46,XY Sex Reversal 5

Mendelian MONDO:0013120 Pathograph 32 Show in embeddings browser Disorder of sex development 46,XY disorder of sex development Gonadal development disorder

A very rare 46,XY disorder of sex development attributed to loss-of-function variants in CBX2, the human orthologue of Drosophila Polycomb (M33) and a chromodomain subunit of Polycomb repressive complex 1. CBX2 acts at the earliest, pre-SRY step of testis determination: rather than behaving purely as a repressive chromatin modifier, it transactivates the male programme (NR5A1/SF1, SOX9) while repressing ovarian determinants (WNT4, PBX1, and indirectly FOXL2), so its loss removes the male bias from the bipotential gonad. The disorder is defined by a single index patient reported in 2009 — a 46,XY girl ascertained through a discrepancy between her prenatal karyotype and her phenotype at birth, who had entirely normal female external genitalia, a uterus and histologically normal ovaries, and carried double-heterozygous CBX2.1 variants. Two later 46,XY individuals carrying variants in the shorter CBX2.2 isoform presented very differently, with atypical external genitalia, perineal hypospadias and non-palpable gonads; one had dysgenetic testes with Sertoli-cell-only tubules and the other no identifiable gonadal tissue at gonadectomy. Their variants impair regulation of a distinct target set including EMX2. Together these define an isoform-split phenotypic spectrum rather than a single stereotyped presentation. CBX2 is not a common cause of gonadal DSD: a dedicated screen of 47 patients with 46,XY or 46,XX gonadal DSD found no pathogenic CBX2 variant, so the caseload this entry rests on is three individuals and the gene-disease relationship rests on functional rather than segregation evidence.

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1
Inheritance
12
Pathophys.
2
Histopath.
14
Phenotypes
2
Hypotheses
3
Gaps
32
Pathograph
1
Genes
4
Medical Actions
2
Subtypes
4
Differentials
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Datasets
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Models
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References
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Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
The OMIM entity (SRXY5) is classified as autosomal recessive on the strength of the index patient, who is described as carrying two loss-of-function CBX2.1 variants as a double heterozygote. No cached source reports phase, so a trans configuration is not asserted here. CBX2 is at 17q25.3, so this is autosomal rather than sex-limited despite the phenotype being expressed only in 46,XY individuals. The recessive assignment rests on a single family; the two later CBX2.2 patients are each reported as carrying one variant, and their zygosity is not stated to be biallelic (see the CBX2.2 zygosity discussion).
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:31719618 SUPPORT In Vitro
"identified through a 46,XY girl with double heterozygous variants on CBX2.1, causing Differences of Sex Development (DSD)"
States that the index patient carried two CBX2.1 variants, the observation the autosomal recessive assignment is based on.
◆

Subtypes

2
CBX2.1 (isoform 1) related, complete female phenotype
The originally described and OMIM-defining presentation: a 46,XY individual with a completely female phenotype — normal female external genitalia, a uterus, and histologically normal ovarian tissue rather than streak gonads. Reported in one girl carrying double-heterozygous variants in the long CBX2.1 isoform, whose mutant protein failed to transactivate NR5A1/SF1. Because the external phenotype is unremarkable, ascertainment depended on a prenatal karyotype, which is why this presentation is expected to be systematically under-detected.
Show evidence (1 reference)
PMID:19361780 SUPPORT Human Clinical
"A girl with a prenatal 46,XY karyotype was born with a completely normal female phenotype, including uterus and histologically normal ovaries."
The single report defining this subtype, including the prenatal-karyotype route of ascertainment.
CBX2.2 (isoform 2) related, undervirilized phenotype with dysgenetic testes
Two unrelated 46,XY individuals carrying distinct variants in the shorter CBX2.2 isoform (p.Cys132Arg and p.Cys154fs) presented with atypical external genitalia, microphallus, perineal hypospadias and no palpable gonads, and were found to have dysgenetic Sertoli-cell-only testes or no residual gonadal tissue, with hypergonadotropic hypogonadism. In vitro these variants fail to regulate a target set distinct from that of CBX2.1, most notably EMX2. This arm is grouped under the same entry because the causal gene is the same, but note the caveats recorded in the entry notes: the zygosity of these variants is not reported as biallelic, so this subtype's relationship to the autosomal recessive CBX2.1 entity is not settled.
Show evidence (1 reference)
PMID:29998616 SUPPORT Human Clinical
"Here, we describe two patients with features of DSD i.e. atypical external genitalia, perineal hypospadias and no palpable gonads, each patient carrying a distinct CBX2.2 variant, p.Cys132Arg (c.394T>C) and p.Cys154fs (c.460delT)."
The single report defining this subtype: both patients, their external phenotype, and the two isoform-2 alleles.
◈

Mechanistic Hypotheses

2
CBX2 as a transactivator upstream of SRY
cbx2_sry_transactivation_model CANONICAL
Evidence balance 2 support 1 refute
The model the disorder was originally built on. CBX2 acts, unusually for a Polycomb protein, as a positive regulator: PRC1 containing CBX2/M33 binds the NR5A1/SF1 locus directly, CBX2-null mouse gonads have reduced Sry and Sox9, forced Sry or Sox9 expression rescues the sex reversal, and the human index patient's mutant CBX2.1 fails to transactivate NR5A1/SF1 in vitro. On this account the lesion is a failure to switch the male programme on.
Retained as CANONICAL because it is what the human functional diagnosis rests on: pathogenicity of the index patient's CBX2.1 variants was established by an NR5A1 transactivation assay, not by a repression assay.
Pathograph links
Failure of CBX2 Transactivation of NR5A1 and SOX9 -> Reduced SRY Expression in the Bipotential Gonad DIRECT
Show evidence (3 references)
PMID:19361780 SUPPORT Human Clinical
"revealed loss-of-function mutations that allowed us, by placing CBX2 upstream of SRY"
The original report's own framing of the mechanism as CBX2 acting upstream of SRY.
PMID:22186409 SUPPORT Model Organism
"Male-to-female sex reversal in Cbx2 KO mice was rescued by crossing them with transgenic mice displaying forced expression of Sry or Sox9."
Rescue by supplying Sry or Sox9 is the central genetic argument that the defect is insufficient male-pathway activation.
PMID:31116734 REFUTE Model Organism
"We show that Sry expression and testis development were rescued in XY Cbx2-/-;Wnt4-/- mice."
Cuts against this hypothesis. If the lesion were a lost activating input to Sry, deleting an ovary-promoting gene could not restore Sry expression; that it does implies the Sry deficit is downstream of unopposed ovarian signalling rather than of a missing activator.
CBX2 as a repressor of the ovary-promoting pathway
cbx2_ovarian_derepression_model ALTERNATIVE
Evidence balance 1 support
The competing account, and the one that fits CBX2's Polycomb identity. Here the primary lesion is loss of H3K27me3-mediated repression of ovary-promoting genes, which then block testis development; reduced Sry is a consequence rather than the cause. Sex-determining genes are bivalent in the bipotential gonad, CBX2 directly binds the Wnt effector Lef1, and deleting Wnt4 rescues both Sry expression and testis development in XY Cbx2-null mice.
This is not a refinement of the canonical model but a direct challenge to it: the authors explicitly investigated it as the alternative to CBX2 being an activator of Sry. The two models are not yet reconciled, and the human data cannot discriminate between them because no human CBX2 gonad has been profiled. Curated as ALTERNATIVE rather than CANONICAL because the decisive experiment is murine and the human diagnostic assay remains the transactivation one.
Pathograph links
Loss of CBX2 Repression of the Ovarian Programme -> Failure of Sertoli Cell Differentiation INDIRECT KNOWN INTERMEDIATES
Loss of CBX2 Repression of the Ovarian Programme -> Ovarian tissue in an individual with a 46,XY karyotype INDIRECT UNKNOWN INTERMEDIATES De-repression of the ovarian programme in an XY gonad is the proposed route to histologically normal ovarian tissue rather than a streak gonad. Recorded as indirect with unknown intermediates because no study has measured ovarian-determinant expression in the index patient's gonad.
Show evidence (1 reference)
PMID:31116734 SUPPORT Model Organism
"Our results suggest that stabilization of the testis fate requires CBX2-mediated repression of bivalent ovary-determining genes, which would otherwise block testis development."
States the alternative model in the authors' own terms.
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Discussions and Knowledge Gaps

3
Why do Cbx2-null mice have adrenal and splenic hypoplasia through reduced SF1, while human CBX2 patients have no reported adrenal or splenic disease, even though the human mutant protein's defining defect is failure to transactivate the same gene, NR5A1/SF1?
HUMAN MODEL MISMATCH OPEN cbx2_adrenal_splenic_mismatch
Attached to
pathophysiology#Failure of CBX2 Transactivation of NR5A1 and SOX9
The mouse work makes SF1 the mechanistic centre of the disorder: PRC1 containing M33 binds the Ad4BP/SF1 locus directly, M33 nulls have significantly reduced SF1, and the resulting adrenal and splenic phenotypes are the ones SF1 haploinsufficiency itself produces. The human index patient's mutant CBX2.1 also fails to transactivate NR5A1/SF1 - that assay is the primary functional evidence for pathogenicity. Yet none of the three published human patients has reported adrenal insufficiency, and a review of the CBX2 transcriptional landscape notes explicitly that human mutants do not appear to recapitulate the murine splenic and adrenal defects. Either the human alleles are hypomorphic enough to spare a less dosage-sensitive human adrenal, or CBX2 is not rate-limiting for human SF1 outside the gonad. The distinction matters clinically: if the first explanation is right, adrenal reserve should be tested in CBX2 patients, and it currently is not.
Proposed experiments
Adrenal reserve testing in CBX2 variant carriers
exp_cbx2_adrenal_reserve
Measure basal and ACTH-stimulated cortisol, along with electrolytes and plasma renin activity, in every ascertained individual with biallelic or isoform-specific CBX2 variants, to convert the current absence of reported adrenal disease into a tested negative.
Would refute
pathophysiology#Failure of CBX2 Transactivation of NR5A1 and SOX9
Refuting outcome
  • Normal ACTH-stimulated cortisol across all carriers would show that human CBX2 loss does not limit SF1-dependent adrenal function, restricting the transactivation defect to the gonadal compartment rather than being a general SF1 deficit.
Comparative SF1 dose-response between mouse and human adrenocortical cells
exp_cbx2_sf1_dose_response
Titrate CBX2 knockdown in human and murine adrenocortical cells in parallel and measure SF1 output, to test whether the human adrenal simply tolerates a lower CBX2 dose than the mouse adrenal does.
Show evidence (2 references)
PMID:31719618 SUPPORT In Vitro
"although human mutants do not seem to recapitulate these defects"
States the mismatch directly: the murine splenic, adrenal and skeletal phenotypes are not seen in human CBX2 patients.
PMID:15899914 SUPPORT Model Organism
"the adrenal glands of M33-KO and Ad4BP/SF1 heterozygous KO mice were smaller than those of the wild-type mice"
Establishes the murine side of the mismatch, and that the adrenal phenotype phenocopies SF1 deficiency.
Is the CBX2.2 arm of this entry the same recessive disorder as the CBX2.1 index case, given that each CBX2.2 patient is reported as carrying a single distinct variant and the phenotypes differ so markedly?
KNOWLEDGE GAP OPEN cbx2_2_zygosity_and_gene_validity
Attached to
has_subtypes#CBX2.2 inheritance#Autosomal recessive
The SRXY5 entity is defined as autosomal recessive on the strength of one double-heterozygous CBX2.1 patient. The two CBX2.2 patients are each described as carrying one distinct variant, with no second allele reported, and one of the two alleles has a population frequency (ExAC minor allele frequency 0.001418) that is high for a fully penetrant recessive DSD allele. Functional data are supportive but functional data alone do not establish a mode of inheritance. Working against a common-cause interpretation, a dedicated screen of 47 patients with 46,XY or 46,XX gonadal DSD found no pathogenic CBX2 variant at all, so there is no independent cohort in which the CBX2.2 signal has been replicated. Until the second allele is reported or excluded, grouping this arm under SRXY5 is a curation convenience and should not be read as an assertion that the two arms share an inheritance mode.
Proposed experiments
Complete allelic characterization of the reported CBX2.2 patients
exp_cbx2_2_second_allele
Re-analyse the existing exome data with attention to deep intronic, regulatory and structural variation at CBX2, plus parental segregation, to determine whether a second CBX2 allele is present in either CBX2.2 patient.
Isoform-resolved CBX2 screening in a large 46,XY DSD cohort
exp_cbx2_isoform_targeted_cohort_screen
Screen an unsolved 46,XY DSD cohort with coverage and annotation specific to both CBX2 isoforms, since the earlier negative screen predates the CBX2.2 report and may not have interrogated the short isoform adequately.
Show evidence (2 references)
PMID:23219007 SUPPORT Human Clinical
"No pathogenic CBX2 mutation was detected."
The absence of any pathogenic CBX2 variant in a dedicated 47-patient gonadal-DSD cohort is what leaves the gene-disease relationship resting on three individuals and functional assays.
PMID:29998616 SUPPORT Human Clinical
"Both variants are rare, with a MAF on ExAC of 0.00001647 (p.Cys132Arg) and 0.001418 (p.Cys154fs)"
Gives the allele frequencies quoted in the rationale, including the one that is high for a fully penetrant recessive allele.
What is the gonadal germ-cell tumour risk in CBX2-related 46,XY DSD, and does the presence of apparently normal ovarian tissue rather than a streak gonad change it?
KNOWLEDGE GAP OPEN cbx2_gonadal_tumour_risk
Attached to
treatments#Gonadectomy phenotypes#Ovarian tissue in an individual with a 46,XY karyotype
Gonadectomy was performed in both CBX2.2 patients, and prophylactic gonadectomy is standard practice in 46,XY gonadal dysgenesis generally because of germ-cell tumour risk. But no tumour has been reported in any CBX2 patient, the publications give no malignancy rationale for either operation, and with three published patients there is no denominator from which any risk estimate could be formed. Importing a percentage from generic 46,XY gonadal dysgenesis series would be unsourced inference, and it is specifically unsafe here: those series describe streak or dysgenetic gonads, whereas the index CBX2.1 patient had histologically normal ovarian tissue, which is not the substrate those risk figures were measured on. This entry therefore records gonadectomy as reported management with no attached risk figure, and this gap is why.
Proposed experiments
Systematic gonadal histology and outcome reporting for CBX2 patients
exp_cbx2_gonadal_histology_registry
Record gonadal histology, germ-cell tumour markers and follow-up duration for every ascertained CBX2 patient in a shared DSD registry, so that a denominator exists before any risk-based management recommendation is made.
Show evidence (1 reference)
PMID:19361780 SUPPORT Human Clinical
"including uterus and histologically normal ovaries"
Establishes that the index gonad was histologically normal ovary, the observation that makes tumour-risk figures derived from streak gonads inapplicable here.
⚙

