47,XYY Syndrome

Genetic MONDO:0019339 Pathograph 22 Show in embeddings browser chromosomal disorder

47,XYY syndrome is a sex-chromosome aneuploidy with an additional Y chromosome, usually arising sporadically from paternal meiotic nondisjunction; 46,XY/47,XYY mosaicism can arise postzygotically. It occurs in approximately 1 in 1,000 male live births and is often unrecognized clinically. Expression varies from few apparent difficulties to language, learning, attention and social-communication impairments. Average height is increased, with variably present macrocephaly, macroorchidism, hypotonia, hypertelorism, clinodactyly and tremor. Asthma and seizures occur in clinical cohorts; genotype-first adult cohorts also associate XYY with venous disease, glaucoma and metabolic morbidity. Most measured childhood testosterone values are normal, and neither behavioral difficulties nor infertility is universal. Better average cognitive outcomes in prenatally ascertained cohorts are subject to referral and age differences and do not demonstrate a causal benefit of prenatal diagnosis.

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1
Inheritance
6
Pathophys.
27
Phenotypes
22
Pathograph
4
Genes
7
Medical Actions
2
Subtypes
3
Differentials
1
Trials
1
Models
11
References
👪

Inheritance

1
Usually sporadic chromosome nondisjunction
Usually a de novo paternal meiotic event; postzygotic nondisjunction can produce 46,XY/47,XYY mosaicism. This is not Mendelian Y-linked inheritance. Clinical expression varies substantially.
Expressivity: VARIABLE
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Jacobs syndrome is not an inherited condition and most commonly arises during meiosis II in the father, at which time an extra Y chromosome is attributed to the resultant sperm."
Describes the usual sporadic paternal meiotic origin of the extra Y chromosome.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"An alternate and less common form of this condition is 46,XY/47,XYY mosaicism, which arises during early embryonic development."
Distinguishes postzygotic mosaicism from the usual nonmosaic complement.
◆

Subtypes

2
Nonmosaic 47,XYY
The additional Y chromosome is present in the tested cell population without a detected 46,XY cell line; detection remains dependent on the tissue and assay examined.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Jacobs syndrome is not an inherited condition and most commonly arises during meiosis II in the father, at which time an extra Y chromosome is attributed to the resultant sperm."
Describes the usual sporadic paternal meiotic origin of the extra Y chromosome.
Mosaic 46,XY/47,XYY
Coexisting XY and XYY cell populations following a postzygotic event. A measured mosaic fraction in one tissue does not establish a precise clinical prognosis.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"An alternate and less common form of this condition is 46,XY/47,XYY mosaicism, which arises during early embryonic development."
Distinguishes postzygotic mosaicism from the usual nonmosaic complement.
⚙

Pathophysiology

6
Additional Y Chromosome
Mechanism confidence: Established
A whole additional Y chromosome creates the 47,XYY complement and increases genomic copy number of Y-linked and shared pseudoautosomal loci.
Downstream
Increased Pseudoautosomal Gene Copy Number The extra Y adds a third copy of loci shared by the X and Y pseudoautosomal regions.
Y-Linked Gene Overexpression An extra Y is associated with predominantly increased expression of Y-linked genes in the studied patient-derived cells; dosage compensation is gene- and cell-specific.
Cell-Type-Specific Transcriptional Dysregulation The XYY complement is associated with broad transcriptional changes beyond the sex chromosomes; the responsible trans-regulatory intermediates are incompletely resolved.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Jacobs syndrome is not an inherited condition and most commonly arises during meiosis II in the father, at which time an extra Y chromosome is attributed to the resultant sperm."
Describes the usual sporadic paternal meiotic origin of the extra Y chromosome.
Increased Pseudoautosomal Gene Copy Number
Nonmosaic XYY cells carry three copies of shared pseudoautosomal genes, including SHOX. Allelic expression analyses in cultured cells show biallelic expression ratios consistent with additional Y-derived dosage and gene-specific expression differences. Identical Y copies are not individually resolved.
SHOX hgnc:10853 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SHOX (hgnc:10853). hgnc:10853 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
SHOX Dosage Contribution to Linear Growth Additional SHOX dosage is a proposed mediator of increased stature, supported by established SHOX biology and human chromosome-dosage associations rather than an XYY growth-plate perturbation experiment.
Show evidence (1 reference)
PMID:40494628 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Biallelic expressed SNPs mapping to the PAR1 region in JS samples were distributed around the values 30% and 60%, suggesting that the X and the two identical Y Chromosomes contribute similarly to the total expression level of the PAR1 transcripts."
Allele-specific RNA measurements support biallelic PAR1 expression consistent with additional Y-derived dosage. The two identical Y copies are not individually resolved, and SHOX expression in growth plates was not measured.
SHOX Dosage Contribution to Linear Growth
Mechanism confidence: Hypothetical
The third SHOX copy is a plausible contributor to increased linear growth. Human height associations support a dosage effect, but do not establish SHOX as the only mediator or quantify its expression in XYY growth plates.
SHOX hgnc:10853 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SHOX (hgnc:10853). hgnc:10853 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Tall Stature SHOX dosage may contribute to increased linear growth; downstream growth-plate effects were not directly measured in these XYY cohorts.
Show evidence (2 references)
PMID:23810129 SUPPORT INDIRECT BACKGROUND Human Clinical
"For example, tall stature is related to the extra copy of the short stature homeobox gene40 in the pseudoautosomal region of the extra Y chromosome."
The authors attribute increased stature to extra SHOX dosage using prior biological evidence; this cohort did not experimentally manipulate SHOX.
PMID:40388606 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"By examining 1,225 individuals with SCAs identified among 928,605 biobank participants, we found that increased Y chromosome dosage conferred a larger effect on height than increased X chromosome dosage"
Adult genotype-first analysis supports a sex-chromosome dosage contribution to height. It does not isolate SHOX as the sole mediator; male sex hormone status was modeled with a proxy rather than measured hormone concentrations.
Y-Linked Gene Overexpression
Mechanism confidence: Provisional
Most differentially expressed non-pseudoautosomal Y genes are increased in XYY fibroblasts, iPSCs and neural stem cells. X-homolog responses differ by gene pair; a universal compensatory or twofold-expression rule is unsupported.
UTY hgnc:12638 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves UTY (hgnc:12638). hgnc:12638 is a gene from the HUGO Gene Nomenclature Committee.
gene expression GO:0010467 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased gene expression (GO:0010467). GO:0010467 is a biological process from the Gene Ontology. ↑ INCREASED
Experimental models
Patient-derived XYY pluripotent and neural stem-cell cultures IPSC DERIVED MODEL RNA sequencing compares non-pseudoautosomal Y-linked expression in XYY and XY cultures.
Downstream
UTY-Dependent KDM6A Upregulation UTY perturbation changes KDM6A expression in the studied male pluripotent cells, but a direct versus indirect regulatory route is unresolved.
Show evidence (1 reference)
PMID:40494628 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Importantly, all NPY DEGs were upregulated in the three cell types except for MXRA5Y, a pseudogene of the X-linked gene MXRA5, which was downregulated in fibroblasts"
RNA sequencing of patient-derived fibroblasts, iPSCs and neural stem cells identifies predominantly increased non-pseudoautosomal Y-linked expression. The claim concerns differentially expressed genes, not uniform doubling of every Y gene.
UTY-Dependent KDM6A Upregulation
Mechanism confidence: Provisional
In XYY iPSCs, increased KDM6A expression depends in part on UTY. UTY knockout reduces KDM6A RNA and protein, whereas UTY overexpression increases KDM6A in male embryonic stem cells. Equivalent induction was not observed in the tested female cell line.
UTY hgnc:12638 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves UTY (hgnc:12638). hgnc:12638 is a gene from the HUGO Gene Nomenclature Committee. KDM6A hgnc:12637 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KDM6A (hgnc:12637). hgnc:12637 is a gene from the HUGO Gene Nomenclature Committee.
Experimental models
Patient-derived XYY pluripotent and neural stem-cell cultures IPSC DERIVED MODEL CRISPR disruption of UTY in XYY iPSCs tests its contribution to KDM6A RNA and protein abundance.
Show evidence (2 references)
PMID:40494628 SUPPORT DIRECT PRIMARY RESULT In Vitro
"The histone demethylase KDM6A and USP9X follow the same expression trend of their Y homologs (UTY and USP9Y) and are upregulated in iPSCs and NSCs."
Documents the higher KDM6A expression state in patient-derived pluripotent and neural stem cells.
PMID:40494628 SUPPORT DIRECT PRIMARY RESULT In Vitro
"KDM6A mRNAs and protein levels were significantly decreased in multiple 47,XYY UTY−/− iPSC clones"
CRISPR disruption of UTY reduced KDM6A RNA and protein in XYY iPSCs. Male-cell UTY overexpression also increased KDM6A; these perturbations support an expression dependency without identifying a direct promoter mechanism.
Cell-Type-Specific Transcriptional Dysregulation
Mechanism confidence: Provisional
Patient-derived XYY fibroblasts, iPSCs and neural stem cells show distinct widespread transcriptional changes, including autosomal loci. Some signatures overlap XXY cells. Expression and enrichment results nominate mechanisms for investigation without demonstrating a specific neuronal functional deficit.
regulation of DNA-templated transcription GO:0006355 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves regulation of DNA-templated transcription (GO:0006355). GO:0006355 is a biological process from the Gene Ontology.
Experimental models
Patient-derived XYY pluripotent and neural stem-cell cultures IPSC DERIVED MODEL RNA sequencing identifies distinct expression signatures in fibroblast, pluripotent and neural stem-cell contexts.
Show evidence (1 reference)
PMID:40494628 SUPPORT DIRECT PRIMARY RESULT In Vitro
"The differential expression analysis (DEA) performed on 47,XYY and 46,XY karyotypes identified 1838, 1789, and 4413 differentially expressed genes (DEGs) in fibroblasts, iPSCs and NSCs, respectively"
Establishes broad, cell-context-dependent transcriptional differences, without proving that UTY alone causes the entire signature or that a specific clinical manifestation follows.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for 47,XYY Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

