPLETED	RA-2 13-cis Retinoic Acid (Isotretinoin)
NCT03396562	Not specified	RECRUITING	The eXtroardinarY Babies Study: Natural History of Health and Neurodevelopment in Infants and Young Children With Sex Chromosome Trisomy
NCT03836300	Not specified	ENROLLING_BY_INVITATION	Parent and Infant Inter(X)Action Intervention (PIXI)
NCT04252001	Not specified	NOT_YET_RECRUITING	Growing up With the Young Endocrine Support System (YESS!)
NCT05581147	Not specified	RECRUITING	Thyroid Function and Structure in Klinefelter Syndrome
NCT07142135	Not specified	ENROLLING_BY_INVITATION	Long-term Systematic Follow-up of Patients With Klinefelter Syndrome Followed at the Department of Growth and Reproduction, Rigshospitalet
NCT00347464	Not specified	WITHDRAWN	Adaptive Behavior Assessment of Men With 49, XXXXY, Klinefelter Syndrome
NCT00523835	Not specified	COMPLETED	Body Composition, Bone Mineral Density, Insulin Sensitivity and Echocardiographic Measurements in Klinefelter Syndrome
NCT00891852	Not specified	UNKNOWN	Non-Invasive Determination of Fetal Chromosome Abnormalities
NCT00896272	Not specified	COMPLETED	Adaptation Among Adolescents and Adults With Klinefelter Syndrome
NCT00999310	Not specified	COMPLETED	Neuropsychologic, Neuroradiologic, Endocrinologic, and Genetic Aspects of Klinefelter Syndrome
NCT01585831	Not specified	COMPLETED	Study of Psychological and Motor Effects of Testosterone in Adolescents With XXY/Klinefelter Syndrome
NCT01678261	Not specified	COMPLETED	X-chromosome Inactivation, Epigenetics and the Transcriptome
NCT01690013	Not specified	COMPLETED	Life Quality and Health in Patients With Klinefelter Syndrome
NCT01750632	Not specified	COMPLETED	Subcapsular Orchiectomy in Men With Klinefelter Syndrome
NCT01817296	Not specified	COMPLETED	Klinefelter Fertility Preservation
NCT01918280	Not specified	COMPLETED	Fertility Preservation in Cases of Klinefelter Syndrome.
NCT02414295	Not specified	COMPLETED	Sperm Production in Kleinfelter Syndrome Patients After Mesenchymal Stem Cell Injection
NCT02430584	Not specified	UNKNOWN	Whole Blood Specimen Collection From Pregnant Subjects
NCT02461303	Not specified	TERMINATED	Fertility Assessment in Patients With Klinefelter Syndrome
NCT02526628	Not specified	COMPLETED	Thrombosis and Neurocognition in Klinefelter Syndrome
NCT02723305	Not specified	COMPLETED	Cardiometabolic Profiles of Boys With Klinefelter Syndrome
NCT02787486	Not specified	COMPLETED	Expanded Noninvasive Genomic Medical Assessment: The Enigma Study
NCT02788136	Not specified	COMPLETED	Human Chorionic Gonadotropin Stimulation Effects on Steroidogenesis in Men With Klinefelter Syndrome
NCT04803474	Not specified	UNKNOWN	Turner And Klinefelter Treatment Target Study
NCT05014997	Not specified	COMPLETED	TyG Index Levels in Klinefelter Syndrome
NCT05425953	Not specified	UNKNOWN	Endocrine, Metabolic, Cardiovascular and Immunological Aspects of Sex Chromosome Abnormalities in Relation to Genotype
NCT05997706	Not specified	UNKNOWN	Unraveling the Klinefelter’s Disease Physiopathology
NCT06687252	Not specified	COMPLETED	Retrospective Analysis of the Neonatal Management of Patients with an Antenatal Diagnosis of Genital Development Variation At the Hospital of Lyon

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
GONADOTROPIN, CHORIONIC	4	2
TESTOSTERONE CYPIONATE	4	2
ALITRETINOIN	4	1
ANASTROZOLE	4	1
CALCITRIOL	4	1
CASTOR OIL	4	1
FENOFIBRATE	4	1
ISOTRETINOIN	4	1
OXANDROLONE	4	1
TESTOSTERONE UNDECANOATE	4	1