Pathophysiology

12
CBX2 Loss of Function
Loss-of-function variants remove the activity of CBX2, the chromodomain subunit through which Polycomb repressive complex 1 is recruited to its target loci. CBX2 is expressed in the human gonad from around week 7 of gestation, before testis determination, and continues to be detected in both male and female gonads from week 9 to week 25. Because the protein acts both as a chromatin modifier and as a direct transactivator, its loss removes two separable activities at once, which is why downstream male genes fall and female genes rise from the same lesion. The node is named for the loss, not for a zygosity: the CBX2.1 index patient carried two variants, but the two CBX2.2 patients are each reported with a single variant, so calling the node biallelic would assert what the zygosity knowledge gap says is unresolved.
chromatin remodeling GO:0006338 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves chromatin remodeling (GO:0006338), qualified as loss of function. GO:0006338 is a biological process from the Gene Ontology. ⇓ LOSS OF FUNCTION
chromatin binding GO:0003682 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves chromatin binding (GO:0003682), qualified as loss of function. GO:0003682 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Failure of CBX2 Transactivation of NR5A1 and SOX9
Loss of CBX2 Repression of the Ovarian Programme
Failure of CBX2.2-Dependent EMX2 Regulation
Impaired Genital Ridge Growth
Show evidence (3 references)
PMID:22200029 SUPPORT Model Organism
"The mouse PcG family member M33/Cbx2 (Chromobox homolog protein 2) is a component of the Polycomb-Repressive Complex 1 (PRC1)."
Identifies CBX2/M33 as a PRC1 component, the molecular identity this node asserts is lost.
PMID:31719618 SUPPORT Other
"CBX2 was shown to be expressed from week 9 to week 25 post-fertilization in both male and female gonads"
Supplies the week 9 to 25 gonadal expression window quoted in this node's description. Graded OTHER rather than HUMAN_CLINICAL because the sentence is in this paper's introduction and reports a single-cell atlas it cites, not data it generated; the primary source is not cached here.
PMID:31719618 SUPPORT Other
"the known expression window of CBX2 in the early male gonad (week 7 of gestation), prior to testis determination"
Sources the week-7 claim in this node's description, and the specific point that expression precedes testis determination. Graded OTHER for the same reason as the item above: an introduction statement citing other work.
Failure of CBX2 Transactivation of NR5A1 and SOX9
CBX2 does not merely silence chromatin; it positively drives the male programme, stimulating NR5A1 (SF1) and SOX9. In the mouse, PRC1 containing M33 binds the Ad4BP/SF1 locus directly and M33-null animals have significantly low Ad4BP/SF-1 expression, establishing CBX2 as an upstream activator rather than a repressor of this gene. The index patient's mutant CBX2.1 failed to transactivate NR5A1/SF1 in vitro, which is the specific molecular defect the human disorder is built on.
CBX2 as a transactivator upstream of SRY
positive regulation of transcription by RNA polymerase II GO:0045944 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased positive regulation of transcription by RNA polymerase II (GO:0045944). GO:0045944 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced SRY Expression in the Bipotential Gonad CBX2 as a transactivator upstream of SRY
Show evidence (3 references)
PMID:15899914 SUPPORT Model Organism
"chromatin immunoprecipitation assays with adrenocortical Y-1 cells revealed direct binding of the M33-containing PcG to the Ad4BP/SF1 gene locus"
Direct chromatin occupancy of the SF1 locus by M33-containing PRC1 supports this as a direct transactivation relationship rather than an indirect one.
PMID:15899914 SUPPORT Model Organism
"indicated significantly low expression of adrenal 4 binding protein/steroidogenic factor-1 (Ad4BP/SF-1), indicating that M33 is an essential upstream regulator of Ad4BP/SF1"
Loss of M33 lowers SF1 expression, establishing the direction of the relationship asserted by this node.
PMID:31719618 SUPPORT In Vitro
"CBX2.1 is a stimulator of the male (through SOX9 and NR5A1 stimulation) and an inhibitor for the female pathway (through inhibition of FOXL2 expression)"
Names SOX9 and NR5A1 as the male-pathway targets CBX2.1 stimulates, which is what this node says is lost.
Loss of CBX2 Repression of the Ovarian Programme
The mirror image of the transactivation defect. CBX2.1 directly represses WNT4 and PBX1 and indirectly represses FOXL2; genome-wide target mapping in Sertoli-like cells identified close to 1600 direct CBX2 targets and concluded that the protein concurrently inhibits the female pathway. Loss of this repression allows ovarian determinants to run unopposed in an XY gonad, which is the most likely explanation for the index patient's histologically normal ovarian tissue — a finding that plain failure of testis determination would not by itself produce.
CBX2 as a repressor of the ovary-promoting pathway
negative regulation of transcription by RNA polymerase II GO:0000122 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of transcription by RNA polymerase II (GO:0000122). GO:0000122 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Cbx2/Wnt4 double-null rescue mouse Mouse rescues Deleting Wnt4 removes the de-repressed ovarian signal and rescues the XY gonad, showing that the block to testis development in Cbx2 nulls runs through unopposed ovarian determinants.
Downstream
Failure of Sertoli Cell Differentiation CBX2 as a repressor of the ovary-promoting pathway
Ovarian tissue in an individual with a 46,XY karyotype De-repression of the ovarian programme in an XY gonad is the proposed route to histologically normal ovarian tissue rather than a streak gonad. Recorded as indirect with unknown intermediates because no study has measured ovarian-determinant expression in the index patient's gonad. CBX2 as a repressor of the ovary-promoting pathway
Show evidence (4 references)
PMID:31719618 SUPPORT In Vitro
"CBX2.1 directly inhibits WNT4 and PBX1 and indirectly inhibits the expression of FOXL2"
Names the ovarian-pathway genes CBX2.1 represses and distinguishes the direct from the indirect targets, as this node states.
PMID:25569159 SUPPORT In Vitro
"We identified close to 1600 direct targets for CBX2."
Supplies the target-count figure quoted in the description and establishes the breadth of direct CBX2 chromatin occupancy.
PMID:31116734 SUPPORT Model Organism
"We show that Sry expression and testis development were rescued in XY Cbx2-/-;Wnt4-/- mice."
Genetic rescue by removing an ovarian determinant is the strongest evidence that loss of ovarian-pathway repression, not loss of a direct activating input, is what blocks testis development when CBX2 is absent.
+ 1 more reference
Failure of CBX2.2-Dependent EMX2 Regulation
A separate molecular arm specific to the short CBX2.2 isoform. Both reported CBX2.2 variants failed to regulate their target genes in transactivation assays, with defective EMX2 expression proposed as the proximate cause of the severe 46,XY phenotype in those patients. EMX2 is required for urogenital ridge development, so this arm converges on the same gonadal endpoint as the CBX2.1 arm by a non-overlapping target route. Independent support for a CBX2-EMX2 axis comes from a different disease gene: a PBX1 variant causing 46,XY gonadal dysgenesis was shown to abolish PBX1's physical interaction with both CBX2 and EMX2, placing the three proteins in one testis-determining module.
regulation of transcription by RNA polymerase II GO:0006357 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Failure of Sertoli Cell Differentiation
Show evidence (2 references)
PMID:29998616 SUPPORT In Vitro
"We show that both CBX2.2 variants fail to regulate the expression of genes essential for sexual development"
Both CBX2.2 alleles were shown in vitro to lose regulatory control of sex-development genes, which is the claim of this node.
PMID:31058389 SUPPORT INDIRECT In Vitro
"The mutation abolishes the physical interaction of PBX1 with two proteins known to be involved in testis-determination, CBX2 and EMX2."
Independent evidence that CBX2 and EMX2 sit in one testis-determining protein module. Indirect: the experiment is about a PBX1 variant, and the inference to a CBX2-EMX2 axis is one step removed from what was measured.
Reduced SRY Expression in the Bipotential Gonad
CBX2 lies upstream of SRY. In mice, gonadal growth defects appear at the time Sry is normally expressed and Cbx2-null gonads have reduced Sry, and the sex reversal is rescued by forced expression of Sry or Sox9 — the strongest available evidence that the sex-determination arm of the phenotype is specifically an Sry-expression failure rather than a general developmental collapse. The human index patient's variants were interpreted the same way, placing CBX2 upstream of SRY in the human cascade.
male sex determination GO:0030238 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased male sex determination (GO:0030238). GO:0030238 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
M33cterm/Cbx2 null mouse (C57BL/6) Mouse recapitulates Cbx2-null gonads have reduced Sry expression, and forced Sry or Sox9 expression rescues the sex reversal. This is the strongest evidence in either species for the node.
Downstream
Failure of Sertoli Cell Differentiation
Show evidence (3 references)
PMID:9641679 SUPPORT Model Organism
"Gonadal growth defects appeared near the time of expression of the Y-chromosome-specific Sry gene, suggesting that M33 deficiency may cause sex reversal by interfering with steps upstream of Sry."
Places the lesion upstream of Sry on developmental-timing grounds.
PMID:22186409 SUPPORT Model Organism
"Male-to-female sex reversal in Cbx2 KO mice was rescued by crossing them with transgenic mice displaying forced expression of Sry or Sox9."
Genetic rescue by Sry or Sox9 is the decisive test that the sex-reversal component is attributable to reduced Sry/Sox9 output rather than to some parallel defect.
PMID:19361780 SUPPORT Human Clinical
"revealed loss-of-function mutations that allowed us, by placing CBX2 upstream of SRY"
The human report's own conclusion places CBX2 upstream of SRY, extending the mouse ordering to the human cascade.
Impaired Genital Ridge Growth
A growth arm that is separable from the sex-determination arm. In M33-null mice the genital ridge forms late in both XX and XY embryos, and when sex reversal is genetically rescued by forced Sry or Sox9 expression the resulting testes are still hypoplastic. Gonadal size and gonadal sex are therefore controlled by different sets of CBX2-dependent genes, and this node carries the size component. It is the mechanistic reason a CBX2 gonad can be small or non-visualized independently of which way it differentiates.
gonad development GO:0008406 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased gonad development (GO:0008406). GO:0008406 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
M33cterm/Cbx2 null mouse (C57BL/6) Mouse recapitulates Genital ridge formation is retarded in both XX and XY nulls, and rescued XY animals still have hypoplastic testes, isolating a growth defect from the sex-determination defect.
Cbx2 null mouse (BALB/c) Mouse recapitulates The majority of XY nulls on this background are not sex-reversed and instead have bilateral testicular hypoplasia, isolating the gonadal growth phenotype from sex reversal within a single line.
Downstream
Dysgenetic Gonad
Show evidence (2 references)
PMID:22186409 SUPPORT Model Organism
"However, testes remained hypoplastic in these mice, indicating that the size and the sex of the gonad are determined by different sets of genes."
Explicitly separates the size defect from the sex-determination defect, which is why this node exists alongside the SRY node rather than inside it.
PMID:22200029 SUPPORT Model Organism
"while the remaining male mutant fetuses exhibited bilateral testicular hypoplasia"
Shows that Cbx2-null XY fetuses that were not sex-reversed still had hypoplastic testes, the growth phenotype in isolation.
Failure of Sertoli Cell Differentiation
Without an adequate SRY/SOX9 pulse, and with ovarian determinants de-repressed, the supporting-cell precursors of the XY gonad do not commit to the Sertoli lineage, or commit incompletely. In the CBX2.2 patient in whom gonadal tissue was recovered, the testes were dysgenetic with immature tubules containing Sertoli cells only and no identifiable Leydig cells; in the mouse, XY knockouts develop ovaries rather than testes.
Sertoli cell CL:0000216 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sertoli cell (CL:0000216). CL:0000216 is a cell type from the Cell Ontology.
Sertoli cell differentiation GO:0060008 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Sertoli cell differentiation (GO:0060008). GO:0060008 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Dysgenetic Gonad
Sertoli cell-only phenotype The two names read as contradictory but are not. Supporting cells that commit incompletely still line the tubule; what is missing is the germ cell population and the Leydig compartment, so the histological result of an arrested Sertoli programme is a tubule containing Sertoli cells and little else. Germ cell loss is the unnamed intermediate, which is why this edge is indirect.
Incomplete Mullerian Duct Regression Anti-Mullerian hormone is a fetal Sertoli cell product, so a gonad without a competent Sertoli compartment does not drive Mullerian regression.
Show evidence (1 reference)
PMID:22186409 SUPPORT Model Organism
"XY knockout (KO) mice develop ovaries but not testes, and the gonads are hypoplastic in both sexes"
The XY gonad follows the ovarian rather than the Sertoli/testicular route when Cbx2 is absent.
Dysgenetic Gonad
The convergence point of the entry: an XY gonad that is hypoplastic, dysgenetic, or has followed the ovarian route. What is found at operation varies strikingly across the three published patients — histologically normal ovarian tissue in the CBX2.1 index girl, Sertoli-cell-only dysgenetic testes in one CBX2.2 patient, and no identifiable gonadal tissue at all in the other. All three lack a functioning fetal testis, which is what the downstream endocrine consequences follow from.
Leydig cell CL:0000178 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Leydig cell (CL:0000178). CL:0000178 is a cell type from the Cell Ontology.
male gonad development GO:0008584 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased male gonad development (GO:0008584). GO:0008584 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
M33cterm/Cbx2 null mouse (C57BL/6) Mouse partially recapitulates XY nulls on this background develop ovaries rather than testes, matching the CBX2.1 index patient's ovarian tissue but not the Sertoli-cell-only dysgenetic testes of the CBX2.2 patients.
Downstream
Absent Fetal Testicular Androgen Output
Loss of Negative Feedback on the Gonadotropic Axis
Gonadal dysgenesis
Bilateral cryptorchidism A dysgenetic gonad does not complete descent; both CBX2.2 patients had non-palpable gonads. The intermediate steps between gonadal dysgenesis and failed descent are not established in this disorder.
Show evidence (2 references)
PMID:19361780 SUPPORT Human Clinical
"A girl with a prenatal 46,XY karyotype was born with a completely normal female phenotype, including uterus and histologically normal ovaries."
Documents the ovarian end of the reported gonadal spectrum in a 46,XY individual.
PMID:29998616 SUPPORT Human Clinical
"A gonadectomy was performed, which revealed no gonadal tissue on histology evaluation"
Documents the opposite end of the same spectrum, where no gonadal tissue remained to be identified.
Absent Fetal Testicular Androgen Output
With no functional Leydig compartment, testosterone is not produced in the fetal window during which the external genitalia are masculinized, nor later. In one CBX2.2 patient an hCG stimulation test at two years produced neither a testosterone rise nor accumulation of steroid precursors, which is the pattern expected from absent steroidogenic tissue rather than from an enzymatic block within the androgen synthesis pathway. It is a single stimulation test in one patient, so it is consistent with that reading rather than decisive for it.
testosterone secretion GO:0035936 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased testosterone secretion (GO:0035936). GO:0035936 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Undervirilization of the External Genitalia
Decreased serum testosterone concentration
Show evidence (1 reference)
PMID:29998616 SUPPORT Human Clinical
"no testosterone increase and steroid precursor accumulation was found"
A flat hCG stimulation test with no precursor accumulation is the functional demonstration that androgen output is absent rather than enzymatically blocked.
Loss of Negative Feedback on the Gonadotropic Axis
Absent gonadal steroid and inhibin output releases the pituitary from negative feedback, so LH and FSH rise. Both CBX2.2 patients were hypergonadotropic, one with an FSH of 78 U/L against a stated upper limit of 12 U/L. This is the endocrine signature that identifies the lesion as primary gonadal rather than central.
gonadotropin secretion GO:0032274 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased gonadotropin secretion (GO:0032274). GO:0032274 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Hypergonadotropic hypogonadism
Elevated circulating follicle stimulating hormone level
Elevated circulating luteinizing hormone level
Undervirilization of the External Genitalia
In the absence of fetal androgen, the external genitalia develop along the default route. The degree is not uniform across the three reported patients: the CBX2.1 index girl had entirely normal female external genitalia, whereas the CBX2.2 patients had partial masculinization with microphallus, perineal hypospadias, bifid scrotum and non-palpable gonads. This variance is the main reason the entry carries two subtypes.
development of primary male sexual characteristics GO:0046546 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased development of primary male sexual characteristics (GO:0046546). GO:0046546 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Female external genitalia in individual with 46,XY karyotype
Perineal hypospadias
Micropenis
Bifid scrotum
Sex reversal
Show evidence (2 references)
PMID:29998616 SUPPORT Human Clinical
"He presented with atypical genitalia, characterized by microphallus (5.0 cm), bilateral cryptorchidism, perineal hypospadias and scrotum biphidus."
Enumerates the undervirilized external phenotype in one CBX2.2 patient.
PMID:19361780 SUPPORT Human Clinical
"was born with a completely normal female phenotype"
Records the fully unvirilized end of the same spectrum, which is why this node's description declines to assert a uniform degree.
Incomplete Mullerian Duct Regression
Anti-Mullerian hormone is a fetal Sertoli cell product, so a gonad that fails to make Sertoli cells does not regress the Mullerian ducts. Mullerian structures were present in two of the three reported patients — a normal uterus in the CBX2.1 index girl and a hypoplastic uterus found unexpectedly at gonadectomy in one CBX2.2 patient — while the other CBX2.2 patient had no Mullerian derivatives on imaging. The inconsistency tracks the gonadal findings: a partially functional fetal Sertoli compartment regresses the ducts partially.
Sertoli cell CL:0000216 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sertoli cell (CL:0000216). CL:0000216 is a cell type from the Cell Ontology.
Downstream
Hypoplasia of the uterus
Show evidence (2 references)
PMID:29998616 SUPPORT Human Clinical
"A gonadectomy was performed, which revealed no gonadal tissue on histology evaluation and furthermore, a hypoplastic uterus was found."
Records persistence of a Mullerian derivative in a 46,XY patient whose gonad had no identifiable tissue, i.e. no fetal Sertoli compartment to regress it.
PMID:19361780 SUPPORT Human Clinical
"born with a completely normal female phenotype, including uterus and histologically normal ovaries"
Documents a fully retained uterus in the index patient, the complete non-regression end of this node's range.
✶