27
Blood 1
Venous Thrombosis HP:0004936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Venous thrombosis (HP:0004936). HP:0004936 is a phenotype from the Human Phenotype Ontology.
Association in an adult genotype-first PheWAS of 1,108 XYY participants across MVP, UK Biobank and FinnGen. Cohort selection, diagnostic coding and unmeasured environmental or lifestyle mediators limit causal and population-frequency interpretation. This evidence does not establish a benefit from routine prophylactic anticoagulation.
Show evidence (1 reference)
PMID:40840450 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"452 | other venous embolism and thrombosis | circulatory | 19.4% | 4.6 (3.7–5.6) | 18.1% | 4.1 (3.3–5.0) | 11.6% | 8.1 (4.2–15.4) | 0.13"
Reports the XYY venous-thromboembolism association: OR 4.1 (95% CI 3.3–5.0).
Cardiovascular 1
Venous Insufficiency HP:0005293 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Venous insufficiency (HP:0005293). HP:0005293 is a phenotype from the Human Phenotype Ontology.
Association in an adult genotype-first PheWAS of 1,108 XYY participants across MVP, UK Biobank and FinnGen. Cohort selection, diagnostic coding and unmeasured environmental or lifestyle mediators limit causal and population-frequency interpretation.
Show evidence (1 reference)
PMID:40840450 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"456 | chronic venous insufficiency | circulatory | 19.6% | 4.7 (3.9–5.8) | 20.1% | 5.6 (4.5–7.0) | 16.0% | 4.6 (2.7–7.6) | 0.50"
Reports the XYY venous-insufficiency association: OR 5.6 (95% CI 4.5–7.0).
Digestive 1
Inguinal Hernia HP:0000023 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inguinal hernia (HP:0000023). HP:0000023 is a phenotype from the Human Phenotype Ontology.
These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population penetrance.
Show evidence (1 reference)
PMID:23810129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Hypospadias was reported in 1/ 90, cryptorchidism in 2/90, and inguinal hernia in 5/90."
Records inguinal hernia in five individuals in the clinical cohort.
Endocrine 1
Diabetes Mellitus HP:0000819 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diabetes mellitus (HP:0000819). HP:0000819 is a phenotype from the Human Phenotype Ontology.
Association in an adult genotype-first PheWAS of 1,108 XYY participants across MVP, UK Biobank and FinnGen. Cohort selection, diagnostic coding and unmeasured environmental or lifestyle mediators limit causal and population-frequency interpretation. The study describes type 2 diabetes. The broader HPO binding follows the association table endpoint, phecode 250 diabetes mellitus, rather than assigning all coded cases to a subtype from the narrative summary.
Show evidence (1 reference)
PMID:40840450 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Examples of other conditions that were significantly more prominent in all three SCT groups include obesity (MIM: 601665), type 2 diabetes (MIM: 125853), dermatophytosis, atopic dermatitis (MIM: 603165), asthma and chronic airway obstruction (MIM: 600807), sleep apnea (MIM: 107650)"
Reports adult metabolic and respiratory associations in all three sex-chromosome trisomies, including XYY.
Eye 2
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Observed in 53/90. These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population penetrance.
Show evidence (1 reference)
PMID:23810129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Macrocephaly (head circumference >2 SD) was noted in 28/84 (33%), hypotonia in 57/90 (63%), clinodactyly in 47/90 (52%), and hypertelorism in 53/90 (59%)."
Observed in 53/90. These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population penetrance.
Glaucoma HP:0000501 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Glaucoma (HP:0000501). HP:0000501 is a phenotype from the Human Phenotype Ontology.
Association in an adult genotype-first PheWAS of 1,108 XYY participants across MVP, UK Biobank and FinnGen. Cohort selection, diagnostic coding and unmeasured environmental or lifestyle mediators limit causal and population-frequency interpretation.
Show evidence (1 reference)
PMID:40840450 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"glaucoma [47,XXY: 2.5 (2.1–2.9), 47,XYY: 2.4 (2.0–2.8), and 47,XXX: 2.3 (1.4–3.5)]"
Reports the XYY glaucoma association: OR 2.4 (95% CI 2.0–2.8).
Genitourinary 4
Macroorchidism HP:0000053 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macroorchidism (HP:0000053). HP:0000053 is a phenotype from the Human Phenotype Ontology.
Testicular volume exceeded 2 SD in 41/82; most measured testosterone values were age-appropriate. Macroorchidism does not establish precocious puberty or preserved/impaired fertility in an individual.
Show evidence (2 references)
PMID:23810129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Most of the boys had testicular volume that was greater than average for age (>0 SDS) in 64/82 (78%), and significantly above average (>2 SD) in 41/82 (50%)."
Quantifies age-adjusted testicular enlargement.
PMID:23810129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Thirty-nine of 42 boys with XYY (93%) had testosterone levels in the normal range for age and pubic hair Tanner staging."
Shows that testicular enlargement does not imply routine androgen excess.
Oligozoospermia HP:0000798 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oligozoospermia (HP:0000798). HP:0000798 is a phenotype from the Human Phenotype Ontology.
Spermatogenic impairment is documented in selected reproductive-clinic patients, while other men have normal semen parameters. Many normozoospermic men in the series sought ART because of female-factor infertility. The adult biobank PheWAS did not find the infertility association observed for XXY; neither dataset establishes universal infertility in XYY.
Show evidence (1 reference)
PMID:40264980 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The fertility of the male patients varied, and 12 patients had normozoospermia. Two‐thirds of the patients presented oligoasthenozoospermia (7 patients), severe oligoasthenozoospermia (12 patients), and azoospermia (5 patients)."
Records semen findings in 36 couples seeking assisted reproduction, including 32 nonmosaic and four mosaic men. Selection prevents estimation of population infertility penetrance.
Azoospermia HP:0000027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Azoospermia (HP:0000027). HP:0000027 is a phenotype from the Human Phenotype Ontology.
Spermatogenic impairment is documented in selected reproductive-clinic patients, while other men have normal semen parameters. Many normozoospermic men in the series sought ART because of female-factor infertility. The adult biobank PheWAS did not find the infertility association observed for XXY; neither dataset establishes universal infertility in XYY.
Show evidence (1 reference)
PMID:40264980 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The fertility of the male patients varied, and 12 patients had normozoospermia. Two‐thirds of the patients presented oligoasthenozoospermia (7 patients), severe oligoasthenozoospermia (12 patients), and azoospermia (5 patients)."
Records semen findings in 36 couples seeking assisted reproduction, including 32 nonmosaic and four mosaic men. Selection prevents estimation of population infertility penetrance.
Male Infertility HP:0003251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Male infertility (HP:0003251). HP:0003251 is a phenotype from the Human Phenotype Ontology.
Spermatogenic impairment is documented in selected reproductive-clinic patients, while other men have normal semen parameters. Many normozoospermic men in the series sought ART because of female-factor infertility. The adult biobank PheWAS did not find the infertility association observed for XXY; neither dataset establishes universal infertility in XYY.
Show evidence (1 reference)
PMID:40264980 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The fertility of the male patients varied, and 12 patients had normozoospermia. Two‐thirds of the patients presented oligoasthenozoospermia (7 patients), severe oligoasthenozoospermia (12 patients), and azoospermia (5 patients)."
Records semen findings in 36 couples seeking assisted reproduction, including 32 nonmosaic and four mosaic men. Selection prevents estimation of population infertility penetrance.
Head and Neck 2
Macrocephaly HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Head circumference exceeded 2 SD in 28/84. These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population penetrance.
Show evidence (1 reference)
PMID:23810129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Macrocephaly (head circumference >2 SD) was noted in 28/84 (33%), hypotonia in 57/90 (63%), clinodactyly in 47/90 (52%), and hypertelorism in 53/90 (59%)."
Head circumference exceeded 2 SD in 28/84. These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population penetrance.
Macrodontia HP:0001572 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrodontia (HP:0001572). HP:0001572 is a phenotype from the Human Phenotype Ontology.
The reported 22% combines several dental findings and cannot be assigned to macrodontia alone.
Show evidence (1 reference)
PMID:23810129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Dental problems were reported in 22%, including prognathic jaw with underbite and macrodontia."
Identifies macrodontia within a combined dental-problem category, not a 22% macrodontia-specific rate.
Immune 1
Asthma HP:0002099 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Asthma (HP:0002099). HP:0002099 is a phenotype from the Human Phenotype Ontology.
These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population penetrance. The adult genotype-first study also reports an association; the pediatric percentage is not a universal rate.
Show evidence (1 reference)
PMID:23810129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Asthma was diagnosed in 35/89 (39%) of XYY patients"
Documents asthma diagnoses in the pediatric clinical cohort.
Limbs 2
Clinodactyly HP:0030084 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Clinodactyly (HP:0030084). HP:0030084 is a phenotype from the Human Phenotype Ontology.
Observed in 47/90. These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population penetrance.
Show evidence (1 reference)
PMID:23810129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Macrocephaly (head circumference >2 SD) was noted in 28/84 (33%), hypotonia in 57/90 (63%), clinodactyly in 47/90 (52%), and hypertelorism in 53/90 (59%)."
Observed in 47/90. These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population penetrance.
Pes Planus HP:0001763 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pes planus (HP:0001763). HP:0001763 is a phenotype from the Human Phenotype Ontology.
Flat feet were reported; the narrative and table round the proportion differently, so no precise population frequency is assigned.
Show evidence (1 reference)
PMID:23810129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Hypotonia was noted in 57/90 (63%) patients, and flat feet were common (52%)."
Records flat feet in the examined cohort.
Musculoskeletal 2
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Observed in 57/90. These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population penetrance.
Show evidence (1 reference)
PMID:23810129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Macrocephaly (head circumference >2 SD) was noted in 28/84 (33%), hypotonia in 57/90 (63%), clinodactyly in 47/90 (52%), and hypertelorism in 53/90 (59%)."
Observed in 57/90. These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population penetrance.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population penetrance.
Show evidence (1 reference)
PMID:23810129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"| Scoliosis | 9% | 16% | 13% | .36 | 4% |"
Table I reports 13% in the combined clinical cohort, compared with prenatal and postnatal subgroups.
Nervous System 8
Delayed Speech and Language Development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
The 8/11 denominator applies to children above 20 months at the initial assessment, not all XYY births. Follow-up language measures and denominators changed; the uncontrolled series cannot establish benefit from prenatal detection or counseling.
Show evidence (1 reference)
PMID:23034220 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Language delay was detected in 8 out of 11 children older than 20 months."
Records initial language findings in a small, selected prenatal follow-up series.
Specific Learning Disability HP:0001328 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Specific learning disability (HP:0001328). HP:0001328 is a phenotype from the Human Phenotype Ontology.
Learning difficulties vary in severity and domain; neither universal intellectual disability nor uniformly normal learning should be inferred from the karyotype.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Patients may benefit from supplemental or special educational resources if learning disabilities exist."
The clinical review recognizes variable learning disabilities and educational needs.
Attention Deficit Hyperactivity Disorder HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population penetrance.
Show evidence (1 reference)
PMID:23810129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The diagnosis of ADHD was most common: 47/90 (52%) of the combined group (40% in prenatal vs 60% in postnatal, P = .08)."
Documents ADHD diagnoses in the referral cohort; the prenatal/postnatal contrast was not statistically significant.
Autistic Behavior HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
ASD history occurred in 26/90 in the pediatric referral cohort. A genotype-first case-control study found XYY-versus-XY OR 2.4 (95% CI 1.6–3.5), and pooling with iPSYCH gave OR 3.2 (2.3–4.4). Pediatric case versus adult volunteer control ascertainment and age/ancestry differences limit inference. Prenatal/postnatal diagnostic-history differences do not prove that prenatal diagnosis prevents ASD; questionnaire/interview cutoff proportions were not significantly different in the clinical study.
Show evidence (2 references)
PMID:23810129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Other diagnoses included ASDs (26/90 [29%] combined, 11% prenatal vs 40% postnatal, P < .004), anxiety (23/90 [26%]), depression (13%), bipolar disorder (8%), and oppositional defiant disorder (6%)."
Records the observed ASD diagnostic history in a selected clinical cohort.
PMID:39406744 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We observed that both 47, XYY (OR, 3.2; 95% CI, 2.3–4.4) and 47, XXY (OR, 1.8; 95% CI, 1.3–2.4) were associated with increased ASD risk"
The pooled case-control analysis associates XYY with ASD diagnosis relative to XY. This odds ratio is not an ASD prevalence or a gene-specific molecular mechanism.
Tremor HP:0001337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tremor (HP:0001337). HP:0001337 is a phenotype from the Human Phenotype Ontology.
These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population penetrance.
Show evidence (1 reference)
PMID:23810129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Mild resting and/or intention tremors were found in 39/90 (43%) patients."
Documents tremor and its generally mild character.
Tics HP:0100033 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tics (HP:0100033). HP:0100033 is a phenotype from the Human Phenotype Ontology.
These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population penetrance.
Show evidence (1 reference)
PMID:23810129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Mild verbal and/or motor tics were noted in 16/89 (18%) boys."
Documents verbal or motor tics in the cohort.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population penetrance. Convulsive or otherwise suspicious episodes warrant evaluation; this proportion does not justify universal screening EEG.
Show evidence (1 reference)
PMID:23810129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Seizure activity had occurred in 12/89 (13%), all but 1 diagnosed postnatally (prenatal vs postnatal, P = .03)."
Records seizure history with its ascertainment imbalance.
Sleep Apnea HP:0010535 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep apnea (HP:0010535). HP:0010535 is a phenotype from the Human Phenotype Ontology.
Association in an adult genotype-first PheWAS of 1,108 XYY participants across MVP, UK Biobank and FinnGen. Cohort selection, diagnostic coding and unmeasured environmental or lifestyle mediators limit causal and population-frequency interpretation.
Show evidence (1 reference)
PMID:40840450 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Examples of other conditions that were significantly more prominent in all three SCT groups include obesity (MIM: 601665), type 2 diabetes (MIM: 125853), dermatophytosis, atopic dermatitis (MIM: 603165), asthma and chronic airway obstruction (MIM: 600807), sleep apnea (MIM: 107650)"
Reports adult metabolic and respiratory associations in all three sex-chromosome trisomies, including XYY.
Growth 2
Tall Stature HP:0000098 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tall stature (HP:0000098). HP:0000098 is a phenotype from the Human Phenotype Ontology.
Mean height was approximately 1 SD above average, but only 13/86 met the 2-SD threshold. Height was age-dependent and was nearer average below six years. No universal frequency band is assigned from this referral cohort.
Show evidence (2 references)
PMID:23810129 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Most boys (67/86, 78%) were taller than the mean and 13 boys (15%) were ≥2 SD above the mean."
Distinguishes above-average height from tall stature at the 2-SD threshold.
PMID:40388606 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"By examining 1,225 individuals with SCAs identified among 928,605 biobank participants, we found that increased Y chromosome dosage conferred a larger effect on height than increased X chromosome dosage"
Adult genotype-first analysis supports a sex-chromosome dosage contribution to height. It does not isolate SHOX as the sole mediator; male sex hormone status was modeled with a proxy rather than measured hormone concentrations.
Obesity HP:0001513 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Obesity (HP:0001513). HP:0001513 is a phenotype from the Human Phenotype Ontology.
Association in an adult genotype-first PheWAS of 1,108 XYY participants across MVP, UK Biobank and FinnGen. Cohort selection, diagnostic coding and unmeasured environmental or lifestyle mediators limit causal and population-frequency interpretation.
Show evidence (1 reference)
PMID:40840450 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Examples of other conditions that were significantly more prominent in all three SCT groups include obesity (MIM: 601665), type 2 diabetes (MIM: 125853), dermatophytosis, atopic dermatitis (MIM: 603165), asthma and chronic airway obstruction (MIM: 600807), sleep apnea (MIM: 107650)"
Reports adult metabolic and respiratory associations in all three sex-chromosome trisomies, including XYY.
🧬