Histopathology

2
Dysgenetic testis with Sertoli-cell-only tubules and absent Leydig cells
Gonadectomy material from the first CBX2.2 patient showed dysgenetic testes: immature seminiferous tubules lined by Sertoli cells only, containing a few atypical spermatogonia, with no Leydig cells identifiable in the interstitium. The absent Leydig compartment is the histological counterpart of the flat hCG stimulation test in the same patient.
Show evidence (1 reference)
PMID:29998616 SUPPORT Human Clinical
"Anatomopathological data showed dysgenetic testes characterized by immature tubules with Sertoli cells only and a few atypical spermatogonias. No Leydig cells were identified in the interstitium."
The full histological description quoted from the report.
Histologically normal ovarian tissue in a 46,XY individual
The index CBX2.1 patient's gonads were histologically normal ovaries. This is the single most distinctive pathological finding of the disorder and the reason it is not simply an allelic form of complete gonadal dysgenesis, where fibrous streak gonads are the expected finding.
Show evidence (1 reference)
PMID:19361780 SUPPORT Human Clinical
"including uterus and histologically normal ovaries"
States the histological result directly.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for 46,XY Sex Reversal 5 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

14
Endocrine 4
Hypergonadotropic hypogonadism HP:0000815 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypergonadotropic hypogonadism (HP:0000815). HP:0000815 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29998616 SUPPORT Human Clinical
"laboratory evaluation showed hypergonadotropic hypogonadism with LH levels of 10 U/L, FSH levels of 78 U/L, and testosterone levels of 75 ng/dL"
States the diagnosis and gives the supporting hormone values.
Elevated circulating follicle stimulating hormone level HP:0008232 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating follicle stimulating hormone level (HP:0008232). HP:0008232 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29998616 SUPPORT Human Clinical
"serum LH level was 16 U/L, FSH level was 54 U/L, and testosterone level was 230 ng/dl"
Records the raised FSH in the first CBX2.2 patient.
Elevated circulating luteinizing hormone level HP:0011969 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating luteinizing hormone level (HP:0011969). HP:0011969 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29998616 SUPPORT Human Clinical
"serum LH level was 16 U/L, FSH level was 54 U/L"
Records the raised LH in the first CBX2.2 patient.
Decreased serum testosterone concentration HP:0040171 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased serum testosterone concentration (HP:0040171). HP:0040171 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29998616 SUPPORT Human Clinical
"FSH levels of 78 U/L, and testosterone levels of 75 ng/dL"
Gives the low measured testosterone value in the second CBX2.2 patient.
Genitourinary 9
Female external genitalia in individual with 46,XY karyotype HP:0008730 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Female external genitalia in individual with 46,XY karyotype (HP:0008730). HP:0008730 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19361780 SUPPORT Human Clinical
"A girl with a prenatal 46,XY karyotype was born with a completely normal female phenotype, including uterus and histologically normal ovaries."
Direct description of a completely female external phenotype in a 46,XY individual.
Sex reversal HP:0012245 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sex reversal (HP:0012245). HP:0012245 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:35263754 SUPPORT Other
"genetic variants or loss-of-function of CBX2 can cause sex reversal in mice and humans"
A review statement that CBX2 loss of function causes sex reversal in humans as well as mice, supporting this as the defining feature.
PMID:9641679 SUPPORT Model Organism
"survivors showed male-to-female sex reversal"
The orthologous mouse phenotype. Recorded as model-organism evidence alongside, not in place of, the human observation. Note the quantifier in the preceding clause of that sentence ("more than half") attaches to pre-weaning mortality, not to the sex-reversal rate; the murine rates are cited separately and by strain below.
PMID:22200029 SUPPORT Model Organism
"the majority of Cbx2 null mice on the B6 background exhibit male to female sex reversal and approximately 50% of surviving adult mice exhibited bilateral ovaries"
The murine sex-reversal rate on the C57BL/6 background, stated as such. This is the sentence the entry uses for a frequency claim, in place of the 1998 abstract's "more than half", which describes mortality.
+ 1 more reference
Gonadal dysgenesis Gonadal dysgenesis, male HP:0008668 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gonadal dysgenesis, male (HP:0008668). HP:0008668 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29998616 SUPPORT Human Clinical
"At 10 years of age he was submitted to exploratory laparotomy which disclosed bilateral atrophic testis that were removed."
Operative confirmation of atrophic, dysgenetic gonads in a CBX2.2 patient.
Sertoli cell-only phenotype HP:0034299 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sertoli cell-only phenotype (HP:0034299). HP:0034299 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29998616 SUPPORT Human Clinical
"dysgenetic testes characterized by immature tubules with Sertoli cells only and a few atypical spermatogonias"
Direct histological description of the Sertoli-cell-only tubules.
Perineal hypospadias HP:0000051 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Perineal hypospadias (HP:0000051). HP:0000051 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29998616 SUPPORT Human Clinical
"two patients with features of DSD i.e. atypical external genitalia, perineal hypospadias and no palpable gonads"
Names perineal hypospadias as a feature of both reported CBX2.2 patients.
Micropenis HP:0000054 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micropenis (HP:0000054). HP:0000054 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29998616 SUPPORT Human Clinical
"atypical genitalia, characterized by microphallus (5.0 cm), bilateral cryptorchidism, perineal hypospadias and scrotum biphidus"
Records the measured microphallus in the second CBX2.2 patient.
Bifid scrotum HP:0000048 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bifid scrotum (HP:0000048). HP:0000048 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29998616 SUPPORT Human Clinical
"perineal hypospadias and scrotum biphidus"
Direct report of a bifid scrotum in this patient.
Bilateral cryptorchidism HP:0008689 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral cryptorchidism (HP:0008689). HP:0008689 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29998616 SUPPORT Human Clinical
"microphallus (5.0 cm), bilateral cryptorchidism, perineal hypospadias"
Explicit report of bilateral cryptorchidism.
Hypoplasia of the uterus HP:0000013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the uterus (HP:0000013). HP:0000013 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29998616 SUPPORT Human Clinical
"furthermore, a hypoplastic uterus was found"
Direct operative report of the hypoplastic uterus.
Other 1
Ovarian tissue in an individual with a 46,XY karyotype
Show evidence (2 references)
PMID:19361780 SUPPORT Human Clinical
"including uterus and histologically normal ovaries"
States that the gonads were histologically normal ovaries, which is the exact claim and the reason a dysgenesis term is not used.
PMID:31719618 SUPPORT Model Organism
"M33 knockout mice are sterile, and 50% of the Sry positive mice are phenotypically female, with ovarian-like tissue"
The mouse counterpart is ovarian-like tissue rather than streak gonads, which is why the human ovarian finding is treated as the expected orthologous outcome rather than an anomaly.
🧬

Genetic Associations

1
CBX2
Gene: CBX2 hgnc:1552 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CBX2 (hgnc:1552). hgnc:1552 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (4 references)
PMID:19361780 SUPPORT Human Clinical
"The analysis of the human homolog of M33, Chromobox homolog 2 (CBX2), in this girl revealed loss-of-function mutations"
Establishes CBX2 loss-of-function variants as the cause in the index patient, the basis for the gene-disease assignment.
PMID:29998616 SUPPORT Human Clinical
"each patient carrying a distinct CBX2.2 variant, p.Cys132Arg (c.394T>C) and p.Cys154fs (c.460delT)"
Names the two CBX2.2 alleles recorded in this entry's allele list.
PMID:29998616 SUPPORT Human Clinical
"ExAC predicts for CBX2 a pLI (probability of LOF intolerance) of 0.95"
Source for the constraint metric quoted in the notes.
+ 1 more reference
🗃️

External Assertions

3
OMIM 46,XY sex reversal 5 record
OMIM disease record OMIM:613080
The OMIM phenotype record that defines SRXY5 and assigns it autosomal recessive inheritance on the strength of the 2009 index patient.
ClinVar CBX2 c.293C>T (p.Pro98Leu)
ClinVar variant classification NM_005189.3(CBX2):c.293C>T
One of the two index-case alleles, classified Pathogenic for 46,XY sex reversal 5. Recorded as an external assertion rather than as an evidence item because no cached publication in this entry names the allele; the classification is ClinVar's, not this entry's.
ClinVar CBX2 c.1328G>C (p.Arg443Pro)
ClinVar variant classification NM_005189.3(CBX2):c.1328G>C
The second index-case allele, classified Pathogenic for 46,XY sex reversal 5. Same caveat as the first: this is ClinVar's classification, carried here for traceability rather than as curated evidence.
💊

Medical Actions

4
Androgen Replacement Therapy
Category: Therapeutic Action: hormone replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hormone replacement therapy (NCIT:C15599). NCIT:C15599 is a clinical intervention from the NCI Thesaurus. Ontology label: Hormone Replacement Therapy NCIT:C15599
Agent: testosterone CHEBI:17347 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses testosterone (CHEBI:17347). CHEBI:17347 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Exogenous testosterone in individuals with a male gender identity and no functioning gonad, to induce and maintain secondary sexual characteristics. Both reported CBX2.2 patients received it: the first started testosterone esters at seventeen years, the second testosterone cypionate after gonadectomy and genitoplasty. This records what was done for two patients, not a dose-finding or outcome study, of which none exists for this disorder. The choice of androgen rather than estrogen replacement follows the sex of rearing, which in the first patient was changed to male at five years of age after psychological evaluation.
Mechanism Target:
Absent Fetal Testicular Androgen Output — Replacement does not restore gonadal function; it substitutes for the missing hormonal output of this node from puberty onward. It cannot reverse the fetal undervirilization that occurred before treatment.
Target Phenotypes: Hypergonadotropic hypogonadism HP:0000815 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypergonadotropic hypogonadism (HP:0000815). HP:0000815 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29998616 SUPPORT Human Clinical
"By 17 years of age, he started androgen replacement with testosterone esters."
Documents androgen replacement in the first CBX2.2 patient and the age at which it began.
PMID:29998616 SUPPORT Human Clinical
"testosterone replacement was started by using testosterone cypionate"
Documents the same intervention, with a different ester, in the second patient.
Gonadectomy
Category: Therapeutic Action: bilateral gonadectomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is bilateral gonadectomy, annotated with Bilateral Orchiectomy (NCIT:C218841). NCIT:C218841 is a clinical intervention from the NCI Thesaurus. Ontology label: Bilateral Orchiectomy NCIT:C218841
Platform: Surgery
Removal of the dysgenetic gonads, performed in both reported CBX2.2 patients. In the first this was an exploratory laparotomy at ten years that disclosed and removed bilateral atrophic testes; in the second a gonadectomy found no gonadal tissue at all. The publication does not state a malignancy rationale for either operation, and no gonadal tumour has been reported in any CBX2 patient, so this entry records gonadectomy as reported management and deliberately attaches no tumour-risk figure to it. Timing and necessity of gonadectomy are actively contested in DSD care generally; see the tumour-risk discussion.
Mechanism Target:
Dysgenetic Gonad — Removes the dysgenetic gonad itself. It is not a mechanistic intervention - nothing upstream is corrected, and the endocrine consequences of an absent gonad are made permanent, which is why androgen replacement is recorded alongside it.
Target Phenotypes: Gonadal dysgenesis, male HP:0008668 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Gonadal dysgenesis, male (HP:0008668). HP:0008668 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29998616 SUPPORT Human Clinical
"exploratory laparotomy which disclosed bilateral atrophic testis that were removed"
Records the operation and its findings in the first CBX2.2 patient.
Genitoplasty and Testicular Prosthesis
Category: Therapeutic Action: genitoplastyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genitoplasty, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Reconstructive genital surgery with testicular prosthesis implantation, performed in the second CBX2.2 patient, who presented as an adult male with perineal hypospadias and a bifid scrotum. Recorded as what was done for one patient; genital surgery in DSD is a contested area in which timing and consent are the substantive questions, and nothing in this single report speaks to them.
Mechanism Target:
Undervirilization of the External Genitalia — Addresses the anatomical result of absent fetal androgen exposure. It acts on the outcome of that node long after the developmental window has closed, and corrects nothing upstream of it.
Target Phenotypes: Perineal hypospadias HP:0000051 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Perineal hypospadias (HP:0000051). HP:0000051 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29998616 SUPPORT Human Clinical
"Genitoplasty, followed by testicular prosthesis implant was performed."
Direct report of the procedures performed.
Multidisciplinary DSD Care and Sex Assignment
Category: Counseling / Informational Action: multidisciplinary disorders-of-sex-development careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is multidisciplinary disorders-of-sex-development care, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Behavioral / lifestyle
Nothing disease-modifying exists for CBX2-related DSD, so care follows the general DSD framework: an individualized multidisciplinary assessment, a sex assignment decision made on the most likely adult gender identity together with diagnosis, genital appearance, fertility potential and psychosocial context, and full disclosure to family and patient. This is a class-level standard imported from DSD care generally, not a CBX2-specific protocol, and it is recorded as such. Its relevance here is concrete rather than decorative: the first CBX2.2 patient was initially raised female and changed to male social sex at five years of age after psychological evaluation, which is exactly the situation this framework governs.
Show evidence (2 references)
PMID:17885459 SUPPORT Other
"All need a sex assignment; recommendations should be based upon what is judged to be the most likely adult gender identity, diagnosis, genital appearance and surgical options, fertility, cultural pressures, family dynamics and social circumstance, with deference given to psychosocial factors..."
States the sex-assignment criteria this treatment records. Graded OTHER because the source is a consensus-based review of management practice rather than a study reporting patient data.
PMID:17885459 SUPPORT Other
"the complex management of these patients must be individualized, considering all aspects, informing as age-appropriate the parents and patient"
Supports the individualized, multidisciplinary and disclosure-based character of the intervention.
🔬

Diagnosis

4
Karyotype-phenotype discordance as the entry point
There is no screening pathway for this disorder; every reported patient reached diagnosis through a mismatch between chromosomal and phenotypic sex. The CBX2.1 index patient is the instructive case: her external genitalia were entirely normal, so nothing at birth would have prompted investigation, and she was identified only because a prenatal 46,XY karyotype already existed to contradict. That route implies the fully sex-reversed presentation is systematically under-ascertained.
karyotyping NCIT:C16768 NCI Thesaurus (NCIT)
Results: A 46,XY karyotype that does not match the observed phenotype.
Show evidence (2 references)
PMID:19361780 SUPPORT Human Clinical
"A girl with a prenatal 46,XY karyotype was born with a completely normal female phenotype, including uterus and histologically normal ovaries."
The prenatal karyotype is what made the discordance visible in a patient whose phenotype was otherwise unremarkable.
PMID:29998616 SUPPORT Human Clinical
"accidentally diagnosed because of a discrepancy between prenatal karyotype and phenotype at birth"
States the ascertainment route explicitly, and characterises it as accidental.
hCG stimulation testing of gonadal steroidogenic capacity
Distinguishes absent or non-functional steroidogenic tissue from an enzymatic block in androgen synthesis, which is the main biochemical differential for an undervirilized 46,XY infant. In the first CBX2.2 patient the test produced neither a testosterone rise nor precursor accumulation, the pattern of an absent Leydig compartment rather than of a steroidogenic-enzyme defect; gonadal histology later showed no Leydig cells.
human chorionic gonadotropin stimulation test NCIT:C74742 NCI Thesaurus (NCIT)
Results: No testosterone rise and no steroid precursor accumulation.
Show evidence (1 reference)
PMID:29998616 SUPPORT Human Clinical
"a human chorionic gonadotropin (hCG) stimulation test was performed (two doses of 2,000 U) and no testosterone increase and steroid precursor accumulation was found"
Records the test, the dose, and the flat result that this diagnostic entry describes.
Gonadotropin and testosterone measurement
Raised LH and FSH with low testosterone localise the lesion to the gonad rather than to the hypothalamic-pituitary axis. Both CBX2.2 patients were hypergonadotropic at presentation; this is the finding that separates primary gonadal failure from central hypogonadism and is the practical trigger for imaging and gonadal assessment.
gonadotropin and sex steroid measurement NCIT:C124351 NCI Thesaurus (NCIT)
Results: Elevated LH and FSH with low serum testosterone.
Show evidence (1 reference)
PMID:29998616 SUPPORT Human Clinical
"laboratory evaluation showed hypergonadotropic hypogonadism with LH levels of 10 U/L, FSH levels of 78 U/L, and testosterone levels of 75 ng/dL"
The measured hormone profile that this diagnostic entry is built on.
CBX2 sequencing and copy-number analysis
Molecular confirmation. A dedicated MLPA probe set for CBX2 copy-number change was developed for the 47-patient gonadal-DSD screen and is the published means of excluding CBX2 deletions and duplications, which sequencing alone would miss. That screen found no pathogenic CBX2 variant and no copy-number change in any patient, which is also the reason CBX2 testing in practice happens as part of a DSD panel or exome rather than as a single-gene test. Isoform coverage matters: the CBX2.2 report postdates that screen, so an assay designed only around CBX2.1 may not interrogate the short isoform adequately.
multiplex ligation-dependent probe amplification NCIT:C116161 NCI Thesaurus (NCIT)
Results: No pathogenic sequence variant and no CBX2 copy-number change in the published gonadal-DSD cohort.
Show evidence (2 references)
PMID:23219007 SUPPORT Human Clinical
"CBX2 gene sequencing and development of a synthetic probe set for multiplex ligation probe amplification (MLPA) to detect CBX2 copy number changes"
Describes the assay pair this diagnostic entry records, including the purpose-built MLPA probe set.
PMID:23219007 SUPPORT Human Clinical
"No deletions or duplications were detected by MLPA."
The copy-number result in that cohort, quoted so the entry's own statement that no CNV was found is sourced rather than asserted.
📊

Prevalence

1
Worldwide
Cases In Literature Not yet documented
No population prevalence or incidence figure has been published. The entire literature this entry draws on describes three individuals: one 46,XY girl with double-heterozygous CBX2.1 variants (2009) and two 46,XY individuals with CBX2.2 variants (2018). That is the set of primary reports found here, not a verified census of the world literature. A dedicated screen of 47 patients with 46,XY or 46,XX gonadal DSD found no pathogenic CBX2 variant, which bounds the contribution of CBX2 to ascertained gonadal DSD from above but yields no population rate. This is a case tally, not an occurrence estimate.
Show evidence (1 reference)
PMID:23219007 SUPPORT Human Clinical
"This study does not support CBX2 gene disruption as a common cause of gonadal DSD."
A targeted CBX2 screen of a gonadal-DSD cohort concluded the gene is not a common cause, supporting the extreme rarity recorded here rather than a numeric rate.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from 46,XY Sex Reversal 5:

46,XY complete gonadal dysgenesis (Swyer syndrome) MONDO:0010765
Overlapping Features The nonsyndromic form, in which a 46,XY individual has female external genitalia, Mullerian structures and bilateral fibrous streak gonads. This is the parent MONDO class of SRXY5 and the most important distinction to make. The dismech entry for 46,XY complete gonadal dysgenesis explicitly places CBX2 outside its scope on the grounds that the canonical CBX2 phenotype had ovarian-like rather than bilateral streak gonads, so the two entries partition rather than overlap.
Distinguishing Features
  • Bilateral fibrous streak gonads rather than histologically normal ovarian tissue
  • Usually attributable to SRY, NR5A1, MAP3K1, DHX37 or SOX9-regulatory lesions rather than CBX2
  • The undervirilized CBX2.2 presentation with dysgenetic Sertoli-cell-only testes is partial rather than complete dysgenesis and does not belong to this class at all
📊

Related Datasets

1
CBX2 is required to stabilize the testis pathway by repressing Wnt signaling geo:GSE130749
house mouse CHIP SEQ
PMID:31116734
Quantitative H3K4me3 and H3K27me3 profiles of FACS-purified XX and XY gonadal supporting cells before (E10.5) and after (E13.5) sex determination, generated for the study that proposed the ovarian-derepression model. This is the one dataset found that is actually about CBX2 in gonadal sex determination: a dataset search on the gene name otherwise returns CBX2 chromatin and cancer studies, and one on the disease name returns word matches on "sex reversal" in unrelated cohorts. Those were triaged out rather than listed. The data are murine gonadal supporting cells, not patient material; no human CBX2-patient dataset exists.
🐁

Animal Models

3
M33cterm/Cbx2 null mouse (C57BL/6)
Targeted disruption of M33/Cbx2 by insertion of a poly(A) capture-type neo vector into the fifth exon, maintained on C57BL/6. More than half of homozygous mutants die before weaning; survivors show male-to-female sex reversal, and genital ridge formation is retarded in both XX and XY embryos. This model is the origin of the entire CBX2 sex-development hypothesis: the human index case was investigated precisely because the girl's phenotype matched it. Later work in the same line established the Sry-expression mechanism and the Sry/Sox9 rescue. Its principal divergence from human disease is the extragonadal phenotype - skeletal, splenic and adrenal - which human CBX2 patients do not report. Note this is one of two distinct published Cbx2 null lines and the two are not interchangeable: the separately curated BALB/c line below uses a different allele and gives a substantially lower sex-reversal rate, and figures from one must not be quoted for the other.
Species
Mouse
Genotype
M33cterm homozygous (poly(A) neo insertion into Cbx2 exon 5)
Background
C57BL/6
Genes
CBX2 hgnc:1552 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns CBX2 (hgnc:1552). hgnc:1552 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:9641679
Pathograph links
Reduced SRY Expression in the Bipotential Gonad recapitulates fidelity: high Cbx2-null gonads have reduced Sry expression, and forced Sry or Sox9 expression rescues the sex reversal. This is the strongest evidence in either species for the node.
Limitations: The ordering is established in mouse; the human equivalent rests on in vitro transactivation assays with the patient's mutant protein rather than on measured SRY levels in a patient gonad.
Readouts
Gonadal Sry transcript level
Direction: DECREASED
Interpretation: Sry expression is altered in the knockout gonad. The direction recorded here is DECREASED, which the cited sentence does not itself state - it says only "affected" - and which follows from the paper's title claim that Cbx2 is required for Sry expression, and from the rescue by forced Sry expression.
Show evidence (2 references)
PMID:22186409 SUPPORT INDIRECT Model Organism
"the expression of Sry, Sox9, Lhx9, Ad4BP/SF-1, Dax-1, Gata4, Arx, and Dmrt1, genes encoding transcription factors essential for gonadal development, is affected in Cbx2 KO gonads"
Reports that Sry expression is altered in Cbx2 knockout gonads by microarray, RT-PCR and immunohistochemistry. Indirect for the direction: the sentence establishes that Sry is affected, and the downward direction follows by inference from the rescue experiment rather than from this quote.
+ 1 more reference
Show evidence (1 reference)
PMID:22186409 SUPPORT Model Organism
"Our study implicates Cbx2 in testis differentiation through regulating Sry gene expression."
The paper's own conclusion that this model is informative for the Cbx2-to-Sry step.
Impaired Genital Ridge Growth recapitulates fidelity: moderate Genital ridge formation is retarded in both XX and XY nulls, and rescued XY animals still have hypoplastic testes, isolating a growth defect from the sex-determination defect.
Limitations: No human CBX2 patient has had gonadal volume measured against a normative standard, so the human counterpart of this readout is inferred from non-visualized or atrophic gonads rather than measured.
Readouts
Testis size after Sry/Sox9 rescue
Direction: DECREASED
Interpretation: Persisting hypoplasia after the sex reversal is rescued is what establishes gonadal size as a separately controlled output.
Show evidence (1 reference)
PMID:22186409 SUPPORT Model Organism
"However, testes remained hypoplastic in these mice, indicating that the size and the sex of the gonad are determined by different sets of genes."
Reports the measurement and the inference drawn from it.
Dysgenetic Gonad partially recapitulates fidelity: moderate XY nulls on this background develop ovaries rather than testes, matching the CBX2.1 index patient's ovarian tissue but not the Sertoli-cell-only dysgenetic testes of the CBX2.2 patients.
Limitations: Even on this background the outcome is not uniform - about half of surviving adults have bilateral ovaries - so the line does not reproduce a single consistent human gonadal outcome. The mouse also has no CBX2.2 equivalent arm, so the second human presentation is unmodelled. Rates from the BALB/c line curated separately below do not apply here.
Readouts
Gonadal histology in XY nulls on C57BL/6
Direction: ALTERED
Interpretation: The XY gonad follows the ovarian route rather than forming a normal testis, in the majority of animals on this background.
Show evidence (1 reference)
PMID:22200029 SUPPORT Model Organism
"the majority of Cbx2 null mice on the B6 background exhibit male to female sex reversal and approximately 50% of surviving adult mice exhibited bilateral ovaries"
States the gonadal outcome specifically for the C57BL/6 background, which is the background of this model. Quoted from a paper that studied the other line precisely because it draws the strain contrast explicitly.
Show evidence (2 references)
PMID:9641679 SUPPORT Model Organism
"More than half of the resultant M33cterm/M33cterm mutant mice died before weaning, and survivors showed male-to-female sex reversal."
Establishes the model's defining phenotype and its use as a model of CBX2-related sex reversal.
PMID:19361780 SUPPORT Human Clinical
"In mice with a similar phenotype, the ablation of M33, an ortholog of Drosophila Polycomb, causes male-to-female sex reversal."
The human report explicitly reasons from this model to the human gene, which is the sense in which the model is informative for this disorder.
Cbx2 null mouse (BALB/c)
A second, independently generated Cbx2 null line carrying a different allele - deletion of the 5' untranslated region including the translation start site and the first four coding exons - and maintained on BALB/c rather than C57BL/6. It is curated separately from the M33cterm line above because the two give materially different phenotypes and the paper that characterised this one makes that contrast its central point: fewer than 30% of BALB/c nulls are sex-reversed, against a majority on B6. Most affected BALB/c males instead have bilateral testicular hypoplasia, which is what makes this line the cleaner one for separating the gonadal growth defect from the sex-determination defect. Quoting a rate from this line for the B6 line, or the reverse, is a strain error.
Species
Mouse
Genotype
Cbx2 homozygous null (5' UTR and first four coding exons deleted)
Background
BALB/c
Genes
CBX2 hgnc:1552 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns CBX2 (hgnc:1552). hgnc:1552 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:22200029
Pathograph links
Impaired Genital Ridge Growth recapitulates fidelity: moderate The majority of XY nulls on this background are not sex-reversed and instead have bilateral testicular hypoplasia, isolating the gonadal growth phenotype from sex reversal within a single line.
Limitations: Gonadal volume in human CBX2 patients has never been measured against a normative standard, so the human counterpart of this readout is inferred from non-visualized or atrophic gonads rather than measured. The BALB/c background is itself the reason the growth phenotype is visible here, so the dissociation may be strain-specific rather than a general property of Cbx2 loss.
Readouts
Gonadal phenotype in XY nulls on BALB/c
Direction: DECREASED
Interpretation: Bilateral testicular hypoplasia in non-sex-reversed XY nulls is the growth defect observed without the confound of sex reversal.
Show evidence (1 reference)
PMID:22200029 SUPPORT Model Organism
"Our analysis revealed sex reversal in 28.6% of XY(-/-) embryos, in which a hypoplastic testis and a contralateral ovary were observed in close proximity to the kidney, while the remaining male mutant fetuses exhibited bilateral testicular hypoplasia."
Reports both the sex-reversal rate on this background and the gonadal phenotype of the remainder, which is the measurement this readout records.
Show evidence (1 reference)
PMID:22200029 SUPPORT Model Organism
"In contrast, our study reveals that in the BALB/C model <30% of mice exhibit sex reversal."
Establishes that this line is informative for the growth arm precisely because most of its XY nulls escape sex reversal.
Show evidence (1 reference)
PMID:22200029 SUPPORT Model Organism
"involved the targeted deletion of the 5′ untranslated region including the translation start site and the first four exons of the Cbx2 coding sequence"
Describes the allele, establishing that this is a different construct from the M33cterm exon-5 insertion curated above.
Cbx2/Wnt4 double-null rescue mouse
An epistasis model rather than a disease model. Removing the ovary-promoting gene Wnt4 from a Cbx2-null XY animal restores both Sry expression and testis development, which is the decisive experiment behind the alternative ovarian-derepression hypothesis. Its value here is that it tests the direction of causation, not that it reproduces the human phenotype - which it deliberately does not.
Species
Mouse
Genotype
Cbx2-/-;Wnt4-/- (XY)
Genes
CBX2 hgnc:1552 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns CBX2 (hgnc:1552). hgnc:1552 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:31116734
Pathograph links
Loss of CBX2 Repression of the Ovarian Programme rescues fidelity: moderate Deleting Wnt4 removes the de-repressed ovarian signal and rescues the XY gonad, showing that the block to testis development in Cbx2 nulls runs through unopposed ovarian determinants.
Limitations: The rescue is genetic and murine. There is no human counterpart, and the experiment cannot say which mechanism dominates in a human gonad carrying hypomorphic rather than null CBX2 alleles.
Readouts
Sry expression and testis development in XY double nulls
Direction: RESTORED
Interpretation: Restoration of both the Sry pulse and testis morphogenesis on removing a single ovarian determinant is what makes this an epistasis result rather than a modifier effect.
Show evidence (1 reference)
PMID:31116734 SUPPORT Model Organism
"We show that Sry expression and testis development were rescued in XY Cbx2-/-;Wnt4-/- mice."
The measured rescue of both readouts in the double-null animals.
Show evidence (1 reference)
PMID:31116734 SUPPORT Model Organism
"Our results suggest that stabilization of the testis fate requires CBX2-mediated repression of bivalent ovary-determining genes, which would otherwise block testis development."
The authors' conclusion that this model is informative for CBX2-mediated repression of the ovarian programme.
Show evidence (1 reference)
PMID:31116734 SUPPORT Model Organism
"loss of CBX2, the subunit of the Polycomb Repressive Complex 1 (PRC1) that binds H3K27me3 and mediates silencing, leads to ovary development in XY mice and humans"
Establishes that the model system is CBX2 loss in an XY gonad, the same lesion as the human disorder.
{ }