Genetic Associations

4
47,XYY chromosome complement (Causal whole-chromosome gain)
relationship_type: CAUSATIVE
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Jacobs syndrome is not an inherited condition and most commonly arises during meiosis II in the father, at which time an extra Y chromosome is attributed to the resultant sperm."
Describes the usual sporadic paternal meiotic origin of the extra Y chromosome.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"An alternate and less common form of this condition is 46,XY/47,XYY mosaicism, which arises during early embryonic development."
Distinguishes postzygotic mosaicism from the usual nonmosaic complement.
SHOX (Candidate dosage contribution to increased stature)
Gene: SHOX hgnc:10853 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SHOX (hgnc:10853). hgnc:10853 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:23810129 SUPPORT INDIRECT BACKGROUND Human Clinical
"For example, tall stature is related to the extra copy of the short stature homeobox gene40 in the pseudoautosomal region of the extra Y chromosome."
The authors attribute increased stature to extra SHOX dosage using prior biological evidence; this cohort did not experimentally manipulate SHOX.
PMID:40388606 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"By examining 1,225 individuals with SCAs identified among 928,605 biobank participants, we found that increased Y chromosome dosage conferred a larger effect on height than increased X chromosome dosage"
Adult genotype-first analysis supports a sex-chromosome dosage contribution to height. It does not isolate SHOX as the sole mediator; male sex hormone status was modeled with a proxy rather than measured hormone concentrations.
UTY (Experimental expression regulator)
Gene: UTY hgnc:12638 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is UTY (hgnc:12638). hgnc:12638 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:40494628 SUPPORT DIRECT PRIMARY RESULT In Vitro
"KDM6A mRNAs and protein levels were significantly decreased in multiple 47,XYY UTY−/− iPSC clones"
CRISPR disruption of UTY reduced KDM6A RNA and protein in XYY iPSCs. Male-cell UTY overexpression also increased KDM6A; these perturbations support an expression dependency without identifying a direct promoter mechanism.
KDM6A (Dosage-responsive X homolog in cultured XYY cells)
Gene: KDM6A hgnc:12637 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KDM6A (hgnc:12637). hgnc:12637 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:40494628 SUPPORT DIRECT PRIMARY RESULT In Vitro
"The histone demethylase KDM6A and USP9X follow the same expression trend of their Y homologs (UTY and USP9Y) and are upregulated in iPSCs and NSCs."
Documents the higher KDM6A expression state in patient-derived pluripotent and neural stem cells.
PMID:40494628 SUPPORT DIRECT PRIMARY RESULT In Vitro
"KDM6A mRNAs and protein levels were significantly decreased in multiple 47,XYY UTY−/− iPSC clones"
CRISPR disruption of UTY reduced KDM6A RNA and protein in XYY iPSCs. Male-cell UTY overexpression also increased KDM6A; these perturbations support an expression dependency without identifying a direct promoter mechanism.
💊

Medical Actions

7
Speech and Language Therapy
Action: Speech Language TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Speech Language Therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. NCIT:C159273
Platform: Behavioral / lifestyle
Offer assessment and individualized speech-language intervention when delay or communication difficulties are present.
Mechanism Target:
Delayed Speech and Language Development — Speech-language therapy addresses the communication phenotype; it does not alter chromosome dosage.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Boys who are diagnosed with Jacobs syndrome may benefit from speech therapy and behavioral interventions from qualified professionals."
Clinical review supports individualized speech-language and behavioral services.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Boys who are diagnosed with Jacobs syndrome may benefit from speech therapy and behavioral interventions from qualified professionals."
Clinical review supports individualized speech-language and behavioral services.
Developmental and Educational Support
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Behavioral / lifestyle
Assess language, learning, attention and social-communication needs and provide individualized educational and behavioral support.
Mechanism Target:
Specific Learning Disability — Educational resources address assessed learning needs.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Patients may benefit from supplemental or special educational resources if learning disabilities exist."
Supports educational assistance matched to assessed needs.
Show evidence (2 references)
PMID:23810129 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Neurodevelopmental screenings also should be performed given the increased risk for developmental delays, language disorders, ADHD, and ASDs."
The clinical cohort authors recommend developmental screening; this is a care recommendation rather than an intervention efficacy trial.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Patients may benefit from supplemental or special educational resources if learning disabilities exist."
Supports educational assistance matched to assessed needs.
Occupational Therapy
Action: Occupational TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Occupational Therapy (NCIT:C121351). NCIT:C121351 is a clinical intervention from the NCI Thesaurus. NCIT:C121351
Consider occupational therapy for functionally important hypotonia, tremor, handwriting or self-care difficulty.
Mechanism Target:
Hypotonia — Occupational therapy supports function affected by hypotonia without correcting the chromosome complement.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Occupational therapy may be needed if hypotonia is present."
Recognizes hypotonia-related occupational needs.
Tremor — Symptomatic occupational support is considered when tremor impairs handwriting or self-care.
Show evidence (1 reference)
PMID:23810129 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Tremor is usually mild, however, if it impairs handwriting, occupational or self-care skills (ie, eating, dressing), then occupational therapy evaluation, educational/workplace supports, and medication treatments can be considered."
Recommends symptom- and function-directed tremor support rather than treatment of every observed tremor.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Occupational therapy may be needed if hypotonia is present."
Recognizes hypotonia-related occupational needs.
PMID:23810129 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Tremor is usually mild, however, if it impairs handwriting, occupational or self-care skills (ie, eating, dressing), then occupational therapy evaluation, educational/workplace supports, and medication treatments can be considered."
Recommends symptom- and function-directed tremor support rather than treatment of every observed tremor.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Explain the chromosome finding, variable expression, prenatal screening versus diagnosis, educational needs and reproductive options.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Families who receive a prenatal diagnosis of 47,XYY syndrome should receive genetic counseling to aid in their understanding of the disease."
Supports informed counseling after prenatal diagnosis.
Symptom-Directed Medical Follow-up
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Assess and treat asthma and dental problems; evaluate clinically suspicious seizures and address other documented comorbidities.
Mechanism Target:
Asthma — Clinical treatment addresses coexisting asthma; no XYY-specific drug response is established.
Show evidence (1 reference)
PMID:23810129 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Once the diagnosis is made, children should be screened carefully and treated for asthma and dental problems."
Supports clinical assessment of recurrent pediatric comorbidities.
Show evidence (2 references)
PMID:23810129 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Once the diagnosis is made, children should be screened carefully and treated for asthma and dental problems."
Supports clinical assessment of recurrent pediatric comorbidities.
PMID:23810129 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"neurologic evaluation and possible electroencephalogram should be considered for atypical staring spells, significant sleep disturbance, or significant unexplained behavioral dysregulation."
Supports EEG when clinical features suggest seizures; it is not a recommendation for universal EEG.
Glaucoma Assessment
Action: Eye ExaminationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Eye Examination (NCIT:C38060). NCIT:C38060 is a clinical intervention from the NCI Thesaurus. NCIT:C38060
Consider ophthalmic assessment in adult care in light of the reported association with glaucoma.
Show evidence (1 reference)
PMID:40840450 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Therefore, glaucoma may be an important age-related SCT comorbidity for which surveillance in individuals with SCT is warranted."
The PheWAS authors propose surveillance based on the adult association.
Individualized Fertility Evaluation and Assisted Reproduction
Action: In Vitro FertilizationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is In Vitro Fertilization (NCIT:C16580). NCIT:C16580 is a clinical intervention from the NCI Thesaurus. NCIT:C16580
For reproductive difficulty, assess semen parameters and reproductive hormones and discuss assisted reproduction where appropriate.
Mechanism Target:
Male Infertility — This link represents IVF/ICSI as an assisted reproductive intervention for selected infertile couples. The evaluation tests themselves are diagnostic and do not treat infertility.
Show evidence (1 reference)
PMID:40264980 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"| Live birth rate (%) a , b | 48.89 (22/45) | 50.00 (19/38) | 42.86 (3/7) | >0.9999 |"
The small retrospective ART study observed 19 live-birth events in 38 PGT transfer cycles and three in seven conventional IVF/ICSI transfer cycles, demonstrating feasibility in selected couples.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Men with 47,XYY who are being seen for infertility should receive a semen analysis, testicular ultrasound, and bloodwork to measure reproductive hormones."
Supports evaluation of men presenting with infertility.
PMID:40264980 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"| Live birth rate (%) a , b | 48.89 (22/45) | 50.00 (19/38) | 42.86 (3/7) | >0.9999 |"
The small retrospective ART study observed 19 live-birth events in 38 PGT transfer cycles and three in seven conventional IVF/ICSI transfer cycles, demonstrating feasibility in selected couples.
🔬

Diagnosis

2
Postnatal Karyotyping (47,XYY or mosaic 46,XY/47,XYY)
Chromosome analysis confirms the extra Y chromosome; interpretation of mosaicism depends on the sampled tissue and number of cells analyzed.
Karyotyping NCIT:C16768 NCI Thesaurus (NCIT)
Clinical appearance alone is insufficient; prenatal ascertainment is not proof of a better outcome caused by earlier diagnosis.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"After birth, diagnosis is made using karyotype analysis from a sample of the patient's blood."
Supports blood karyotype confirmation of the chromosome complement.
Prenatal Screening and Cytogenetic Confirmation
Cell-free DNA testing screens for sex-chromosome aneuploidy. A positive screen requires appropriate diagnostic cytogenetic confirmation; the cited study used amniocentesis.
Karyotyping NCIT:C16768 NCI Thesaurus (NCIT)
Only one of two XYY-positive screens in this series had diagnostic follow-up. The resulting 1/1 confirmed-positive observation does not establish general 100% predictive value, and untested screen-negative pregnancies prevent estimation of sensitivity.
Show evidence (1 reference)
PMID:32188487 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Karyotyping by amniocentesis was selected as a method to confirm the NIPT results."
Distinguishes a screening result from cytogenetic confirmation.
📊