Source YAML

click to show 
name: 46,XY Sex Reversal 5
creation_date: "2026-09-01T00:00:00Z"
category: Mendelian
synonyms:
- SRXY5
- 46,XY sex reversal type 5
- disorder of sex development, 46,XY, CBX2-related
- CBX2-related 46,XY disorder of sex development
- 46,XY gonadal dysgenesis, complete, CBX2-related
description: >-
  A very rare 46,XY disorder of sex development attributed to loss-of-function
  variants in CBX2, the human orthologue of Drosophila Polycomb (M33) and a
  chromodomain subunit of Polycomb repressive complex 1. CBX2 acts at the
  earliest, pre-SRY step of testis determination: rather than behaving purely as
  a repressive chromatin modifier, it transactivates the male programme
  (NR5A1/SF1, SOX9) while repressing ovarian determinants (WNT4, PBX1, and
  indirectly FOXL2), so its loss removes the male bias from the bipotential
  gonad. The disorder is defined by a single index patient reported in 2009 — a
  46,XY girl ascertained through a discrepancy between her prenatal karyotype
  and her phenotype at birth, who had entirely normal female external genitalia,
  a uterus and histologically normal ovaries, and carried double-heterozygous
  CBX2.1 variants. Two later 46,XY individuals carrying variants in the shorter
  CBX2.2 isoform presented very differently, with atypical external genitalia,
  perineal hypospadias and non-palpable gonads; one had dysgenetic testes with
  Sertoli-cell-only tubules and the other no identifiable gonadal tissue at
  gonadectomy. Their variants impair regulation of a distinct target set
  including EMX2. Together these define an isoform-split phenotypic spectrum
  rather than a single stereotyped presentation. CBX2 is not a common cause of
  gonadal DSD: a dedicated screen of 47 patients with 46,XY or 46,XX gonadal DSD
  found no pathogenic CBX2 variant, so the caseload this entry rests on is three
  individuals and the gene-disease relationship rests on functional rather than
  segregation evidence.
disease_term:
  preferred_term: 46,XY sex reversal 5
  term:
    id: MONDO:0013120
    label: 46,XY sex reversal 5
parents:
- Disorder of sex development
- 46,XY disorder of sex development
- Gonadal development disorder
has_subtypes:
- name: CBX2.1
  display_name: CBX2.1 (isoform 1) related, complete female phenotype
  description: >-
    The originally described and OMIM-defining presentation: a 46,XY individual
    with a completely female phenotype — normal female external genitalia, a
    uterus, and histologically normal ovarian tissue rather than streak gonads.
    Reported in one girl carrying double-heterozygous variants in the long
    CBX2.1 isoform, whose mutant protein failed to transactivate NR5A1/SF1.
    Because the external phenotype is unremarkable, ascertainment depended on a
    prenatal karyotype, which is why this presentation is expected to be
    systematically under-detected.
  evidence:
  - reference: PMID:19361780
    reference_title: "Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A girl with a prenatal 46,XY karyotype was born with a completely normal female phenotype, including uterus and histologically normal ovaries."
    explanation: >-
      The single report defining this subtype, including the prenatal-karyotype
      route of ascertainment.
- name: CBX2.2
  display_name: CBX2.2 (isoform 2) related, undervirilized phenotype with dysgenetic testes
  description: >-
    Two unrelated 46,XY individuals carrying distinct variants in the shorter
    CBX2.2 isoform (p.Cys132Arg and p.Cys154fs) presented with atypical external
    genitalia, microphallus, perineal hypospadias and no palpable gonads, and
    were found to have dysgenetic Sertoli-cell-only testes or no residual
    gonadal tissue, with hypergonadotropic hypogonadism. In vitro these variants
    fail to regulate a target set distinct from that of CBX2.1, most notably
    EMX2. This arm is grouped under the same entry because the causal gene is
    the same, but note the caveats recorded in the entry notes: the zygosity of
    these variants is not reported as biallelic, so this subtype's relationship
    to the autosomal recessive CBX2.1 entity is not settled.
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe two patients with features of DSD i.e. atypical external genitalia, perineal hypospadias and no palpable gonads, each patient carrying a distinct CBX2.2 variant, p.Cys132Arg (c.394T>C) and p.Cys154fs (c.460delT)."
    explanation: >-
      The single report defining this subtype: both patients, their external
      phenotype, and the two isoform-2 alleles.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population prevalence or incidence figure has been published. The entire
    literature this entry draws on describes three individuals: one 46,XY girl
    with double-heterozygous CBX2.1 variants (2009) and two 46,XY individuals
    with CBX2.2 variants (2018). That is the set of primary reports found here,
    not a verified census of the world literature. A dedicated screen of 47 patients with 46,XY or
    46,XX gonadal DSD found no pathogenic CBX2 variant, which bounds the
    contribution of CBX2 to ascertained gonadal DSD from above but yields no
    population rate. This is a case tally, not an occurrence estimate.
  evidence:
  - reference: PMID:23219007
    reference_title: "CBX2 gene analysis in patients with 46,XY and 46,XX gonadal disorders of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study does not support CBX2 gene disruption as a common cause of gonadal DSD."
    explanation: >-
      A targeted CBX2 screen of a gonadal-DSD cohort concluded the gene is not a
      common cause, supporting the extreme rarity recorded here rather than a
      numeric rate.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    The OMIM entity (SRXY5) is classified as autosomal recessive on the strength
    of the index patient, who is described as carrying two loss-of-function
    CBX2.1 variants as a double heterozygote. No cached source reports phase, so
    a trans configuration is not asserted here. CBX2 is at 17q25.3, so this is autosomal
    rather than sex-limited despite the phenotype being expressed only in 46,XY
    individuals. The recessive assignment rests on a single family; the two
    later CBX2.2 patients are each reported as carrying one variant, and their
    zygosity is not stated to be biallelic (see the CBX2.2 zygosity discussion).
  evidence:
  - reference: PMID:31719618
    reference_title: "CBX2-dependent transcriptional landscape: implications for human sex development and its defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "identified through a 46,XY girl with double heterozygous variants on CBX2.1, causing Differences of Sex Development (DSD)"
    explanation: >-
      States that the index patient carried two CBX2.1 variants, the observation
      the autosomal recessive assignment is based on.
genetic:
- name: CBX2
  gene_term:
    preferred_term: CBX2
    term:
      id: hgnc:1552
      label: CBX2
  relationship_type: CAUSATIVE
  notes: >-
    CBX2 (chromobox homolog 2, formerly M33) at 17q25.3 encodes a chromodomain
    subunit of Polycomb repressive complex 1. Two protein isoforms are produced:
    the long CBX2.1 and the short CBX2.2, which have partly non-overlapping
    target sets and are implicated in the two phenotypically distinct arms of
    this disorder. Reported disease alleles are the double-heterozygous CBX2.1
    variants of the index patient, and the CBX2.2 changes c.394T>C
    (p.Cys132Arg) and c.460delT (p.Cys154fs). The index alleles are reported as
    p.Pro98Leu and p.Arg443Pro; both are recorded in ClinVar as pathogenic for
    this condition, but no cached publication in this entry names them, so they
    are given here without an evidence item rather than attributed to a source
    that does not state them. On constraint: the 2018 CBX2.2 report quotes an
    ExAC pLI of 0.95 for CBX2. Current gnomAD constraint says the opposite:
    pLI 0.024, observed/expected LoF 0.52 (90% CI 0.33-0.87), LoF Z 1.85
    (gnomAD API, GRCh38, queried 2026-09-01; the deep-research report committed
    with this entry reports the same figures independently). CBX2 is therefore
    not loss-of-function intolerant, heterozygous LoF is tolerated in the
    general population, and that is what a recessive mechanism predicts. The
    0.95 figure is retained above only because it is what the cited paper
    reported, and it should not be used to argue for dominance.
  evidence:
  - reference: PMID:19361780
    reference_title: "Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The analysis of the human homolog of M33, Chromobox homolog 2 (CBX2), in this girl revealed loss-of-function mutations"
    explanation: >-
      Establishes CBX2 loss-of-function variants as the cause in the index
      patient, the basis for the gene-disease assignment.
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "each patient carrying a distinct CBX2.2 variant, p.Cys132Arg (c.394T>C) and p.Cys154fs (c.460delT)"
    explanation: >-
      Names the two CBX2.2 alleles recorded in this entry's allele list.
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ExAC predicts for CBX2 a pLI (probability of LOF intolerance) of 0.95"
    explanation: >-
      Source for the constraint metric quoted in the notes.
  - reference: PMID:35263754
    reference_title: "CBX2 in DSD: The Quirky Kid on the Block."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CBX2 was shown to be an essential factor for gonadal development in mammals, as genetic variants or loss-of-function of CBX2 can cause sex reversal in mice and humans."
    explanation: >-
      A review-level statement that CBX2 loss of function causes sex reversal in
      both species, cited here as the synthesis claim rather than as primary
      data.
external_assertions:
- name: OMIM 46,XY sex reversal 5 record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:613080
  url: https://omim.org/entry/613080
  description: >-
    The OMIM phenotype record that defines SRXY5 and assigns it autosomal
    recessive inheritance on the strength of the 2009 index patient.
- name: ClinVar CBX2 c.293C>T (p.Pro98Leu)
  source: ClinVar
  assertion_type: variant_classification
  external_id: NM_005189.3(CBX2):c.293C>T
  description: >-
    One of the two index-case alleles, classified Pathogenic for 46,XY sex
    reversal 5. Recorded as an external assertion rather than as an evidence
    item because no cached publication in this entry names the allele; the
    classification is ClinVar's, not this entry's.
- name: ClinVar CBX2 c.1328G>C (p.Arg443Pro)
  source: ClinVar
  assertion_type: variant_classification
  external_id: NM_005189.3(CBX2):c.1328G>C
  description: >-
    The second index-case allele, classified Pathogenic for 46,XY sex reversal
    5. Same caveat as the first: this is ClinVar's classification, carried here
    for traceability rather than as curated evidence.
mechanistic_hypotheses:
- hypothesis_group_id: cbx2_sry_transactivation_model
  hypothesis_label: CBX2 as a transactivator upstream of SRY
  status: CANONICAL
  description: >-
    The model the disorder was originally built on. CBX2 acts, unusually for a
    Polycomb protein, as a positive regulator: PRC1 containing CBX2/M33 binds
    the NR5A1/SF1 locus directly, CBX2-null mouse gonads have reduced Sry and
    Sox9, forced Sry or Sox9 expression rescues the sex reversal, and the human
    index patient's mutant CBX2.1 fails to transactivate NR5A1/SF1 in vitro.
    On this account the lesion is a failure to switch the male programme on.
  notes: >-
    Retained as CANONICAL because it is what the human functional diagnosis
    rests on: pathogenicity of the index patient's CBX2.1 variants was
    established by an NR5A1 transactivation assay, not by a repression assay.
  evidence:
  - reference: PMID:19361780
    reference_title: "Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed loss-of-function mutations that allowed us, by placing CBX2 upstream of SRY"
    explanation: >-
      The original report's own framing of the mechanism as CBX2 acting
      upstream of SRY.
  - reference: PMID:22186409
    reference_title: "Cbx2, a polycomb group gene, is required for Sry gene expression in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Male-to-female sex reversal in Cbx2 KO mice was rescued by crossing them with transgenic mice displaying forced expression of Sry or Sox9."
    explanation: >-
      Rescue by supplying Sry or Sox9 is the central genetic argument that the
      defect is insufficient male-pathway activation.
  - reference: PMID:31116734
    reference_title: CBX2 is required to stabilize the testis pathway by repressing Wnt signaling.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "We show that Sry expression and testis development were rescued in XY Cbx2-/-;Wnt4-/- mice."
    explanation: >-
      Cuts against this hypothesis. If the lesion were a lost activating input
      to Sry, deleting an ovary-promoting gene could not restore Sry expression;
      that it does implies the Sry deficit is downstream of unopposed ovarian
      signalling rather than of a missing activator.
- hypothesis_group_id: cbx2_ovarian_derepression_model
  hypothesis_label: CBX2 as a repressor of the ovary-promoting pathway
  status: ALTERNATIVE
  description: >-
    The competing account, and the one that fits CBX2's Polycomb identity. Here
    the primary lesion is loss of H3K27me3-mediated repression of ovary-promoting
    genes, which then block testis development; reduced Sry is a consequence
    rather than the cause. Sex-determining genes are bivalent in the bipotential
    gonad, CBX2 directly binds the Wnt effector Lef1, and deleting Wnt4 rescues
    both Sry expression and testis development in XY Cbx2-null mice.
  notes: >-
    This is not a refinement of the canonical model but a direct challenge to
    it: the authors explicitly investigated it as the alternative to CBX2 being
    an activator of Sry. The two models are not yet reconciled, and the human
    data cannot discriminate between them because no human CBX2 gonad has been
    profiled. Curated as ALTERNATIVE rather than CANONICAL because the decisive
    experiment is murine and the human diagnostic assay remains the
    transactivation one.
  evidence:
  - reference: PMID:31116734
    reference_title: CBX2 is required to stabilize the testis pathway by repressing Wnt signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our results suggest that stabilization of the testis fate requires CBX2-mediated repression of bivalent ovary-determining genes, which would otherwise block testis development."
    explanation: >-
      States the alternative model in the authors' own terms.
pathophysiology:
- name: CBX2 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Loss-of-function variants remove the activity of CBX2, the chromodomain
    subunit through which Polycomb repressive complex 1 is recruited to its
    target loci. CBX2 is expressed in the human gonad from around week 7 of
    gestation, before testis determination, and continues to be detected in both
    male and female gonads from week 9 to week 25. Because the protein acts both
    as a chromatin modifier and as a direct transactivator, its loss removes two
    separable activities at once, which is why downstream male genes fall and
    female genes rise from the same lesion. The node is named for the loss, not
    for a zygosity: the CBX2.1 index patient carried two variants, but the two
    CBX2.2 patients are each reported with a single variant, so calling the node
    biallelic would assert what the zygosity knowledge gap says is unresolved.
  biological_processes:
  - preferred_term: chromatin remodeling
    term:
      id: GO:0006338
      label: chromatin remodeling
    modifier: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: chromatin binding
    term:
      id: GO:0003682
      label: chromatin binding
    modifier: LOSS_OF_FUNCTION
  downstream:
  - target: Failure of CBX2 Transactivation of NR5A1 and SOX9
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31719618
      reference_title: "CBX2-dependent transcriptional landscape: implications for human sex development and its defects."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The mutated CBX2.1 failed to adequately regulate downstream targets important for sex development in humans, specifically steroidogenic factor 1 (NR5A1/SF1)."
      explanation: >-
        Directly links the patient's mutant CBX2.1 protein to failed regulation
        of NR5A1/SF1, which is the step this edge asserts.
  - target: Loss of CBX2 Repression of the Ovarian Programme
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25569159
      reference_title: "Genome-wide identification of CBX2 targets: insights in the human sex development network."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Overall, our findings suggest that CBX2 role in the sex development cascade is to stimulate the male pathway and concurrently inhibit the female pathway."
      explanation: >-
        Establishes that inhibition of the female pathway is a CBX2 function, so
        its loss is expected to de-repress that pathway.
  - target: Failure of CBX2.2-Dependent EMX2 Regulation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29998616
      reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We show that both CBX2.2 variants fail to regulate the expression of genes essential for sexual development"
      explanation: >-
        Attributes failed regulation of sex-development genes directly to the
        CBX2.2 variants themselves.
  - target: Impaired Genital Ridge Growth
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9641679
      reference_title: Male-to-female sex reversal in M33 mutant mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Formation of genital ridges was retarded in both XX and XY M33cterm/M33cterm embryos."
      explanation: >-
        Shows that loss of the mouse orthologue retards genital ridge formation,
        the growth arm of this lesion, and that it does so independently of
        chromosomal sex.
  evidence:
  - reference: PMID:22200029
    reference_title: "Role of polycomb group protein cbx2/m33 in meiosis onset and maintenance of chromosome stability in the Mammalian germline."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The mouse PcG family member M33/Cbx2 (Chromobox homolog protein 2) is a component of the Polycomb-Repressive Complex 1 (PRC1)."
    explanation: >-
      Identifies CBX2/M33 as a PRC1 component, the molecular identity this node
      asserts is lost.
  - reference: PMID:31719618
    reference_title: "CBX2-dependent transcriptional landscape: implications for human sex development and its defects."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CBX2 was shown to be expressed from week 9 to week 25 post-fertilization in both male and female gonads"
    explanation: >-
      Supplies the week 9 to 25 gonadal expression window quoted in this node's
      description. Graded OTHER rather than HUMAN_CLINICAL because the sentence
      is in this paper's introduction and reports a single-cell atlas it cites,
      not data it generated; the primary source is not cached here.
  - reference: PMID:31719618
    reference_title: "CBX2-dependent transcriptional landscape: implications for human sex development and its defects."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the known expression window of CBX2 in the early male gonad (week 7 of gestation), prior to testis determination"