Prevalence

1
Male live births
Birth Prevalence 100.0 per 100,000 >1 in 1,000 (births)
Approximate male-live-birth prevalence of 1 in 1,000, reported as background in a prenatal follow-up study. Clinical underrecognition does not imply uniformly normal development. A separate genotype-first adult study found no recorded XYY diagnosis in 98.6% of its 1,108 XYY participants; that cohort-specific documentation fraction is not a birth-prevalence estimate.
Show evidence (2 references)
PMID:23034220 SUPPORT DIRECT BACKGROUND Human Clinical
"47, XYY karyotype occurs in about one out of 1,000 newborn males"
Provides the ~1 in 1,000 male birth prevalence.
PMID:40840450 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We identified 2,769 individuals with SCTs (47,XXY: 1,319; 47,XYY: 1,108; and 47,XXX: 342), most of whom had no documented clinical diagnosis (47,XXY: 73.8%; 47,XYY: 98.6%; and 47,XXX: 93.6%)."
Records underrecognition among genotyped adult participants, separately from male birth prevalence.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from 47,XYY Syndrome:

Klinefelter Syndrome
Overlapping Features Another sex-chromosome trisomy that may present with tall stature and learning or reproductive difficulties.
Distinguishing Features
  • 47,XXY rather than 47,XYY on chromosome analysis; small testes and hypogonadism are more characteristic of XXY.
Show evidence (1 reference)
PMID:40840450 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Notable exceptions to this include infertility, gynecomastia, and osteoporosis, which were associated with 47,XXY (both diagnosed and undiagnosed) but not 47,XYY."
Distinguishes adult comorbidity profiles in the same genotype-first study without implying these findings are impossible in XYY.
Sotos Syndrome
Overlapping Features Overgrowth, macrocephaly, learning difficulties and hypotonia may overlap.
Distinguishing Features
  • An NSD1-related disorder rather than an extra Y chromosome; molecular and cytogenetic testing distinguish the diagnoses.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Hallmark features include excessive growth during childhood, macrocephaly, learning disabilities, hypotonia, and seizure disorders."
The Sotos differential paragraph identifies the overlapping overgrowth and developmental features.
Marfan Syndrome
Overlapping Features Tall stature can overlap, with connective-tissue manifestations directing the differential assessment.
Distinguishing Features
  • Aortic-root disease and other connective-tissue findings favor Marfan syndrome; targeted evaluation and genetic testing are used when indicated. A normal echocardiogram alone does not exclude it.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Marfan syndrome is a connective tissue disorder that, in contrast to Jacobs syndrome, often presents with cardiac abnormalities such as aortic root dilatation and mitral valve prolapse."
Identifies aortic and valvular findings relevant to the differential.
🔬

Clinical Trials

1
NCT07718997 PHASE_I RECRUITING
TRICXY-SMT is a single-group, multiple-baseline feasibility study of ten sessions of online Social Management Training in people with sex-chromosome aneuploidies, including XYY. Mental health is the primary outcome, with executive and social/autism measures as secondary outcomes.
Show evidence (2 references)
clinicaltrials:NCT07718997 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"We will examine is Social Management Training, a 10-session group-based psychosocial intervention will improve the primary outcome mental health, and secondary outcomes executive functions and autism symptoms, in a multiple baseline design with 3 pre-measurement points and 3 post-measurement..."
Registry description of the planned intervention and outcomes, not evidence of clinical efficacy.
url:https://clinicaltrials.gov/api/v2/studies/NCT07718997 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Genetically confirmed SCA. Participants provide medical confirmation of diagnosis, unless participants are recruited via Frambu (where medical confirmation is available in the user registry for KS 47,XXY karyotype; Jacobs 47,XYY karyotype; Triple X, 47,XXX karyotype; and Turner 45,X karyotype)."
The full protocol explicitly includes XYY alongside other sex-chromosome aneuploidies.
🧫

Experimental Models

1
Patient-derived XYY pluripotent and neural stem-cell cultures IPSC_DERIVED_MODEL
Fibroblasts from three nonmosaic XYY donors were reprogrammed to iPSCs and differentiated to neural stem cells, with XY comparisons. Transcriptomic analyses span fibroblasts, pluripotent cells and neural stem cells; UTY perturbation experiments use pluripotent cultures.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:40494628
Pathograph links
Y-Linked Gene Overexpression measures fidelity: low observes: cellular RNA sequencing compares non-pseudoautosomal Y-linked expression in XYY and XY cultures.
Limitations: Only three XYY donor backgrounds were studied. Clones are not independent patients; pluripotent and neural stem cells do not establish mature-neuron or behavioral phenotypes. UTY knockout is an experimental perturbation, not a clinical rescue.
Readouts
Y-linked differential transcript abundance
Direction: INCREASED
Interpretation: Direction is relative to the matched comparison used in the experiment; the knockout readout is relative to UTY-intact XYY iPSCs.
Show evidence (1 reference)
PMID:40494628 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Importantly, all NPY DEGs were upregulated in the three cell types except for MXRA5Y, a pseudogene of the X-linked gene MXRA5, which was downregulated in fibroblasts"
RNA sequencing of patient-derived fibroblasts, iPSCs and neural stem cells identifies predominantly increased non-pseudoautosomal Y-linked expression. The claim concerns differentially expressed genes, not uniform doubling of every Y gene.
Show evidence (1 reference)
PMID:40494628 SUPPORT DIRECT PRIMARY RESULT In Vitro
"Importantly, all NPY DEGs were upregulated in the three cell types except for MXRA5Y, a pseudogene of the X-linked gene MXRA5, which was downregulated in fibroblasts"
RNA sequencing of patient-derived fibroblasts, iPSCs and neural stem cells identifies predominantly increased non-pseudoautosomal Y-linked expression. The claim concerns differentially expressed genes, not uniform doubling of every Y gene.
Cell-Type-Specific Transcriptional Dysregulation measures fidelity: low observes: cellular RNA sequencing identifies distinct expression signatures in fibroblast, pluripotent and neural stem-cell contexts.
Limitations: Only three XYY donor backgrounds were studied. Clones are not independent patients; pluripotent and neural stem cells do not establish mature-neuron or behavioral phenotypes. UTY knockout is an experimental perturbation, not a clinical rescue.
Readouts
Cell-type-specific differential expression
Direction: ALTERED
Interpretation: Direction is relative to the matched comparison used in the experiment; the knockout readout is relative to UTY-intact XYY iPSCs.
Show evidence (1 reference)
PMID:40494628 SUPPORT DIRECT PRIMARY RESULT In Vitro
"The differential expression analysis (DEA) performed on 47,XYY and 46,XY karyotypes identified 1838, 1789, and 4413 differentially expressed genes (DEGs) in fibroblasts, iPSCs and NSCs, respectively"
Establishes broad, cell-context-dependent transcriptional differences, without proving that UTY alone causes the entire signature or that a specific clinical manifestation follows.
Show evidence (1 reference)
PMID:40494628 SUPPORT DIRECT PRIMARY RESULT In Vitro
"The differential expression analysis (DEA) performed on 47,XYY and 46,XY karyotypes identified 1838, 1789, and 4413 differentially expressed genes (DEGs) in fibroblasts, iPSCs and NSCs, respectively"
Establishes broad, cell-context-dependent transcriptional differences, without proving that UTY alone causes the entire signature or that a specific clinical manifestation follows.
UTY-Dependent KDM6A Upregulation perturbs fidelity: low observes: cellular CRISPR disruption of UTY in XYY iPSCs tests its contribution to KDM6A RNA and protein abundance.
Limitations: Only three XYY donor backgrounds were studied. Clones are not independent patients; pluripotent and neural stem cells do not establish mature-neuron or behavioral phenotypes. UTY knockout is an experimental perturbation, not a clinical rescue.
Readouts
KDM6A RNA and protein after UTY knockout
Direction: DECREASED
Interpretation: Direction is relative to the matched comparison used in the experiment; the knockout readout is relative to UTY-intact XYY iPSCs.
Show evidence (1 reference)
PMID:40494628 SUPPORT DIRECT PRIMARY RESULT In Vitro
"KDM6A mRNAs and protein levels were significantly decreased in multiple 47,XYY UTY−/− iPSC clones"
CRISPR disruption of UTY reduced KDM6A RNA and protein in XYY iPSCs. Male-cell UTY overexpression also increased KDM6A; these perturbations support an expression dependency without identifying a direct promoter mechanism.
Show evidence (1 reference)
PMID:40494628 SUPPORT DIRECT PRIMARY RESULT In Vitro
"KDM6A mRNAs and protein levels were significantly decreased in multiple 47,XYY UTY−/− iPSC clones"
CRISPR disruption of UTY reduced KDM6A RNA and protein in XYY iPSCs. Male-cell UTY overexpression also increased KDM6A; these perturbations support an expression dependency without identifying a direct promoter mechanism.
Companion embryonic stem-cell overexpression experiments show context-dependent UTY–KDM6A regulation. No clinical treatment effect, mature-neuron functional assay or proof of a gene-specific autism mechanism follows from this model.
{ }

Source YAML

click to show 
name: 47,XYY Syndrome
creation_date: '2026-08-22T00:00:00Z'
description: >-
  47,XYY syndrome is a sex-chromosome aneuploidy with an additional Y chromosome, usually arising sporadically
  from paternal meiotic nondisjunction; 46,XY/47,XYY mosaicism can arise postzygotically. It occurs in
  approximately 1 in 1,000 male live births and is often unrecognized clinically. Expression varies from
  few apparent difficulties to language, learning, attention and social-communication impairments. Average
  height is increased, with variably present macrocephaly, macroorchidism, hypotonia, hypertelorism, clinodactyly
  and tremor. Asthma and seizures occur in clinical cohorts; genotype-first adult cohorts also associate
  XYY with venous disease, glaucoma and metabolic morbidity. Most measured childhood testosterone values
  are normal, and neither behavioral difficulties nor infertility is universal. Better average cognitive
  outcomes in prenatally ascertained cohorts are subject to referral and age differences and do not demonstrate
  a causal benefit of prenatal diagnosis.
category: Genetic
synonyms:
- XYY syndrome
- Jacobs syndrome
- 47,XYY karyotype
- double Y syndrome
parents:
- chromosomal disorder
disease_term:
  preferred_term: 47,XYY syndrome
  term:
    id: MONDO:0019339
    label: 47,XYY syndrome
prevalence:
- population: Male live births
  measure_type: BIRTH_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 100.0
  notes: >-
    Approximate male-live-birth prevalence of 1 in 1,000, reported as background in a prenatal follow-up
    study. Clinical underrecognition does not imply uniformly normal development. A separate genotype-first
    adult study found no recorded XYY diagnosis in 98.6% of its 1,108 XYY participants; that cohort-specific
    documentation fraction is not a birth-prevalence estimate.
  evidence:
  - reference: PMID:23034220
    reference_title: >-
      Early manifestations in a cohort of children prenatally diagnosed with 47,XYY. Role of multidisciplinary
      counseling for parental guidance and prevention of aggressive behavior.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 47, XYY karyotype occurs in about one out of 1,000 newborn males
    explanation: Provides the ~1 in 1,000 male birth prevalence.
    quote_role: BACKGROUND
    directness: DIRECT
  - reference: PMID:40840450
    reference_title: >-
      Phenome-wide association study of male and female sex chromosome trisomies in 1.5 million participants
      of MVP, FinnGen, and UK Biobank.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      We identified 2,769 individuals with SCTs (47,XXY: 1,319; 47,XYY: 1,108; and 47,XXX: 342), most
      of whom had no documented clinical diagnosis (47,XXY: 73.8%; 47,XYY: 98.6%; and 47,XXX: 93.6%).
    explanation: Records underrecognition among genotyped adult participants, separately from male birth prevalence.
pathophysiology:
- name: Additional Y Chromosome
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    A whole additional Y chromosome creates the 47,XYY complement and increases genomic copy number of
    Y-linked and shared pseudoautosomal loci.
  evidence:
  - &id009
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/
    reference_title: Jacobs Syndrome - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Jacobs syndrome is not an inherited condition and most commonly arises during meiosis II in the
      father, at which time an extra Y chromosome is attributed to the resultant sperm.
    explanation: Describes the usual sporadic paternal meiotic origin of the extra Y chromosome.
  downstream:
  - target: Increased Pseudoautosomal Gene Copy Number
    causal_link_type: DIRECT
    description: The extra Y adds a third copy of loci shared by the X and Y pseudoautosomal regions.
    evidence:
    - &id001
      reference: PMID:40494628
      reference_title: >-
        An iPSC-based model of 47,XYY Jacobs syndrome reveals a DNA methylation-independent transcriptional
        dysregulation shared with male X aneuploid cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        Biallelic expressed SNPs mapping to the PAR1 region in JS samples were distributed around the
        values 30% and 60%, suggesting that the X and the two identical Y Chromosomes contribute similarly
        to the total expression level of the PAR1 transcripts.
      explanation: >-
        Allele-specific RNA measurements support biallelic PAR1 expression consistent with additional
        Y-derived dosage. The two identical Y copies are not individually resolved, and SHOX expression
        in growth plates was not measured.
  - target: Y-Linked Gene Overexpression
    causal_link_type: DIRECT
    description: >-
      An extra Y is associated with predominantly increased expression of Y-linked genes in the studied
      patient-derived cells; dosage compensation is gene- and cell-specific.
    evidence:
    - &id003
      reference: PMID:40494628
      reference_title: >-
        An iPSC-based model of 47,XYY Jacobs syndrome reveals a DNA methylation-independent transcriptional
        dysregulation shared with male X aneuploid cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        Importantly, all NPY DEGs were upregulated in the three cell types except for MXRA5Y, a pseudogene
        of the X-linked gene MXRA5, which was downregulated in fibroblasts
      explanation: >-
        RNA sequencing of patient-derived fibroblasts, iPSCs and neural stem cells identifies predominantly
        increased non-pseudoautosomal Y-linked expression. The claim concerns differentially expressed
        genes, not uniform doubling of every Y gene.
  - target: Cell-Type-Specific Transcriptional Dysregulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The XYY complement is associated with broad transcriptional changes beyond the sex chromosomes;
      the responsible trans-regulatory intermediates are incompletely resolved.
    evidence:
    - &id005
      reference: PMID:40494628
      reference_title: >-
        An iPSC-based model of 47,XYY Jacobs syndrome reveals a DNA methylation-independent transcriptional
        dysregulation shared with male X aneuploid cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        The differential expression analysis (DEA) performed on 47,XYY and 46,XY karyotypes identified
        1838, 1789, and 4413 differentially expressed genes (DEGs) in fibroblasts, iPSCs and NSCs, respectively
      explanation: >-
        Establishes broad, cell-context-dependent transcriptional differences, without proving that UTY
        alone causes the entire signature or that a specific clinical manifestation follows.
- name: Increased Pseudoautosomal Gene Copy Number
  biological_scale: MOLECULAR
  description: >-
    Nonmosaic XYY cells carry three copies of shared pseudoautosomal genes, including SHOX. Allelic expression
    analyses in cultured cells show biallelic expression ratios consistent with additional Y-derived dosage
    and gene-specific expression differences. Identical Y copies are not individually resolved.
  genes:
  - preferred_term: SHOX
    term:
      id: hgnc:10853
      label: SHOX
  evidence:
  - *id001
  downstream:
  - target: SHOX Dosage Contribution to Linear Growth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Additional SHOX dosage is a proposed mediator of increased stature, supported by established SHOX
      biology and human chromosome-dosage associations rather than an XYY growth-plate perturbation experiment.
    evidence:
    - &id002
      reference: PMID:23810129
      reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: >-
        For example, tall stature is related to the extra copy of the short stature homeobox gene40 in
        the pseudoautosomal region of the extra Y chromosome.
      explanation: >-
        The authors attribute increased stature to extra SHOX dosage using prior biological evidence;
        this cohort did not experimentally manipulate SHOX.
- name: SHOX Dosage Contribution to Linear Growth
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The third SHOX copy is a plausible contributor to increased linear growth. Human height associations
    support a dosage effect, but do not establish SHOX as the only mediator or quantify its expression
    in XYY growth plates.
  genes:
  - preferred_term: SHOX
    term:
      id: hgnc:10853
      label: SHOX
  evidence:
  - *id002
  - &id006
    reference: PMID:40388606
    reference_title: 'X and Y gene dosage effects are primary contributors to human sexual dimorphism: The case of height.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: >-
      By examining 1,225 individuals with SCAs identified among 928,605 biobank participants, we found
      that increased Y chromosome dosage conferred a larger effect on height than increased X chromosome
      dosage
    explanation: >-
      Adult genotype-first analysis supports a sex-chromosome dosage contribution to height. It does not
      isolate SHOX as the sole mediator; male sex hormone status was modeled with a proxy rather than
      measured hormone concentrations.
  notes: >-
    The 2025 study estimates a 3.1-cm contrast between modeled Y and inactive-X contributions, not a 3.1-cm
    XYY-versus-XY effect. Its binary male-hormone proxy does not provide complete endocrine adjustment.
  downstream:
  - target: Tall Stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      SHOX dosage may contribute to increased linear growth; downstream growth-plate effects were not
      directly measured in these XYY cohorts.
    evidence:
    - *id002
- name: Y-Linked Gene Overexpression
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Most differentially expressed non-pseudoautosomal Y genes are increased in XYY fibroblasts, iPSCs
    and neural stem cells. X-homolog responses differ by gene pair; a universal compensatory or twofold-expression
    rule is unsupported.
  genes:
  - preferred_term: UTY
    term:
      id: hgnc:12638
      label: UTY
  biological_processes:
  - preferred_term: gene expression
    term:
      id: GO:0010467
      label: gene expression
    modifier: INCREASED
  evidence:
  - *id003
  downstream:
  - target: UTY-Dependent KDM6A Upregulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      UTY perturbation changes KDM6A expression in the studied male pluripotent cells, but a direct versus
      indirect regulatory route is unresolved.
    evidence:
    - &id004
      reference: PMID:40494628
      reference_title: >-
        An iPSC-based model of 47,XYY Jacobs syndrome reveals a DNA methylation-independent transcriptional
        dysregulation shared with male X aneuploid cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: KDM6A mRNAs and protein levels were significantly decreased in multiple 47,XYY UTY−/− iPSC clones
      explanation: >-
        CRISPR disruption of UTY reduced KDM6A RNA and protein in XYY iPSCs. Male-cell UTY overexpression
        also increased KDM6A; these perturbations support an expression dependency without identifying
        a direct promoter mechanism.
- name: UTY-Dependent KDM6A Upregulation
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    In XYY iPSCs, increased KDM6A expression depends in part on UTY. UTY knockout reduces KDM6A RNA and
    protein, whereas UTY overexpression increases KDM6A in male embryonic stem cells. Equivalent induction
    was not observed in the tested female cell line.
  genes:
  - preferred_term: UTY
    term:
      id: hgnc:12638
      label: UTY
  - preferred_term: KDM6A
    term:
      id: hgnc:12637
      label: KDM6A
  evidence:
  - &id010
    reference: PMID:40494628
    reference_title: >-
      An iPSC-based model of 47,XYY Jacobs syndrome reveals a DNA methylation-independent transcriptional
      dysregulation shared with male X aneuploid cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      The histone demethylase KDM6A and USP9X follow the same expression trend of their Y homologs (UTY
      and USP9Y) and are upregulated in iPSCs and NSCs.
    explanation: Documents the higher KDM6A expression state in patient-derived pluripotent and neural stem cells.
  - *id004
  notes: >-
    The molecular dependency is experimentally supported in cultured cells. The study does not establish
    changed histone-demethylase activity, a direct promoter interaction, clinical causation, or therapeutic
    rescue. UTY siRNA cross-reacted with KDM6A, so the CRISPR and overexpression experiments are the stronger
    support.
- name: Cell-Type-Specific Transcriptional Dysregulation
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Patient-derived XYY fibroblasts, iPSCs and neural stem cells show distinct widespread transcriptional
    changes, including autosomal loci. Some signatures overlap XXY cells. Expression and enrichment results
    nominate mechanisms for investigation without demonstrating a specific neuronal functional deficit.
  biological_processes:
  - preferred_term: regulation of DNA-templated transcription
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
  evidence:
  - *id005
  notes: >-
    The study derives XYY cultures from three patient donors; clone counts are not independent patient
    counts. GO enrichment does not prove altered axon guidance or neuronal migration. Only 63 differential
    methylation regions were detected in iPSCs versus 4,197 in fibroblasts, so limited methylation changes
    in iPSCs do not establish methylation independence in every tissue. No causal edge to autism or language
    impairment is asserted from these experiments.
phenotypes:
- name: Macrocephaly
  category: Craniofacial
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Macrocephaly (head circumference >2 SD) was noted in 28/84 (33%), hypotonia in 57/90 (63%), clinodactyly
      in 47/90 (52%), and hypertelorism in 53/90 (59%).
    explanation: >-
      Head circumference exceeded 2 SD in 28/84. These are observations in a specialty-clinic cohort of
      90 nonmosaic males and do not estimate population penetrance.
  notes: >-
    Head circumference exceeded 2 SD in 28/84. These are observations in a specialty-clinic cohort of
    90 nonmosaic males and do not estimate population penetrance.
- name: Hypotonia
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Macrocephaly (head circumference >2 SD) was noted in 28/84 (33%), hypotonia in 57/90 (63%), clinodactyly
      in 47/90 (52%), and hypertelorism in 53/90 (59%).
    explanation: >-
      Observed in 57/90. These are observations in a specialty-clinic cohort of 90 nonmosaic males and
      do not estimate population penetrance.
  notes: >-
    Observed in 57/90. These are observations in a specialty-clinic cohort of 90 nonmosaic males and do
    not estimate population penetrance.
- name: Clinodactyly
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Clinodactyly
    term:
      id: HP:0030084
      label: Clinodactyly
  evidence:
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Macrocephaly (head circumference >2 SD) was noted in 28/84 (33%), hypotonia in 57/90 (63%), clinodactyly
      in 47/90 (52%), and hypertelorism in 53/90 (59%).
    explanation: >-
      Observed in 47/90. These are observations in a specialty-clinic cohort of 90 nonmosaic males and
      do not estimate population penetrance.
  notes: >-
    Observed in 47/90. These are observations in a specialty-clinic cohort of 90 nonmosaic males and do
    not estimate population penetrance.
- name: Hypertelorism
  category: Craniofacial
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Macrocephaly (head circumference >2 SD) was noted in 28/84 (33%), hypotonia in 57/90 (63%), clinodactyly
      in 47/90 (52%), and hypertelorism in 53/90 (59%).
    explanation: >-
      Observed in 53/90. These are observations in a specialty-clinic cohort of 90 nonmosaic males and
      do not estimate population penetrance.
  notes: >-
    Observed in 53/90. These are observations in a specialty-clinic cohort of 90 nonmosaic males and do
    not estimate population penetrance.
- name: Tall Stature
  category: Growth
  phenotype_term:
    preferred_term: Tall stature
    term:
      id: HP:0000098
      label: Tall stature
  evidence:
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Most boys (67/86, 78%) were taller than the mean and 13 boys (15%) were ≥2 SD above the mean.
    explanation: Distinguishes above-average height from tall stature at the 2-SD threshold.
  - *id006
  notes: >-
    Mean height was approximately 1 SD above average, but only 13/86 met the 2-SD threshold. Height was
    age-dependent and was nearer average below six years. No universal frequency band is assigned from
    this referral cohort.
- name: Macroorchidism
  category: Reproductive
  phenotype_term:
    preferred_term: Macroorchidism
    term:
      id: HP:0000053
      label: Macroorchidism
  evidence:
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Most of the boys had testicular volume that was greater than average for age (>0 SDS) in 64/82 (78%),
      and significantly above average (>2 SD) in 41/82 (50%).
    explanation: Quantifies age-adjusted testicular enlargement.
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Thirty-nine of 42 boys with XYY (93%) had testosterone levels in the normal range for age and pubic
      hair Tanner staging.
    explanation: Shows that testicular enlargement does not imply routine androgen excess.
  notes: >-
    Testicular volume exceeded 2 SD in 41/82; most measured testosterone values were age-appropriate.
    Macroorchidism does not establish precocious puberty or preserved/impaired fertility in an individual.
- name: Delayed Speech and Language Development
  category: Developmental
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:23034220
    reference_title: >-
      Early manifestations in a cohort of children prenatally diagnosed with 47,XYY. Role of multidisciplinary
      counseling for parental guidance and prevention of aggressive behavior.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Language delay was detected in 8 out of 11 children older than 20 months.
    explanation: Records initial language findings in a small, selected prenatal follow-up series.
  notes: >-
    The 8/11 denominator applies to children above 20 months at the initial assessment, not all XYY births.
    Follow-up language measures and denominators changed; the uncontrolled series cannot establish benefit
    from prenatal detection or counseling.
- name: Specific Learning Disability
  category: Developmental
  phenotype_term:
    preferred_term: Specific learning disability
    term:
      id: HP:0001328
      label: Specific learning disability
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/
    reference_title: Jacobs Syndrome - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Patients may benefit from supplemental or special educational resources if learning disabilities exist.