    explanation: >-
      Sources the week-7 claim in this node's description, and the specific
      point that expression precedes testis determination. Graded OTHER for the
      same reason as the item above: an introduction statement citing other
      work.
- name: Failure of CBX2 Transactivation of NR5A1 and SOX9
  biological_scale: MOLECULAR
  description: >-
    CBX2 does not merely silence chromatin; it positively drives the male
    programme, stimulating NR5A1 (SF1) and SOX9. In the mouse, PRC1 containing
    M33 binds the Ad4BP/SF1 locus directly and M33-null animals have significantly
    low Ad4BP/SF-1 expression, establishing CBX2 as an upstream activator rather
    than a repressor of this gene. The index patient's mutant
    CBX2.1 failed to transactivate NR5A1/SF1 in vitro, which is the specific
    molecular defect the human disorder is built on.
  biological_processes:
  - preferred_term: positive regulation of transcription by RNA polymerase II
    term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    modifier: DECREASED
  downstream:
  - target: Reduced SRY Expression in the Bipotential Gonad
    causal_link_type: DIRECT
    hypothesis_groups:
    - cbx2_sry_transactivation_model
    evidence:
    - reference: PMID:22186409
      reference_title: "Cbx2, a polycomb group gene, is required for Sry gene expression in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "the expression of Sry, Sox9, Lhx9, Ad4BP/SF-1, Dax-1, Gata4, Arx, and Dmrt1, genes encoding transcription factors essential for gonadal development, is affected in Cbx2 KO gonads"
      explanation: >-
        Places reduced Sry expression downstream of Cbx2 loss in the same gonads
        in which Ad4BP/SF-1 is also affected, which is the step this edge makes.
  evidence:
  - reference: PMID:15899914
    reference_title: Mouse Polycomb M33 is required for splenic vascular and adrenal gland formation through regulating Ad4BP/SF1 expression.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "chromatin immunoprecipitation assays with adrenocortical Y-1 cells revealed direct binding of the M33-containing PcG to the Ad4BP/SF1 gene locus"
    explanation: >-
      Direct chromatin occupancy of the SF1 locus by M33-containing PRC1
      supports this as a direct transactivation relationship rather than an
      indirect one.
  - reference: PMID:15899914
    reference_title: Mouse Polycomb M33 is required for splenic vascular and adrenal gland formation through regulating Ad4BP/SF1 expression.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "indicated significantly low expression of adrenal 4 binding protein/steroidogenic factor-1 (Ad4BP/SF-1), indicating that M33 is an essential upstream regulator of Ad4BP/SF1"
    explanation: >-
      Loss of M33 lowers SF1 expression, establishing the direction of the
      relationship asserted by this node.
  - reference: PMID:31719618
    reference_title: "CBX2-dependent transcriptional landscape: implications for human sex development and its defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CBX2.1 is a stimulator of the male (through SOX9 and NR5A1 stimulation) and an inhibitor for the female pathway (through inhibition of FOXL2 expression)"
    explanation: >-
      Names SOX9 and NR5A1 as the male-pathway targets CBX2.1 stimulates, which
      is what this node says is lost.
- name: Loss of CBX2 Repression of the Ovarian Programme
  biological_scale: MOLECULAR
  description: >-
    The mirror image of the transactivation defect. CBX2.1 directly represses
    WNT4 and PBX1 and indirectly represses FOXL2; genome-wide target mapping in
    Sertoli-like cells identified close to 1600 direct CBX2 targets and
    concluded that the protein concurrently inhibits the female pathway. Loss of
    this repression allows ovarian determinants to run unopposed in an XY gonad,
    which is the most likely explanation for the index patient's histologically
    normal ovarian tissue — a finding that plain failure of testis determination
    would not by itself produce.
  biological_processes:
  - preferred_term: negative regulation of transcription by RNA polymerase II
    term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    modifier: DECREASED
  downstream:
  - target: Failure of Sertoli Cell Differentiation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - cbx2_ovarian_derepression_model
  - target: Ovarian tissue in an individual with a 46,XY karyotype
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      De-repression of the ovarian programme in an XY gonad is the proposed
      route to histologically normal ovarian tissue rather than a streak gonad.
      Recorded as indirect with unknown intermediates because no study has
      measured ovarian-determinant expression in the index patient's gonad.
    hypothesis_groups:
    - cbx2_ovarian_derepression_model
  evidence:
  - reference: PMID:31719618
    reference_title: "CBX2-dependent transcriptional landscape: implications for human sex development and its defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CBX2.1 directly inhibits WNT4 and PBX1 and indirectly inhibits the expression of FOXL2"
    explanation: >-
      Names the ovarian-pathway genes CBX2.1 represses and distinguishes the
      direct from the indirect targets, as this node states.
  - reference: PMID:25569159
    reference_title: "Genome-wide identification of CBX2 targets: insights in the human sex development network."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We identified close to 1600 direct targets for CBX2."
    explanation: >-
      Supplies the target-count figure quoted in the description and establishes
      the breadth of direct CBX2 chromatin occupancy.
  - reference: PMID:31116734
    reference_title: CBX2 is required to stabilize the testis pathway by repressing Wnt signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We show that Sry expression and testis development were rescued in XY Cbx2-/-;Wnt4-/- mice."
    explanation: >-
      Genetic rescue by removing an ovarian determinant is the strongest
      evidence that loss of ovarian-pathway repression, not loss of a direct
      activating input, is what blocks testis development when CBX2 is absent.
  - reference: PMID:31116734
    reference_title: CBX2 is required to stabilize the testis pathway by repressing Wnt signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we show that CBX2 directly binds the downstream Wnt signaler Lef1, an ovary-promoting gene that remains bivalent in Sertoli cells"
    explanation: >-
      Direct chromatin binding of an ovary-promoting gene establishes the
      repression as a direct CBX2 activity rather than a downstream consequence.
- name: Failure of CBX2.2-Dependent EMX2 Regulation
  biological_scale: MOLECULAR
  description: >-
    A separate molecular arm specific to the short CBX2.2 isoform. Both reported
    CBX2.2 variants failed to regulate their target genes in transactivation
    assays, with defective EMX2 expression proposed as the proximate cause of
    the severe 46,XY phenotype in those patients. EMX2 is required for
    urogenital ridge development, so this arm converges on the same gonadal
    endpoint as the CBX2.1 arm by a non-overlapping target route. Independent
    support for a CBX2-EMX2 axis comes from a different disease gene: a PBX1
    variant causing 46,XY gonadal dysgenesis was shown to abolish PBX1's
    physical interaction with both CBX2 and EMX2, placing the three proteins in
    one testis-determining module.
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: DECREASED
  downstream:
  - target: Failure of Sertoli Cell Differentiation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29998616
      reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "leading to a severe 46,XY DSD defect, likely because of a defective expression of EMX2 in the developing gonad"
      explanation: >-
        States the proposed route from defective EMX2 regulation to the gonadal
        phenotype, and its own hedging ("likely") is why this edge is recorded
        as indirect.
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that both CBX2.2 variants fail to regulate the expression of genes essential for sexual development"
    explanation: >-
      Both CBX2.2 alleles were shown in vitro to lose regulatory control of
      sex-development genes, which is the claim of this node.
  - reference: PMID:31058389
    reference_title: The TALE homeodomain of PBX1 is involved in human primary testis-determination.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "The mutation abolishes the physical interaction of PBX1 with two proteins known to be involved in testis-determination, CBX2 and EMX2."
    explanation: >-
      Independent evidence that CBX2 and EMX2 sit in one testis-determining
      protein module. Indirect: the experiment is about a PBX1 variant, and the
      inference to a CBX2-EMX2 axis is one step removed from what was measured.
- name: Reduced SRY Expression in the Bipotential Gonad
  biological_scale: CELLULAR
  description: >-
    CBX2 lies upstream of SRY. In mice, gonadal growth defects appear at the
    time Sry is normally expressed and Cbx2-null gonads have reduced Sry, and
    the sex reversal is rescued by forced expression of Sry or Sox9 — the
    strongest available evidence that the sex-determination arm of the phenotype
    is specifically an Sry-expression failure rather than a general
    developmental collapse. The human index patient's variants were interpreted
    the same way, placing CBX2 upstream of SRY in the human cascade.
  biological_processes:
  - preferred_term: male sex determination
    term:
      id: GO:0030238
      label: male sex determination
    modifier: DECREASED
  downstream:
  - target: Failure of Sertoli Cell Differentiation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22186409
      reference_title: "Cbx2, a polycomb group gene, is required for Sry gene expression in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our study implicates Cbx2 in testis differentiation through regulating Sry gene expression."
      explanation: >-
        States that the route from Cbx2 to testis differentiation runs through
        Sry expression, which is exactly this edge.
  evidence:
  - reference: PMID:9641679
    reference_title: Male-to-female sex reversal in M33 mutant mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Gonadal growth defects appeared near the time of expression of the Y-chromosome-specific Sry gene, suggesting that M33 deficiency may cause sex reversal by interfering with steps upstream of Sry."
    explanation: >-
      Places the lesion upstream of Sry on developmental-timing grounds.
  - reference: PMID:22186409
    reference_title: "Cbx2, a polycomb group gene, is required for Sry gene expression in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Male-to-female sex reversal in Cbx2 KO mice was rescued by crossing them with transgenic mice displaying forced expression of Sry or Sox9."
    explanation: >-
      Genetic rescue by Sry or Sox9 is the decisive test that the sex-reversal
      component is attributable to reduced Sry/Sox9 output rather than to some
      parallel defect.
  - reference: PMID:19361780
    reference_title: "Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed loss-of-function mutations that allowed us, by placing CBX2 upstream of SRY"
    explanation: >-
      The human report's own conclusion places CBX2 upstream of SRY, extending
      the mouse ordering to the human cascade.
- name: Impaired Genital Ridge Growth
  biological_scale: TISSUE
  description: >-
    A growth arm that is separable from the sex-determination arm. In M33-null
    mice the genital ridge forms late in both XX and XY embryos, and when sex
    reversal is genetically rescued by forced Sry or Sox9 expression the
    resulting testes are still hypoplastic. Gonadal size and gonadal sex are
    therefore controlled by different sets of CBX2-dependent genes, and this
    node carries the size component. It is the mechanistic reason a CBX2 gonad
    can be small or non-visualized independently of which way it differentiates.
  biological_processes:
  - preferred_term: gonad development
    term:
      id: GO:0008406
      label: gonad development
    modifier: DECREASED
  downstream:
  - target: Dysgenetic Gonad
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:22186409
    reference_title: "Cbx2, a polycomb group gene, is required for Sry gene expression in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, testes remained hypoplastic in these mice, indicating that the size and the sex of the gonad are determined by different sets of genes."
    explanation: >-
      Explicitly separates the size defect from the sex-determination defect,
      which is why this node exists alongside the SRY node rather than inside
      it.
  - reference: PMID:22200029
    reference_title: "Role of polycomb group protein cbx2/m33 in meiosis onset and maintenance of chromosome stability in the Mammalian germline."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "while the remaining male mutant fetuses exhibited bilateral testicular hypoplasia"
    explanation: >-
      Shows that Cbx2-null XY fetuses that were not sex-reversed still had
      hypoplastic testes, the growth phenotype in isolation.
- name: Failure of Sertoli Cell Differentiation
  biological_scale: CELLULAR
  description: >-
    Without an adequate SRY/SOX9 pulse, and with ovarian determinants
    de-repressed, the supporting-cell precursors of the XY gonad do not commit
    to the Sertoli lineage, or commit incompletely. In the CBX2.2 patient in
    whom gonadal tissue was recovered, the testes were dysgenetic with immature
    tubules containing Sertoli cells only and no identifiable Leydig cells; in
    the mouse, XY knockouts develop ovaries rather than testes.
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  biological_processes:
  - preferred_term: Sertoli cell differentiation
    term:
      id: GO:0060008
      label: Sertoli cell differentiation
    modifier: DECREASED
  downstream:
  - target: Dysgenetic Gonad
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29998616
      reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Anatomopathological data showed dysgenetic testes characterized by immature tubules with Sertoli cells only and a few atypical spermatogonias."
      explanation: >-
        The histology of the resected gonad shows arrested Sertoli-lineage
        tubules constituting a dysgenetic gonad, which is this edge.
  - target: Sertoli cell-only phenotype
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The two names read as contradictory but are not. Supporting cells that
      commit incompletely still line the tubule; what is missing is the germ
      cell population and the Leydig compartment, so the histological result of
      an arrested Sertoli programme is a tubule containing Sertoli cells and
      little else. Germ cell loss is the unnamed intermediate, which is why this
      edge is indirect.
  - target: Incomplete Mullerian Duct Regression
    causal_link_type: DIRECT
    description: >-
      Anti-Mullerian hormone is a fetal Sertoli cell product, so a gonad without
      a competent Sertoli compartment does not drive Mullerian regression.
  evidence:
  - reference: PMID:22186409
    reference_title: "Cbx2, a polycomb group gene, is required for Sry gene expression in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "XY knockout (KO) mice develop ovaries but not testes, and the gonads are hypoplastic in both sexes"
    explanation: >-
      The XY gonad follows the ovarian rather than the Sertoli/testicular route
      when Cbx2 is absent.
- name: Dysgenetic Gonad
  biological_scale: TISSUE
  description: >-
    The convergence point of the entry: an XY gonad that is hypoplastic,
    dysgenetic, or has followed the ovarian route. What is found at operation
    varies strikingly across the three published patients — histologically
    normal ovarian tissue in the CBX2.1 index girl, Sertoli-cell-only dysgenetic
    testes in one CBX2.2 patient, and no identifiable gonadal tissue at all in
    the other. All three lack a functioning fetal testis, which is what the
    downstream endocrine consequences follow from.
  cell_types:
  - preferred_term: Leydig cell
    term:
      id: CL:0000178
      label: Leydig cell
  biological_processes:
  - preferred_term: male gonad development
    term:
      id: GO:0008584
      label: male gonad development
    modifier: DECREASED
  downstream:
  - target: Absent Fetal Testicular Androgen Output
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29998616
      reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "No Leydig cells were identified in the interstitium."
      explanation: >-
        Absence of the androgen-producing cell type in the dysgenetic gonad is
        the direct anatomical basis for absent androgen output.
  - target: Loss of Negative Feedback on the Gonadotropic Axis
    causal_link_type: DIRECT
  - target: Gonadal dysgenesis
    causal_link_type: DIRECT
  - target: Bilateral cryptorchidism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A dysgenetic gonad does not complete descent; both CBX2.2 patients had
      non-palpable gonads. The intermediate steps between gonadal dysgenesis and
      failed descent are not established in this disorder.
  evidence:
  - reference: PMID:19361780
    reference_title: "Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A girl with a prenatal 46,XY karyotype was born with a completely normal female phenotype, including uterus and histologically normal ovaries."
    explanation: >-
      Documents the ovarian end of the reported gonadal spectrum in a 46,XY
      individual.
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A gonadectomy was performed, which revealed no gonadal tissue on histology evaluation"
    explanation: >-
      Documents the opposite end of the same spectrum, where no gonadal tissue
      remained to be identified.
- name: Absent Fetal Testicular Androgen Output
  biological_scale: ORGANISM
  description: >-
    With no functional Leydig compartment, testosterone is not produced in the
    fetal window during which the external genitalia are masculinized, nor
    later. In one CBX2.2 patient an hCG stimulation test at two years produced
    neither a testosterone rise nor accumulation of steroid precursors, which is
    the pattern expected from absent steroidogenic tissue rather than from an
    enzymatic block within the androgen synthesis pathway. It is a single
    stimulation test in one patient, so it is consistent with that reading
    rather than decisive for it.
  biological_processes:
  - preferred_term: testosterone secretion
    term:
      id: GO:0035936
      label: testosterone secretion
    modifier: DECREASED
  downstream:
  - target: Undervirilization of the External Genitalia
    causal_link_type: DIRECT
  - target: Decreased serum testosterone concentration
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "no testosterone increase and steroid precursor accumulation was found"
    explanation: >-
      A flat hCG stimulation test with no precursor accumulation is the
      functional demonstration that androgen output is absent rather than
      enzymatically blocked.
- name: Loss of Negative Feedback on the Gonadotropic Axis
  biological_scale: ORGANISM
  description: >-
    Absent gonadal steroid and inhibin output releases the pituitary from
    negative feedback, so LH and FSH rise. Both CBX2.2 patients were
    hypergonadotropic, one with an FSH of 78 U/L against a stated upper limit of
    12 U/L. This is the endocrine signature that identifies the lesion as
    primary gonadal rather than central.
  biological_processes:
  - preferred_term: gonadotropin secretion
    term:
      id: GO:0032274
      label: gonadotropin secretion
    modifier: INCREASED
  downstream:
  - target: Hypergonadotropic hypogonadism
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29998616
      reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "laboratory evaluation showed hypergonadotropic hypogonadism with LH levels of 10 U/L, FSH levels of 78 U/L, and testosterone levels of 75 ng/dL"
      explanation: >-
        Records the raised gonadotropins with low testosterone that this edge
        asserts follows from loss of gonadal feedback.
  - target: Elevated circulating follicle stimulating hormone level
    causal_link_type: DIRECT
  - target: Elevated circulating luteinizing hormone level
    causal_link_type: DIRECT
- name: Undervirilization of the External Genitalia
  biological_scale: ORGANISM
  description: >-
    In the absence of fetal androgen, the external genitalia develop along the
    default route. The degree is not uniform across the three reported patients:
    the CBX2.1 index girl had entirely normal female external genitalia, whereas
    the CBX2.2 patients had partial masculinization with microphallus, perineal
    hypospadias, bifid scrotum and non-palpable gonads. This variance is the main
    reason the entry carries two subtypes.
  biological_processes:
  - preferred_term: development of primary male sexual characteristics
    term:
      id: GO:0046546
      label: development of primary male sexual characteristics
    modifier: DECREASED
  downstream:
  - target: Female external genitalia in individual with 46,XY karyotype
    causal_link_type: DIRECT
  - target: Perineal hypospadias
    causal_link_type: DIRECT
  - target: Micropenis
    causal_link_type: DIRECT
  - target: Bifid scrotum
    causal_link_type: DIRECT
  - target: Sex reversal
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He presented with atypical genitalia, characterized by microphallus (5.0 cm), bilateral cryptorchidism, perineal hypospadias and scrotum biphidus."
    explanation: >-
      Enumerates the undervirilized external phenotype in one CBX2.2 patient.
  - reference: PMID:19361780
    reference_title: "Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "was born with a completely normal female phenotype"
    explanation: >-
      Records the fully unvirilized end of the same spectrum, which is why this
      node's description declines to assert a uniform degree.
- name: Incomplete Mullerian Duct Regression
  biological_scale: ORGANISM
  description: >-
    Anti-Mullerian hormone is a fetal Sertoli cell product, so a gonad that
    fails to make Sertoli cells does not regress the Mullerian ducts. Mullerian
    structures were present in two of the three reported patients — a normal
    uterus in the CBX2.1 index girl and a hypoplastic uterus found unexpectedly
    at gonadectomy in one CBX2.2 patient — while the other CBX2.2 patient had no
    Mullerian derivatives on imaging. The inconsistency tracks the gonadal
    findings: a partially functional fetal Sertoli compartment regresses the
    ducts partially.
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  downstream:
  - target: Hypoplasia of the uterus
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A gonadectomy was performed, which revealed no gonadal tissue on histology evaluation and furthermore, a hypoplastic uterus was found."
    explanation: >-
      Records persistence of a Mullerian derivative in a 46,XY patient whose
      gonad had no identifiable tissue, i.e. no fetal Sertoli compartment to
      regress it.
  - reference: PMID:19361780
    reference_title: "Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "born with a completely normal female phenotype, including uterus and histologically normal ovaries"
    explanation: >-
      Documents a fully retained uterus in the index patient, the complete
      non-regression end of this node's range.
phenotypes:
- name: Female external genitalia in individual with 46,XY karyotype
  category: Anatomical
  subtype: CBX2.1
  description: >-
    Entirely normal female external genitalia in a 46,XY individual, with no
    virilization detectable at birth. In the index patient this was complete
    enough that the discordance was only recognized because a prenatal karyotype
    had already been obtained.
  phenotype_term:
    preferred_term: Female external genitalia in individual with 46,XY karyotype
    term:
      id: HP:0008730
      label: Female external genitalia in individual with 46,XY karyotype
  diagnostic: true
  evidence:
  - reference: PMID:19361780
    reference_title: "Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A girl with a prenatal 46,XY karyotype was born with a completely normal female phenotype, including uterus and histologically normal ovaries."
    explanation: >-
      Direct description of a completely female external phenotype in a 46,XY
      individual.
- name: Sex reversal
  category: Anatomical
  description: >-
    Discordance between chromosomal sex and gonadal or phenotypic sex, shared by
    the human index patient and the mouse models. No frequency is asserted
    despite the disease name, because the term fits the two arms unevenly: the
    CBX2.1 index patient was fully sex-reversed, whereas the CBX2.2 patients
    were undervirilized 46,XY individuals who lived as male, which is a
    difference of sex development rather than a reversal in the usual sense.
    Recording OBLIGATE would let the OMIM series name stand in for an
    observation.
  phenotype_term:
    preferred_term: Sex reversal
    term:
      id: HP:0012245
      label: Sex reversal
  diagnostic: true
  evidence:
  - reference: PMID:35263754
    reference_title: "CBX2 in DSD: The Quirky Kid on the Block."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "genetic variants or loss-of-function of CBX2 can cause sex reversal in mice and humans"
    explanation: >-
      A review statement that CBX2 loss of function causes sex reversal in
      humans as well as mice, supporting this as the defining feature.
  - reference: PMID:9641679
    reference_title: Male-to-female sex reversal in M33 mutant mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "survivors showed male-to-female sex reversal"
    explanation: >-
      The orthologous mouse phenotype. Recorded as model-organism evidence
      alongside, not in place of, the human observation. Note the quantifier in
      the preceding clause of that sentence ("more than half") attaches to
      pre-weaning mortality, not to the sex-reversal rate; the murine rates are
      cited separately and by strain below.
  - reference: PMID:22200029
    reference_title: "Role of polycomb group protein cbx2/m33 in meiosis onset and maintenance of chromosome stability in the Mammalian germline."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the majority of Cbx2 null mice on the B6 background exhibit male to female sex reversal and approximately 50% of surviving adult mice exhibited bilateral ovaries"
    explanation: >-
      The murine sex-reversal rate on the C57BL/6 background, stated as such.
      This is the sentence the entry uses for a frequency claim, in place of the
      1998 abstract's "more than half", which describes mortality.
  - reference: PMID:22200029
    reference_title: "Role of polycomb group protein cbx2/m33 in meiosis onset and maintenance of chromosome stability in the Mammalian germline."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In contrast, our study reveals that in the BALB/C model <30% of mice exhibit sex reversal."
    explanation: >-
      The same phenotype on a different background and a different null allele,
      at less than half the rate. Cited to make explicit that the murine
      sex-reversal frequency is strain-dependent and that no single number
      characterises "the mouse model".
- name: Ovarian tissue in an individual with a 46,XY karyotype
  category: Anatomical
  subtype: CBX2.1
  description: >-
    The most unusual feature of the index case and the reason CBX2 disease is
    not simply a form of complete gonadal dysgenesis. The gonads were
    histologically normal ovaries, not fibrous streaks. HPO has no term for
    ovarian tissue in a 46,XY individual, and neither the streak-gonad nor the
    abnormal-ovary terms would be accurate here, so this phenotype is
    deliberately left with a free-text preferred term rather than a
    near-miss binding.
  phenotype_term:
    preferred_term: Ovarian tissue in an individual with a 46,XY karyotype
  evidence:
  - reference: PMID:19361780
    reference_title: "Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including uterus and histologically normal ovaries"
    explanation: >-
      States that the gonads were histologically normal ovaries, which is the
      exact claim and the reason a dysgenesis term is not used.
  - reference: PMID:31719618
    reference_title: "CBX2-dependent transcriptional landscape: implications for human sex development and its defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "M33 knockout mice are sterile, and 50% of the Sry positive mice are phenotypically female, with ovarian-like tissue"
    explanation: >-
      The mouse counterpart is ovarian-like tissue rather than streak gonads,
      which is why the human ovarian finding is treated as the expected
      orthologous outcome rather than an anomaly.
- name: Gonadal dysgenesis
  category: Anatomical
  subtype: CBX2.2
  description: >-
    Dysgenetic or non-visualized gonads in the CBX2.2 arm. One patient had
    bilateral atrophic testes removed at ten years of age; the other had no
    gonadal tissue identifiable at gonadectomy. Bound to the male-specific child
    term rather than to HP:0000133, whose own HPO definition asks that it be
    avoided for new annotations in favour of more specific terms.
  phenotype_term:
    preferred_term: Gonadal dysgenesis, male
    term:
      id: HP:0008668
      label: Gonadal dysgenesis, male
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 10 years of age he was submitted to exploratory laparotomy which disclosed bilateral atrophic testis that were removed."
    explanation: >-
      Operative confirmation of atrophic, dysgenetic gonads in a CBX2.2 patient.
- name: Sertoli cell-only phenotype
  category: Histological
  subtype: CBX2.2
  description: >-
    Gonadal histology in the first CBX2.2 patient showed immature tubules
    containing Sertoli cells only, with a few atypical spermatogonia and no
    Leydig cells in the interstitium. The HPO term is defined as tubules lined
    by Sertoli cells alone, so the residual atypical spermatogonia are a partial
    rather than exact fit; the binding follows the report's own use of the
    Sertoli-cell-only description.
  phenotype_term:
    preferred_term: Sertoli cell-only phenotype
    term:
      id: HP:0034299
      label: Sertoli cell-only phenotype
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dysgenetic testes characterized by immature tubules with Sertoli cells only and a few atypical spermatogonias"
    explanation: >-
      Direct histological description of the Sertoli-cell-only tubules.
- name: Perineal hypospadias
  category: Anatomical
  subtype: CBX2.2
  description: >-
    Perineal placement of the urethral meatus, present in both reported CBX2.2
    patients.
  phenotype_term:
    preferred_term: Perineal hypospadias
    term:
      id: HP:0000051
      label: Perineal hypospadias
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two patients with features of DSD i.e. atypical external genitalia, perineal hypospadias and no palpable gonads"
    explanation: >-
      Names perineal hypospadias as a feature of both reported CBX2.2 patients.
- name: Micropenis
  category: Anatomical
  subtype: CBX2.2
  description: >-
    Microphallus, measured at 2.5 cm in the first CBX2.2 patient in infancy and
    5.0 cm in the second at adult presentation.
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "atypical genitalia, characterized by microphallus (5.0 cm), bilateral cryptorchidism, perineal hypospadias and scrotum biphidus"
    explanation: >-
      Records the measured microphallus in the second CBX2.2 patient.
- name: Bifid scrotum
  category: Anatomical
  subtype: CBX2.2
  description: >-
    Scrotum biphidus, reported in the second CBX2.2 patient.
  phenotype_term:
    preferred_term: Bifid scrotum
    term:
      id: HP:0000048
      label: Bifid scrotum
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "perineal hypospadias and scrotum biphidus"
    explanation: >-
      Direct report of a bifid scrotum in this patient.
- name: Bilateral cryptorchidism
  category: Anatomical
  subtype: CBX2.2
  description: >-
    Undescended gonads bilaterally; both CBX2.2 patients had no palpable gonads
    at presentation.
  phenotype_term:
    preferred_term: Bilateral cryptorchidism
    term:
      id: HP:0008689
      label: Bilateral cryptorchidism
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microphallus (5.0 cm), bilateral cryptorchidism, perineal hypospadias"
    explanation: >-
      Explicit report of bilateral cryptorchidism.
- name: Hypergonadotropic hypogonadism
  category: Endocrine
  subtype: CBX2.2
  description: >-
    Raised gonadotropins with low testosterone, the endocrine signature of
    primary gonadal failure. Documented in both CBX2.2 patients.
  phenotype_term:
    preferred_term: Hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  diagnostic: true
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "laboratory evaluation showed hypergonadotropic hypogonadism with LH levels of 10 U/L, FSH levels of 78 U/L, and testosterone levels of 75 ng/dL"
    explanation: >-
      States the diagnosis and gives the supporting hormone values.
- name: Elevated circulating follicle stimulating hormone level
  category: Endocrine
  subtype: CBX2.2
  description: >-
    FSH of 54 U/L in the first CBX2.2 patient and 78 U/L in the second, against
    a stated reference range of 1.0-12 U/L.
  phenotype_term:
    preferred_term: Elevated circulating follicle stimulating hormone level
    term:
      id: HP:0008232
      label: Elevated circulating follicle stimulating hormone level
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "serum LH level was 16 U/L, FSH level was 54 U/L, and testosterone level was 230 ng/dl"
    explanation: >-
      Records the raised FSH in the first CBX2.2 patient.
- name: Elevated circulating luteinizing hormone level
  category: Endocrine
  subtype: CBX2.2
  description: >-
    LH of 16 U/L in the first CBX2.2 patient and 10 U/L in the second, against a
    stated reference range of 1.4-9.2 U/L.
  phenotype_term:
    preferred_term: Elevated circulating luteinizing hormone level
    term:
      id: HP:0011969
      label: Elevated circulating luteinizing hormone level
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "serum LH level was 16 U/L, FSH level was 54 U/L"
    explanation: >-
      Records the raised LH in the first CBX2.2 patient.
- name: Decreased serum testosterone concentration
  category: Endocrine
  subtype: CBX2.2
  description: >-
    Testosterone of 75 ng/dL in the second CBX2.2 patient against a stated adult
    male range of 271-965 ng/dL, and no rise on hCG stimulation in the first.
  phenotype_term:
    preferred_term: Decreased serum testosterone concentration
    term:
      id: HP:0040171
      label: Decreased serum testosterone concentration
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FSH levels of 78 U/L, and testosterone levels of 75 ng/dL"
    explanation: >-
      Gives the low measured testosterone value in the second CBX2.2 patient.
- name: Hypoplasia of the uterus
  category: Anatomical
  subtype: CBX2.2
  description: >-
    A hypoplastic uterus found incidentally at gonadectomy in the second CBX2.2
    patient, who was raised and lived as male and had had no Mullerian
    structures reported on prior imaging.
  phenotype_term:
    preferred_term: Hypoplasia of the uterus
    term:
      id: HP:0000013
      label: Hypoplasia of the uterus
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "furthermore, a hypoplastic uterus was found"
    explanation: >-
      Direct operative report of the hypoplastic uterus.
diagnosis:
- name: Karyotype-phenotype discordance as the entry point
  description: >-
    There is no screening pathway for this disorder; every reported patient
    reached diagnosis through a mismatch between chromosomal and phenotypic sex.
    The CBX2.1 index patient is the instructive case: her external genitalia
    were entirely normal, so nothing at birth would have prompted investigation,
    and she was identified only because a prenatal 46,XY karyotype already
    existed to contradict. That route implies the fully sex-reversed
    presentation is systematically under-ascertained.
  diagnosis_term:
    preferred_term: karyotyping
    term:
      id: NCIT:C16768
      label: Karyotyping
  results: A 46,XY karyotype that does not match the observed phenotype.
  evidence:
  - reference: PMID:19361780
    reference_title: "Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A girl with a prenatal 46,XY karyotype was born with a completely normal female phenotype, including uterus and histologically normal ovaries."
    explanation: >-
      The prenatal karyotype is what made the discordance visible in a patient
      whose phenotype was otherwise unremarkable.
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "accidentally diagnosed because of a discrepancy between prenatal karyotype and phenotype at birth"
    explanation: >-
      States the ascertainment route explicitly, and characterises it as
      accidental.
- name: hCG stimulation testing of gonadal steroidogenic capacity
  description: >-
    Distinguishes absent or non-functional steroidogenic tissue from an
    enzymatic block in androgen synthesis, which is the main biochemical
    differential for an undervirilized 46,XY infant. In the first CBX2.2 patient
    the test produced neither a testosterone rise nor precursor accumulation,
    the pattern of an absent Leydig compartment rather than of a
    steroidogenic-enzyme defect; gonadal histology later showed no Leydig cells.
  diagnosis_term:
    preferred_term: human chorionic gonadotropin stimulation test
    term:
      id: NCIT:C74742
      label: Hormone Measurement
  results: No testosterone rise and no steroid precursor accumulation.
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a human chorionic gonadotropin (hCG) stimulation test was performed (two doses of 2,000 U) and no testosterone increase and steroid precursor accumulation was found"
    explanation: >-
      Records the test, the dose, and the flat result that this diagnostic entry
      describes.
- name: Gonadotropin and testosterone measurement
  description: >-
    Raised LH and FSH with low testosterone localise the lesion to the gonad
    rather than to the hypothalamic-pituitary axis. Both CBX2.2 patients were
    hypergonadotropic at presentation; this is the finding that separates
    primary gonadal failure from central hypogonadism and is the practical
    trigger for imaging and gonadal assessment.
  diagnosis_term:
    preferred_term: gonadotropin and sex steroid measurement