    explanation: The clinical review recognizes variable learning disabilities and educational needs.
  notes: >-
    Learning difficulties vary in severity and domain; neither universal intellectual disability nor uniformly
    normal learning should be inferred from the karyotype.
- name: Attention Deficit Hyperactivity Disorder
  category: Behavioral
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      The diagnosis of ADHD was most common: 47/90 (52%) of the combined group (40% in prenatal vs 60%
      in postnatal, P = .08).
    explanation: >-
      Documents ADHD diagnoses in the referral cohort; the prenatal/postnatal contrast was not statistically
      significant.
  notes: >-
    These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population
    penetrance.
- name: Autistic Behavior
  category: Behavioral
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Other diagnoses included ASDs (26/90 [29%] combined, 11% prenatal vs 40% postnatal, P < .004), anxiety
      (23/90 [26%]), depression (13%), bipolar disorder (8%), and oppositional defiant disorder (6%).
    explanation: Records the observed ASD diagnostic history in a selected clinical cohort.
  - reference: PMID:39406744
    reference_title: >-
      A genome-first study of sex chromosome aneuploidies provides evidence of Y chromosome dosage effects
      on autism risk.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      We observed that both 47, XYY (OR, 3.2; 95% CI, 2.3–4.4) and 47, XXY (OR, 1.8; 95% CI, 1.3–2.4)
      were associated with increased ASD risk
    explanation: >-
      The pooled case-control analysis associates XYY with ASD diagnosis relative to XY. This odds ratio
      is not an ASD prevalence or a gene-specific molecular mechanism.
  notes: >-
    ASD history occurred in 26/90 in the pediatric referral cohort. A genotype-first case-control study
    found XYY-versus-XY OR 2.4 (95% CI 1.6–3.5), and pooling with iPSYCH gave OR 3.2 (2.3–4.4). Pediatric
    case versus adult volunteer control ascertainment and age/ancestry differences limit inference. Prenatal/postnatal
    diagnostic-history differences do not prove that prenatal diagnosis prevents ASD; questionnaire/interview
    cutoff proportions were not significantly different in the clinical study.
- name: Tremor
  category: Neurologic
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Mild resting and/or intention tremors were found in 39/90 (43%) patients.
    explanation: Documents tremor and its generally mild character.
  notes: >-
    These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population
    penetrance.
- name: Tics
  category: Neurologic
  phenotype_term:
    preferred_term: Tics
    term:
      id: HP:0100033
      label: Tics
  evidence:
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Mild verbal and/or motor tics were noted in 16/89 (18%) boys.
    explanation: Documents verbal or motor tics in the cohort.
  notes: >-
    These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population
    penetrance.
- name: Seizures
  category: Neurologic
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Seizure activity had occurred in 12/89 (13%), all but 1 diagnosed postnatally (prenatal vs postnatal,
      P = .03).
    explanation: Records seizure history with its ascertainment imbalance.
  notes: >-
    These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population
    penetrance. Convulsive or otherwise suspicious episodes warrant evaluation; this proportion does not
    justify universal screening EEG.
- name: Asthma
  category: Respiratory
  phenotype_term:
    preferred_term: Asthma
    term:
      id: HP:0002099
      label: Asthma
  evidence:
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Asthma was diagnosed in 35/89 (39%) of XYY patients
    explanation: Documents asthma diagnoses in the pediatric clinical cohort.
  notes: >-
    These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population
    penetrance. The adult genotype-first study also reports an association; the pediatric percentage is
    not a universal rate.
- name: Pes Planus
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
  evidence:
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Hypotonia was noted in 57/90 (63%) patients, and flat feet were common (52%).
    explanation: Records flat feet in the examined cohort.
  notes: >-
    Flat feet were reported; the narrative and table round the proportion differently, so no precise population
    frequency is assigned.
- name: Scoliosis
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: '| Scoliosis | 9% | 16% | 13% | .36 | 4% |'
    explanation: Table I reports 13% in the combined clinical cohort, compared with prenatal and postnatal subgroups.
  notes: >-
    These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population
    penetrance.
- name: Macrodontia
  category: Dental
  phenotype_term:
    preferred_term: Macrodontia
    term:
      id: HP:0001572
      label: Macrodontia
  evidence:
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Dental problems were reported in 22%, including prognathic jaw with underbite and macrodontia.
    explanation: Identifies macrodontia within a combined dental-problem category, not a 22% macrodontia-specific rate.
  notes: The reported 22% combines several dental findings and cannot be assigned to macrodontia alone.
- name: Inguinal Hernia
  category: Abdominal
  phenotype_term:
    preferred_term: Inguinal hernia
    term:
      id: HP:0000023
      label: Inguinal hernia
  evidence:
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Hypospadias was reported in 1/ 90, cryptorchidism in 2/90, and inguinal hernia in 5/90.
    explanation: Records inguinal hernia in five individuals in the clinical cohort.
  notes: >-
    These are observations in a specialty-clinic cohort of 90 nonmosaic males and do not estimate population
    penetrance.
- name: Oligozoospermia
  category: Reproductive
  phenotype_term:
    preferred_term: Oligozoospermia
    term:
      id: HP:0000798
      label: Oligozoospermia
  evidence:
  - &id007
    reference: PMID:40264980
    reference_title: >-
      Preimplantation genetic testing might not be the necessity for male patients with 47,XYY syndrome:
      A pilot study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      The fertility of the male patients varied, and 12 patients had normozoospermia. Two‐thirds of the
      patients presented oligoasthenozoospermia (7 patients), severe oligoasthenozoospermia (12 patients),
      and azoospermia (5 patients).
    explanation: >-
      Records semen findings in 36 couples seeking assisted reproduction, including 32 nonmosaic and four
      mosaic men. Selection prevents estimation of population infertility penetrance.
  notes: >-
    Spermatogenic impairment is documented in selected reproductive-clinic patients, while other men have
    normal semen parameters. Many normozoospermic men in the series sought ART because of female-factor
    infertility. The adult biobank PheWAS did not find the infertility association observed for XXY; neither
    dataset establishes universal infertility in XYY.
- name: Azoospermia
  category: Reproductive
  phenotype_term:
    preferred_term: Azoospermia
    term:
      id: HP:0000027
      label: Azoospermia
  evidence:
  - *id007
  notes: >-
    Spermatogenic impairment is documented in selected reproductive-clinic patients, while other men have
    normal semen parameters. Many normozoospermic men in the series sought ART because of female-factor
    infertility. The adult biobank PheWAS did not find the infertility association observed for XXY; neither
    dataset establishes universal infertility in XYY.
- name: Male Infertility
  category: Reproductive
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - *id007
  notes: >-
    Spermatogenic impairment is documented in selected reproductive-clinic patients, while other men have
    normal semen parameters. Many normozoospermic men in the series sought ART because of female-factor
    infertility. The adult biobank PheWAS did not find the infertility association observed for XXY; neither
    dataset establishes universal infertility in XYY.
- name: Venous Thrombosis
  category: Cardiovascular
  phenotype_term:
    preferred_term: Venous thrombosis
    term:
      id: HP:0004936
      label: Venous thrombosis
  evidence:
  - reference: PMID:40840450
    reference_title: >-
      Phenome-wide association study of male and female sex chromosome trisomies in 1.5 million participants
      of MVP, FinnGen, and UK Biobank.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      452 | other venous embolism and thrombosis | circulatory | 19.4% | 4.6 (3.7–5.6) | 18.1% | 4.1 (3.3–5.0)
      | 11.6% | 8.1 (4.2–15.4) | 0.13
    explanation: 'Reports the XYY venous-thromboembolism association: OR 4.1 (95% CI 3.3–5.0).'
  notes: >-
    Association in an adult genotype-first PheWAS of 1,108 XYY participants across MVP, UK Biobank and
    FinnGen. Cohort selection, diagnostic coding and unmeasured environmental or lifestyle mediators limit
    causal and population-frequency interpretation. This evidence does not establish a benefit from routine
    prophylactic anticoagulation.
- name: Venous Insufficiency
  category: Cardiovascular
  phenotype_term:
    preferred_term: Venous insufficiency
    term:
      id: HP:0005293
      label: Venous insufficiency
  evidence:
  - reference: PMID:40840450
    reference_title: >-
      Phenome-wide association study of male and female sex chromosome trisomies in 1.5 million participants
      of MVP, FinnGen, and UK Biobank.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      456 | chronic venous insufficiency | circulatory | 19.6% | 4.7 (3.9–5.8) | 20.1% | 5.6 (4.5–7.0)
      | 16.0% | 4.6 (2.7–7.6) | 0.50
    explanation: 'Reports the XYY venous-insufficiency association: OR 5.6 (95% CI 4.5–7.0).'
  notes: >-
    Association in an adult genotype-first PheWAS of 1,108 XYY participants across MVP, UK Biobank and
    FinnGen. Cohort selection, diagnostic coding and unmeasured environmental or lifestyle mediators limit
    causal and population-frequency interpretation.
- name: Glaucoma
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
  evidence:
  - reference: PMID:40840450
    reference_title: >-
      Phenome-wide association study of male and female sex chromosome trisomies in 1.5 million participants
      of MVP, FinnGen, and UK Biobank.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 'glaucoma [47,XXY: 2.5 (2.1–2.9), 47,XYY: 2.4 (2.0–2.8), and 47,XXX: 2.3 (1.4–3.5)]'
    explanation: 'Reports the XYY glaucoma association: OR 2.4 (95% CI 2.0–2.8).'
  notes: >-
    Association in an adult genotype-first PheWAS of 1,108 XYY participants across MVP, UK Biobank and
    FinnGen. Cohort selection, diagnostic coding and unmeasured environmental or lifestyle mediators limit
    causal and population-frequency interpretation.
- name: Diabetes Mellitus
  category: Metabolic
  phenotype_term:
    preferred_term: Diabetes mellitus
    term:
      id: HP:0000819
      label: Diabetes mellitus
  evidence:
  - &id008
    reference: PMID:40840450
    reference_title: >-
      Phenome-wide association study of male and female sex chromosome trisomies in 1.5 million participants
      of MVP, FinnGen, and UK Biobank.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Examples of other conditions that were significantly more prominent in all three SCT groups include
      obesity (MIM: 601665), type 2 diabetes (MIM: 125853), dermatophytosis, atopic dermatitis (MIM: 603165),
      asthma and chronic airway obstruction (MIM: 600807), sleep apnea (MIM: 107650)
    explanation: Reports adult metabolic and respiratory associations in all three sex-chromosome trisomies, including XYY.
  notes: >-
    Association in an adult genotype-first PheWAS of 1,108 XYY participants across MVP, UK Biobank and
    FinnGen. Cohort selection, diagnostic coding and unmeasured environmental or lifestyle mediators limit
    causal and population-frequency interpretation. The study describes type 2 diabetes. The broader HPO
    binding follows the association table endpoint, phecode 250 diabetes mellitus, rather than assigning
    all coded cases to a subtype from the narrative summary.
- name: Obesity
  category: Growth
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  evidence:
  - *id008
  notes: >-
    Association in an adult genotype-first PheWAS of 1,108 XYY participants across MVP, UK Biobank and
    FinnGen. Cohort selection, diagnostic coding and unmeasured environmental or lifestyle mediators limit
    causal and population-frequency interpretation.
- name: Sleep Apnea
  category: Respiratory
  phenotype_term:
    preferred_term: Sleep apnea
    term:
      id: HP:0010535
      label: Sleep apnea
  evidence:
  - *id008
  notes: >-
    Association in an adult genotype-first PheWAS of 1,108 XYY participants across MVP, UK Biobank and
    FinnGen. Cohort selection, diagnostic coding and unmeasured environmental or lifestyle mediators limit
    causal and population-frequency interpretation.
genetic:
- name: 47,XYY chromosome complement
  association: Causal whole-chromosome gain
  relationship_type: CAUSATIVE
  notes: >-
    An additional Y chromosome, generally sporadic; mosaic 46,XY/47,XYY is also recognized. The karyotype
    does not determine an individual cognitive, behavioral or reproductive outcome.
  evidence:
  - *id009
  - &id017
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/
    reference_title: Jacobs Syndrome - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      An alternate and less common form of this condition is 46,XY/47,XYY mosaicism, which arises during
      early embryonic development.
    explanation: Distinguishes postzygotic mosaicism from the usual nonmosaic complement.
- name: SHOX
  gene_term:
    preferred_term: SHOX
    term:
      id: hgnc:10853
      label: SHOX
  association: Candidate dosage contribution to increased stature
  notes: >-
    The extra Y adds a third SHOX copy. Human chromosome-height associations support a dosage hypothesis
    without isolating SHOX as the sole clinical mediator.
  evidence:
  - *id002
  - *id006
- name: UTY
  gene_term:
    preferred_term: UTY
    term:
      id: hgnc:12638
      label: UTY
  association: Experimental expression regulator
  notes: >-
    Patient-derived pluripotent-cell experiments support a UTY-dependent KDM6A expression relationship,
    not a monogenic explanation of all XYY manifestations.
  evidence:
  - *id004
- name: KDM6A
  gene_term:
    preferred_term: KDM6A
    term:
      id: hgnc:12637
      label: KDM6A
  association: Dosage-responsive X homolog in cultured XYY cells
  notes: >-
    Upregulated in XYY iPSCs and neural stem cells, with reduced RNA/protein after UTY knockout. This
    is an expression effect, not an additional KDM6A copy or a germline KDM6A sequence disorder.
  evidence:
  - *id010
  - *id004
diagnosis:
- name: Postnatal Karyotyping
  diagnosis_term:
    preferred_term: Karyotyping
    term:
      id: NCIT:C16768
      label: Karyotyping
  presence: 47,XYY or mosaic 46,XY/47,XYY
  description: >-
    Chromosome analysis confirms the extra Y chromosome; interpretation of mosaicism depends on the sampled
    tissue and number of cells analyzed.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/
    reference_title: Jacobs Syndrome - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: After birth, diagnosis is made using karyotype analysis from a sample of the patient's blood.
    explanation: Supports blood karyotype confirmation of the chromosome complement.
  notes: >-
    Clinical appearance alone is insufficient; prenatal ascertainment is not proof of a better outcome
    caused by earlier diagnosis.
- name: Prenatal Screening and Cytogenetic Confirmation
  diagnosis_term:
    preferred_term: Karyotyping
    term:
      id: NCIT:C16768
      label: Karyotyping
  description: >-
    Cell-free DNA testing screens for sex-chromosome aneuploidy. A positive screen requires appropriate
    diagnostic cytogenetic confirmation; the cited study used amniocentesis.
  evidence:
  - reference: PMID:32188487
    reference_title: 'Cell-free DNA screening for sex chromosomal aneuploidies in 9985 pregnancies: Italian single experience.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Karyotyping by amniocentesis was selected as a method to confirm the NIPT results.
    explanation: Distinguishes a screening result from cytogenetic confirmation.
  notes: >-
    Only one of two XYY-positive screens in this series had diagnostic follow-up. The resulting 1/1 confirmed-positive
    observation does not establish general 100% predictive value, and untested screen-negative pregnancies
    prevent estimation of sensitivity.
treatments:
- name: Speech and Language Therapy
  description: >-
    Offer assessment and individualized speech-language intervention when delay or communication difficulties
    are present.
  treatment_term:
    preferred_term: Speech Language Therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  evidence:
  - &id011
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/
    reference_title: Jacobs Syndrome - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Boys who are diagnosed with Jacobs syndrome may benefit from speech therapy and behavioral interventions
      from qualified professionals.
    explanation: Clinical review supports individualized speech-language and behavioral services.
  therapeutic_modality: BEHAVIORAL
  target_mechanisms:
  - target: Delayed Speech and Language Development
    description: >-
      Speech-language therapy addresses the communication phenotype; it does not alter chromosome dosage.
    evidence:
    - *id011
- name: Developmental and Educational Support
  description: >-
    Assess language, learning, attention and social-communication needs and provide individualized educational
    and behavioral support.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Neurodevelopmental screenings also should be performed given the increased risk for developmental
      delays, language disorders, ADHD, and ASDs.
    explanation: >-
      The clinical cohort authors recommend developmental screening; this is a care recommendation rather
      than an intervention efficacy trial.
  - &id012
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/
    reference_title: Jacobs Syndrome - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Patients may benefit from supplemental or special educational resources if learning disabilities exist.
    explanation: Supports educational assistance matched to assessed needs.
  notes: >-
    Prenatal counseling series were uncontrolled and do not establish prevention of aggression or improved
    IQ. Services should follow the individual assessment.
  therapeutic_modality: BEHAVIORAL
  target_mechanisms:
  - target: Specific Learning Disability
    description: >-
      Educational resources address assessed learning needs.
    evidence:
    - *id012
- name: Occupational Therapy
  description: >-
    Consider occupational therapy for functionally important hypotonia, tremor, handwriting or self-care
    difficulty.
  treatment_term:
    preferred_term: Occupational Therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  evidence:
  - &id013
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/
    reference_title: Jacobs Syndrome - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Occupational therapy may be needed if hypotonia is present.
    explanation: Recognizes hypotonia-related occupational needs.
  - &id014
    reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Tremor is usually mild, however, if it impairs handwriting, occupational or self-care skills (ie,
      eating, dressing), then occupational therapy evaluation, educational/workplace supports, and medication
      treatments can be considered.
    explanation: Recommends symptom- and function-directed tremor support rather than treatment of every observed tremor.
  target_mechanisms:
  - target: Hypotonia
    description: >-
      Occupational therapy supports function affected by hypotonia without correcting the chromosome complement.
    evidence:
    - *id013
  - target: Tremor
    description: >-
      Symptomatic occupational support is considered when tremor impairs handwriting or self-care.
    evidence:
    - *id014
- name: Genetic Counseling
  description: >-
    Explain the chromosome finding, variable expression, prenatal screening versus diagnosis, educational
    needs and reproductive options.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/
    reference_title: Jacobs Syndrome - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Families who receive a prenatal diagnosis of 47,XYY syndrome should receive genetic counseling to
      aid in their understanding of the disease.
    explanation: Supports informed counseling after prenatal diagnosis.
  notes: >-
    Counseling should distinguish observed group risks from individual prognosis. The karyotype does not
    imply inevitable aggression, androgen excess or infertility.
- name: Symptom-Directed Medical Follow-up
  description: >-
    Assess and treat asthma and dental problems; evaluate clinically suspicious seizures and address other
    documented comorbidities.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - &id015
    reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Once the diagnosis is made, children should be screened carefully and treated for asthma and dental problems.
    explanation: Supports clinical assessment of recurrent pediatric comorbidities.
  - reference: PMID:23810129
    reference_title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      neurologic evaluation and possible electroencephalogram should be considered for atypical staring
      spells, significant sleep disturbance, or significant unexplained behavioral dysregulation.
    explanation: Supports EEG when clinical features suggest seizures; it is not a recommendation for universal EEG.
  target_mechanisms:
  - target: Asthma
    description: >-
      Clinical treatment addresses coexisting asthma; no XYY-specific drug response is established.
    evidence:
    - *id015
- name: Glaucoma Assessment
  description: Consider ophthalmic assessment in adult care in light of the reported association with glaucoma.
  treatment_term:
    preferred_term: Eye Examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  evidence:
  - reference: PMID:40840450
    reference_title: >-
      Phenome-wide association study of male and female sex chromosome trisomies in 1.5 million participants
      of MVP, FinnGen, and UK Biobank.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Therefore, glaucoma may be an important age-related SCT comorbidity for which surveillance in individuals
      with SCT is warranted.
    explanation: The PheWAS authors propose surveillance based on the adult association.
  notes: >-
    This is an observational-study recommendation across sex-chromosome trisomies. An XYY-specific interval,
    screening efficacy or preventive drug regimen was not established. This is a non-therapeutic screening
    action. It has no treatment-style target link, consistent with the schema restriction on screening
    and monitoring.
- name: Individualized Fertility Evaluation and Assisted Reproduction
  description: >-
    For reproductive difficulty, assess semen parameters and reproductive hormones and discuss assisted
    reproduction where appropriate.
  treatment_term:
    preferred_term: In Vitro Fertilization
    term:
      id: NCIT:C16580
      label: In Vitro Fertilization
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/
    reference_title: Jacobs Syndrome - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Men with 47,XYY who are being seen for infertility should receive a semen analysis, testicular ultrasound,
      and bloodwork to measure reproductive hormones.
    explanation: Supports evaluation of men presenting with infertility.
  - &id016
    reference: PMID:40264980
    reference_title: >-
      Preimplantation genetic testing might not be the necessity for male patients with 47,XYY syndrome:
      A pilot study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: '| Live birth rate (%) a , b | 48.89 (22/45) | 50.00 (19/38) | 42.86 (3/7) | >0.9999 |'
    explanation: >-
      The small retrospective ART study observed 19 live-birth events in 38 PGT transfer cycles and three
      in seven conventional IVF/ICSI transfer cycles, demonstrating feasibility in selected couples.
  notes: >-
    The 36-couple study was nonrandomized, included repeat cycles, had only six conventional-treatment
    couples, and had incomplete pregnancy follow-up. Nonsignificant differences do not establish equal
    success or offspring safety, or that PGT is unnecessary. Five successful micro-TESE retrievals in
    selected azoospermic men do not establish a general 100% retrieval rate. The IVF ontology binding
    and phenotype target describe only the assisted-reproduction component; semen analysis, ultrasound
    and hormone measurements are diagnostic assessments.
  target_mechanisms:
  - target: Male Infertility
    description: >-
      This link represents IVF/ICSI as an assisted reproductive intervention for selected infertile couples.
      The evaluation tests themselves are diagnostic and do not treat infertility.
    evidence:
    - *id016
references:
- reference: PMID:23034220
  title: >-
    Early manifestations in a cohort of children prenatally diagnosed with 47,XYY. Role of multidisciplinary
    counseling for parental guidance and prevention of aggressive behavior.
- reference: PMID:23810129
  title: '47,XYY syndrome: clinical phenotype and timing of ascertainment.'
- reference: PMID:32188487
  title: 'Cell-free DNA screening for sex chromosomal aneuploidies in 9985 pregnancies: Italian single experience.'
- reference: PMID:39406744
  title: >-
    A genome-first study of sex chromosome aneuploidies provides evidence of Y chromosome dosage effects
    on autism risk.
- reference: PMID:40264980
  title: >-
    Preimplantation genetic testing might not be the necessity for male patients with 47,XYY syndrome:
    A pilot study.
- reference: PMID:40388606
  title: 'X and Y gene dosage effects are primary contributors to human sexual dimorphism: The case of height.'
- reference: PMID:40494628
  title: >-
    An iPSC-based model of 47,XYY Jacobs syndrome reveals a DNA methylation-independent transcriptional
    dysregulation shared with male X aneuploid cells.
- reference: PMID:40840450
  title: >-
    Phenome-wide association study of male and female sex chromosome trisomies in 1.5 million participants
    of MVP, FinnGen, and UK Biobank.
- reference: clinicaltrials:NCT07718997
  title: >-
    A Multiple Baseline Feasibility Trial of Social Management Training for People With Sex Chromosome
    Aneuploidies
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07718997
  title: https://clinicaltrials.gov/api/v2/studies/NCT07718997
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/
  title: Jacobs Syndrome - StatPearls - NCBI Bookshelf
  tags:
  - StatPearls
notes: >-
  Clinical-series proportions below describe their stated referral populations rather than population
  penetrance. The principal pediatric study included 90 nonmosaic males aged 0.5–36.5 years at two specialty
  centers (35 prenatal and 55 postnatal diagnoses). Adult biobank associations describe coded comorbidities
  in selected populations, not inevitable manifestations or established causal pathways. The molecular
  links from Y dosage to most clinical findings remain unresolved; disconnected phenotypes are retained
  without invented causal intermediates.
inheritance:
- name: Usually sporadic chromosome nondisjunction
  expressivity: VARIABLE
  description: >-
    Usually a de novo paternal meiotic event; postzygotic nondisjunction can produce 46,XY/47,XYY mosaicism.
    This is not Mendelian Y-linked inheritance. Clinical expression varies substantially.
  evidence:
  - *id009
  - *id017
has_subtypes:
- name: Nonmosaic 47,XYY
  description: >-
    The additional Y chromosome is present in the tested cell population without a detected 46,XY cell
    line; detection remains dependent on the tissue and assay examined.
  evidence:
  - *id009
- name: Mosaic 46,XY/47,XYY
  description: >-
    Coexisting XY and XYY cell populations following a postzygotic event. A measured mosaic fraction in
    one tissue does not establish a precise clinical prognosis.
  evidence:
  - *id017
differential_diagnoses:
- name: Klinefelter Syndrome
  description: Another sex-chromosome trisomy that may present with tall stature and learning or reproductive difficulties.
  distinguishing_features:
  - >-
    47,XXY rather than 47,XYY on chromosome analysis; small testes and hypogonadism are more characteristic
    of XXY.
  evidence:
  - reference: PMID:40840450
    reference_title: >-
      Phenome-wide association study of male and female sex chromosome trisomies in 1.5 million participants
      of MVP, FinnGen, and UK Biobank.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Notable exceptions to this include infertility, gynecomastia, and osteoporosis, which were associated
      with 47,XXY (both diagnosed and undiagnosed) but not 47,XYY.
    explanation: >-
      Distinguishes adult comorbidity profiles in the same genotype-first study without implying these
      findings are impossible in XYY.
- name: Sotos Syndrome
  description: Overgrowth, macrocephaly, learning difficulties and hypotonia may overlap.
  distinguishing_features:
  - >-
    An NSD1-related disorder rather than an extra Y chromosome; molecular and cytogenetic testing distinguish
    the diagnoses.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/
    reference_title: Jacobs Syndrome - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Hallmark features include excessive growth during childhood, macrocephaly, learning disabilities,
      hypotonia, and seizure disorders.
    explanation: The Sotos differential paragraph identifies the overlapping overgrowth and developmental features.
- name: Marfan Syndrome
  description: Tall stature can overlap, with connective-tissue manifestations directing the differential assessment.
  distinguishing_features:
  - >-
    Aortic-root disease and other connective-tissue findings favor Marfan syndrome; targeted evaluation
    and genetic testing are used when indicated. A normal echocardiogram alone does not exclude it.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/
    reference_title: Jacobs Syndrome - StatPearls - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Marfan syndrome is a connective tissue disorder that, in contrast to Jacobs syndrome, often presents
      with cardiac abnormalities such as aortic root dilatation and mitral valve prolapse.
    explanation: Identifies aortic and valvular findings relevant to the differential.
clinical_trials:
- name: NCT07718997
  description: >-
    TRICXY-SMT is a single-group, multiple-baseline feasibility study of ten sessions of online Social
    Management Training in people with sex-chromosome aneuploidies, including XYY. Mental health is the
    primary outcome, with executive and social/autism measures as secondary outcomes.
  phase: PHASE_I
  status: RECRUITING
  evidence:
  - reference: clinicaltrials:NCT07718997
    reference_title: >-
      A Multiple Baseline Feasibility Trial of Social Management Training for People With Sex Chromosome
      Aneuploidies
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      We will examine is Social Management Training, a 10-session group-based psychosocial intervention
      will improve the primary outcome mental health, and secondary outcomes executive functions and autism
      symptoms, in a multiple baseline design with 3 pre-measurement points and 3 post-measurement points
      spanning 30 weeks, including the 10 weeks of intervention.
    explanation: Registry description of the planned intervention and outcomes, not evidence of clinical efficacy.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07718997
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT07718997
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Genetically confirmed SCA. Participants provide medical confirmation of diagnosis, unless participants
      are recruited via Frambu (where medical confirmation is available in the user registry for KS 47,XXY
      karyotype; Jacobs 47,XYY karyotype; Triple X, 47,XXX karyotype; and Turner 45,X karyotype).
    explanation: The full protocol explicitly includes XYY alongside other sex-chromosome aneuploidies.
  notes: >-
    Recruiting status and registry phase designation verified on 2026-09-21 against the July 2026 posted
    record. Estimated enrollment is 30 across eligible aneuploidies, not 30 XYY participants; no results
    are posted. PHASE_I reproduces the registry designation for this behavioral feasibility study. The
    structured and narrative upper age limits differ, so no fixed eligibility age is inferred here. The
    API URL is the full ClinicalTrials.gov record for TRICXY-SMT; its generated URL title is retained
    to match the reference cache.
review_notes: >-
  Reviewed the full Bardsley and Lalatta clinical articles, the Astro cellular study, adult height and
  PheWAS analyses, genotype-first ASD study, ART pilot, prenatal-screening study, StatPearls clinical
  chapter and current trial protocol. Referral/volunteer selection, age differences, assay context and
  table denominators constrain each conclusion. Excluded unsupported universal frequency bands, candidate-gene
  assertions of proven autism causation, NIPT-as-diagnosis wording, deterministic criminality/testosterone
  explanations, PGT-equivalence claims and routine VTE prophylaxis. The original study records language
  problems and care needs but does not prove counseling prevents aggression. StatPearls is used for supported
  counseling and clinical evaluation statements; its claim that NIPT replaces diagnostic cytogenetics
  and its suggestion that normal cardiac tests exclude Marfan syndrome are not adopted. Follow-up review
  adds supported symptomatic-treatment targets while leaving screening and genetic counseling without
  therapeutic edges. The selected ART series does not establish individual causal mediation from semen
  findings to infertility, so no additional phenotype-sequela edges are inferred.
experimental_models:
- name: Patient-derived XYY pluripotent and neural stem-cell cultures
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Fibroblasts from three nonmosaic XYY donors were reprogrammed to iPSCs and differentiated to neural
    stem cells, with XY comparisons. Transcriptomic analyses span fibroblasts, pluripotent cells and neural
    stem cells; UTY perturbation experiments use pluripotent cultures.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:40494628
  modeled_mechanisms:
  - target: Y-Linked Gene Overexpression
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: LOW
    description: RNA sequencing compares non-pseudoautosomal Y-linked expression in XYY and XY cultures.
    limitations: >-
      Only three XYY donor backgrounds were studied. Clones are not independent patients; pluripotent
      and neural stem cells do not establish mature-neuron or behavioral phenotypes. UTY knockout is an
      experimental perturbation, not a clinical rescue.
    evidence:
    - *id003
    readouts:
    - name: Y-linked differential transcript abundance
      target: Y-Linked Gene Overexpression
      direction: INCREASED
      interpretation: >-
        Direction is relative to the matched comparison used in the experiment; the knockout readout is
        relative to UTY-intact XYY iPSCs.
      evidence:
      - *id003
  - target: Cell-Type-Specific Transcriptional Dysregulation
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: LOW
    description: >-
      RNA sequencing identifies distinct expression signatures in fibroblast, pluripotent and neural stem-cell
      contexts.
    limitations: >-
      Only three XYY donor backgrounds were studied. Clones are not independent patients; pluripotent
      and neural stem cells do not establish mature-neuron or behavioral phenotypes. UTY knockout is an
      experimental perturbation, not a clinical rescue.
    evidence:
    - *id005
    readouts:
    - name: Cell-type-specific differential expression
      target: Cell-Type-Specific Transcriptional Dysregulation
      direction: ALTERED
      interpretation: >-
        Direction is relative to the matched comparison used in the experiment; the knockout readout is
        relative to UTY-intact XYY iPSCs.
      evidence:
      - *id005
  - target: UTY-Dependent KDM6A Upregulation
    relationship: PERTURBS
    model_scale: CELLULAR
    fidelity: LOW
    description: CRISPR disruption of UTY in XYY iPSCs tests its contribution to KDM6A RNA and protein abundance.
    limitations: >-
      Only three XYY donor backgrounds were studied. Clones are not independent patients; pluripotent
      and neural stem cells do not establish mature-neuron or behavioral phenotypes. UTY knockout is an
      experimental perturbation, not a clinical rescue.
    evidence:
    - *id004
    readouts:
    - name: KDM6A RNA and protein after UTY knockout
      target: UTY-Dependent KDM6A Upregulation
      direction: DECREASED
      interpretation: >-
        Direction is relative to the matched comparison used in the experiment; the knockout readout is
        relative to UTY-intact XYY iPSCs.
      evidence:
      - *id004
  notes: >-
    Companion embryonic stem-cell overexpression experiments show context-dependent UTY–KDM6A regulation.
    No clinical treatment effect, mature-neuron functional assay or proof of a gene-specific autism mechanism
    follows from this model.
📚

References & Deep Research

References

11
PMID:23034220
Early manifestations in a cohort of children prenatally diagnosed with 47,XYY. Role of multidisciplinary counseling for parental guidance and prevention of aggressive behavior.
No top-level findings curated for this source.
PMID:23810129
47,XYY syndrome: clinical phenotype and timing of ascertainment.
No top-level findings curated for this source.
PMID:32188487
Cell-free DNA screening for sex chromosomal aneuploidies in 9985 pregnancies: Italian single experience.
No top-level findings curated for this source.
PMID:39406744
A genome-first study of sex chromosome aneuploidies provides evidence of Y chromosome dosage effects on autism risk.
No top-level findings curated for this source.
PMID:40264980
Preimplantation genetic testing might not be the necessity for male patients with 47,XYY syndrome: A pilot study.
No top-level findings curated for this source.
PMID:40388606
X and Y gene dosage effects are primary contributors to human sexual dimorphism: The case of height.
No top-level findings curated for this source.
PMID:40494628
An iPSC-based model of 47,XYY Jacobs syndrome reveals a DNA methylation-independent transcriptional dysregulation shared with male X aneuploid cells.
No top-level findings curated for this source.
PMID:40840450
Phenome-wide association study of male and female sex chromosome trisomies in 1.5 million participants of MVP, FinnGen, and UK Biobank.
No top-level findings curated for this source.
clinicaltrials:NCT07718997
A Multiple Baseline Feasibility Trial of Social Management Training for People With Sex Chromosome Aneuploidies
No top-level findings curated for this source.
url:https://clinicaltrials.gov/api/v2/studies/NCT07718997
https://clinicaltrials.gov/api/v2/studies/NCT07718997
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK557699/
Jacobs Syndrome - StatPearls - NCBI Bookshelf
No top-level findings curated for this source.