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: Elevated LH and FSH with low serum testosterone.
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "laboratory evaluation showed hypergonadotropic hypogonadism with LH levels of 10 U/L, FSH levels of 78 U/L, and testosterone levels of 75 ng/dL"
    explanation: >-
      The measured hormone profile that this diagnostic entry is built on.
- name: CBX2 sequencing and copy-number analysis
  description: >-
    Molecular confirmation. A dedicated MLPA probe set for CBX2 copy-number
    change was developed for the 47-patient gonadal-DSD screen and is the
    published means of excluding CBX2 deletions and duplications, which
    sequencing alone would miss. That screen found no pathogenic CBX2 variant
    and no copy-number change in any patient, which is also the reason CBX2
    testing in practice happens as part of a DSD panel or exome rather than as a
    single-gene test. Isoform coverage matters: the CBX2.2 report postdates that
    screen, so an assay designed only around CBX2.1 may not interrogate the
    short isoform adequately.
  diagnosis_term:
    preferred_term: multiplex ligation-dependent probe amplification
    term:
      id: NCIT:C116161
      label: Multiplex Ligation-dependent Probe Amplification
  results: >-
    No pathogenic sequence variant and no CBX2 copy-number change in the
    published gonadal-DSD cohort.
  evidence:
  - reference: PMID:23219007
    reference_title: "CBX2 gene analysis in patients with 46,XY and 46,XX gonadal disorders of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CBX2 gene sequencing and development of a synthetic probe set for multiplex ligation probe amplification (MLPA) to detect CBX2 copy number changes"
    explanation: >-
      Describes the assay pair this diagnostic entry records, including the
      purpose-built MLPA probe set.
  - reference: PMID:23219007
    reference_title: "CBX2 gene analysis in patients with 46,XY and 46,XX gonadal disorders of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No deletions or duplications were detected by MLPA."
    explanation: >-
      The copy-number result in that cohort, quoted so the entry's own statement
      that no CNV was found is sourced rather than asserted.
treatments:
- name: Androgen Replacement Therapy
  action_category: THERAPEUTIC
  description: >-
    Exogenous testosterone in individuals with a male gender identity and no
    functioning gonad, to induce and maintain secondary sexual characteristics.
    Both reported CBX2.2 patients received it: the first started testosterone
    esters at seventeen years, the second testosterone cypionate after
    gonadectomy and genitoplasty. This records what was done for two patients,
    not a dose-finding or outcome study, of which none exists for this disorder.
    The choice of androgen rather than estrogen replacement follows the sex of
    rearing, which in the first patient was changed to male at five years of age
    after psychological evaluation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: hormone replacement therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
    therapeutic_agent:
    - preferred_term: testosterone
      term:
        id: CHEBI:17347
        label: testosterone
  target_phenotypes:
  - preferred_term: Hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  target_mechanisms:
  - target: Absent Fetal Testicular Androgen Output
    description: >-
      Replacement does not restore gonadal function; it substitutes for the
      missing hormonal output of this node from puberty onward. It cannot
      reverse the fetal undervirilization that occurred before treatment.
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By 17 years of age, he started androgen replacement with testosterone esters."
    explanation: >-
      Documents androgen replacement in the first CBX2.2 patient and the age at
      which it began.
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "testosterone replacement was started by using testosterone cypionate"
    explanation: >-
      Documents the same intervention, with a different ester, in the second
      patient.
- name: Gonadectomy
  action_category: THERAPEUTIC
  description: >-
    Removal of the dysgenetic gonads, performed in both reported CBX2.2
    patients. In the first this was an exploratory laparotomy at ten years that
    disclosed and removed bilateral atrophic testes; in the second a gonadectomy
    found no gonadal tissue at all. The publication does not state a malignancy
    rationale for either operation, and no gonadal tumour has been reported in
    any CBX2 patient, so this entry records gonadectomy as reported management
    and deliberately attaches no tumour-risk figure to it. Timing and necessity
    of gonadectomy are actively contested in DSD care generally; see the
    tumour-risk discussion.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: bilateral gonadectomy
    term:
      id: NCIT:C218841
      label: Bilateral Orchiectomy
  target_phenotypes:
  - preferred_term: Gonadal dysgenesis, male
    term:
      id: HP:0008668
      label: Gonadal dysgenesis, male
  target_mechanisms:
  - target: Dysgenetic Gonad
    description: >-
      Removes the dysgenetic gonad itself. It is not a mechanistic
      intervention - nothing upstream is corrected, and the endocrine
      consequences of an absent gonad are made permanent, which is why
      androgen replacement is recorded alongside it.
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "exploratory laparotomy which disclosed bilateral atrophic testis that were removed"
    explanation: >-
      Records the operation and its findings in the first CBX2.2 patient.
- name: Genitoplasty and Testicular Prosthesis
  action_category: THERAPEUTIC
  description: >-
    Reconstructive genital surgery with testicular prosthesis implantation,
    performed in the second CBX2.2 patient, who presented as an adult male with
    perineal hypospadias and a bifid scrotum. Recorded as what was done for one
    patient; genital surgery in DSD is a contested area in which timing and
    consent are the substantive questions, and nothing in this single report
    speaks to them.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: genitoplasty
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Perineal hypospadias
    term:
      id: HP:0000051
      label: Perineal hypospadias
  target_mechanisms:
  - target: Undervirilization of the External Genitalia
    description: >-
      Addresses the anatomical result of absent fetal androgen exposure. It acts
      on the outcome of that node long after the developmental window has
      closed, and corrects nothing upstream of it.
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genitoplasty, followed by testicular prosthesis implant was performed."
    explanation: >-
      Direct report of the procedures performed.
- name: Multidisciplinary DSD Care and Sex Assignment
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    Nothing disease-modifying exists for CBX2-related DSD, so care follows the
    general DSD framework: an individualized multidisciplinary assessment, a sex
    assignment decision made on the most likely adult gender identity together
    with diagnosis, genital appearance, fertility potential and psychosocial
    context, and full disclosure to family and patient. This is a class-level
    standard imported from DSD care generally, not a CBX2-specific protocol, and
    it is recorded as such. Its relevance here is concrete rather than
    decorative: the first CBX2.2 patient was initially raised female and changed
    to male social sex at five years of age after psychological evaluation,
    which is exactly the situation this framework governs.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: multidisciplinary disorders-of-sex-development care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:17885459
    reference_title: Disorders of sex development.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "All need a sex assignment; recommendations should be based upon what is judged to be the most likely adult gender identity, diagnosis, genital appearance and surgical options, fertility, cultural pressures, family dynamics and social circumstance, with deference given to psychosocial factors when the outcome is unpredictable."
    explanation: >-
      States the sex-assignment criteria this treatment records. Graded OTHER
      because the source is a consensus-based review of management practice
      rather than a study reporting patient data.
  - reference: PMID:17885459
    reference_title: Disorders of sex development.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the complex management of these patients must be individualized, considering all aspects, informing as age-appropriate the parents and patient"
    explanation: >-
      Supports the individualized, multidisciplinary and disclosure-based
      character of the intervention.
histopathology:
- name: Dysgenetic testis with Sertoli-cell-only tubules and absent Leydig cells
  description: >-
    Gonadectomy material from the first CBX2.2 patient showed dysgenetic testes:
    immature seminiferous tubules lined by Sertoli cells only, containing a few
    atypical spermatogonia, with no Leydig cells identifiable in the
    interstitium. The absent Leydig compartment is the histological counterpart
    of the flat hCG stimulation test in the same patient.
  evidence:
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anatomopathological data showed dysgenetic testes characterized by immature tubules with Sertoli cells only and a few atypical spermatogonias. No Leydig cells were identified in the interstitium."
    explanation: >-
      The full histological description quoted from the report.
- name: Histologically normal ovarian tissue in a 46,XY individual
  description: >-
    The index CBX2.1 patient's gonads were histologically normal ovaries. This
    is the single most distinctive pathological finding of the disorder and the
    reason it is not simply an allelic form of complete gonadal dysgenesis,
    where fibrous streak gonads are the expected finding.
  evidence:
  - reference: PMID:19361780
    reference_title: "Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including uterus and histologically normal ovaries"
    explanation: >-
      States the histological result directly.
animal_models:
- name: M33cterm/Cbx2 null mouse (C57BL/6)
  species: Mouse
  genotype: M33cterm homozygous (poly(A) neo insertion into Cbx2 exon 5)
  background: C57BL/6
  genes:
  - preferred_term: CBX2
    term:
      id: hgnc:1552
      label: CBX2
  publication: PMID:9641679
  description: >-
    Targeted disruption of M33/Cbx2 by insertion of a poly(A) capture-type neo
    vector into the fifth exon, maintained on C57BL/6. More than half of
    homozygous mutants die before weaning; survivors show male-to-female sex
    reversal, and genital ridge formation is retarded in both XX and XY embryos.
    This model is the origin of the entire CBX2 sex-development hypothesis: the
    human index case was investigated precisely because the girl's phenotype
    matched it. Later work in the same line established the Sry-expression
    mechanism and the Sry/Sox9 rescue. Its principal divergence from human
    disease is the extragonadal phenotype - skeletal, splenic and adrenal -
    which human CBX2 patients do not report. Note this is one of two distinct
    published Cbx2 null lines and the two are not interchangeable: the
    separately curated BALB/c line below uses a different allele and gives a
    substantially lower sex-reversal rate, and figures from one must not be
    quoted for the other.
  modeled_mechanisms:
  - target: Reduced SRY Expression in the Bipotential Gonad
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Cbx2-null gonads have reduced Sry expression, and forced Sry or Sox9
      expression rescues the sex reversal. This is the strongest evidence in
      either species for the node.
    limitations: >-
      The ordering is established in mouse; the human equivalent rests on in
      vitro transactivation assays with the patient's mutant protein rather than
      on measured SRY levels in a patient gonad.
    readouts:
    - name: Gonadal Sry transcript level
      target: Reduced SRY Expression in the Bipotential Gonad
      direction: DECREASED
      interpretation: >-
        Sry expression is altered in the knockout gonad. The direction recorded
        here is DECREASED, which the cited sentence does not itself state - it
        says only "affected" - and which follows from the paper's title claim
        that Cbx2 is required for Sry expression, and from the rescue by forced
        Sry expression.
      evidence:
      - reference: PMID:22186409
        reference_title: "Cbx2, a polycomb group gene, is required for Sry gene expression in mice."
        supports: SUPPORT
        directness: INDIRECT
        evidence_source: MODEL_ORGANISM
        snippet: "the expression of Sry, Sox9, Lhx9, Ad4BP/SF-1, Dax-1, Gata4, Arx, and Dmrt1, genes encoding transcription factors essential for gonadal development, is affected in Cbx2 KO gonads"
        explanation: >-
          Reports that Sry expression is altered in Cbx2 knockout gonads by
          microarray, RT-PCR and immunohistochemistry. Indirect for the
          direction: the sentence establishes that Sry is affected, and the
          downward direction follows by inference from the rescue experiment
          rather than from this quote.
      - reference: PMID:31116734
        reference_title: CBX2 is required to stabilize the testis pathway by repressing Wnt signaling.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "We show that Sry expression and testis development were rescued in XY Cbx2-/-;Wnt4-/- mice."
        explanation: >-
          A rescue of Sry expression presupposes that it was reduced, which is
          the direct support for the DECREASED direction that the item above
          only supports by inference.
    evidence:
    - reference: PMID:22186409
      reference_title: "Cbx2, a polycomb group gene, is required for Sry gene expression in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our study implicates Cbx2 in testis differentiation through regulating Sry gene expression."
      explanation: >-
        The paper's own conclusion that this model is informative for the
        Cbx2-to-Sry step.
  - target: Impaired Genital Ridge Growth
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Genital ridge formation is retarded in both XX and XY nulls, and rescued
      XY animals still have hypoplastic testes, isolating a growth defect from
      the sex-determination defect.
    limitations: >-
      No human CBX2 patient has had gonadal volume measured against a normative
      standard, so the human counterpart of this readout is inferred from
      non-visualized or atrophic gonads rather than measured.
    readouts:
    - name: Testis size after Sry/Sox9 rescue
      target: Impaired Genital Ridge Growth
      direction: DECREASED
      interpretation: >-
        Persisting hypoplasia after the sex reversal is rescued is what
        establishes gonadal size as a separately controlled output.
      evidence:
      - reference: PMID:22186409
        reference_title: "Cbx2, a polycomb group gene, is required for Sry gene expression in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "However, testes remained hypoplastic in these mice, indicating that the size and the sex of the gonad are determined by different sets of genes."
        explanation: >-
          Reports the measurement and the inference drawn from it.
  - target: Dysgenetic Gonad
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      XY nulls on this background develop ovaries rather than testes, matching
      the CBX2.1 index patient's ovarian tissue but not the Sertoli-cell-only
      dysgenetic testes of the CBX2.2 patients.
    limitations: >-
      Even on this background the outcome is not uniform - about half of
      surviving adults have bilateral ovaries - so the line does not reproduce a
      single consistent human gonadal outcome. The mouse also has no CBX2.2
      equivalent arm, so the second human presentation is unmodelled. Rates from
      the BALB/c line curated separately below do not apply here.
    readouts:
    - name: Gonadal histology in XY nulls on C57BL/6
      target: Dysgenetic Gonad
      direction: ALTERED
      interpretation: >-
        The XY gonad follows the ovarian route rather than forming a normal
        testis, in the majority of animals on this background.
      evidence:
      - reference: PMID:22200029
        reference_title: "Role of polycomb group protein cbx2/m33 in meiosis onset and maintenance of chromosome stability in the Mammalian germline."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "the majority of Cbx2 null mice on the B6 background exhibit male to female sex reversal and approximately 50% of surviving adult mice exhibited bilateral ovaries"
        explanation: >-
          States the gonadal outcome specifically for the C57BL/6 background,
          which is the background of this model. Quoted from a paper that
          studied the other line precisely because it draws the strain contrast
          explicitly.
  evidence:
  - reference: PMID:9641679
    reference_title: Male-to-female sex reversal in M33 mutant mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "More than half of the resultant M33cterm/M33cterm mutant mice died before weaning, and survivors showed male-to-female sex reversal."
    explanation: >-
      Establishes the model's defining phenotype and its use as a model of
      CBX2-related sex reversal.
  - reference: PMID:19361780
    reference_title: "Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In mice with a similar phenotype, the ablation of M33, an ortholog of Drosophila Polycomb, causes male-to-female sex reversal."
    explanation: >-
      The human report explicitly reasons from this model to the human gene,
      which is the sense in which the model is informative for this disorder.
- name: Cbx2 null mouse (BALB/c)
  species: Mouse
  genotype: Cbx2 homozygous null (5' UTR and first four coding exons deleted)
  background: BALB/c
  genes:
  - preferred_term: CBX2
    term:
      id: hgnc:1552
      label: CBX2
  publication: PMID:22200029
  description: >-
    A second, independently generated Cbx2 null line carrying a different
    allele - deletion of the 5' untranslated region including the translation
    start site and the first four coding exons - and maintained on BALB/c rather
    than C57BL/6. It is curated separately from the M33cterm line above because
    the two give materially different phenotypes and the paper that
    characterised this one makes that contrast its central point: fewer than 30%
    of BALB/c nulls are sex-reversed, against a majority on B6. Most affected
    BALB/c males instead have bilateral testicular hypoplasia, which is what
    makes this line the cleaner one for separating the gonadal growth defect
    from the sex-determination defect. Quoting a rate from this line for the B6
    line, or the reverse, is a strain error.
  modeled_mechanisms:
  - target: Impaired Genital Ridge Growth
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The majority of XY nulls on this background are not sex-reversed and
      instead have bilateral testicular hypoplasia, isolating the gonadal growth
      phenotype from sex reversal within a single line.
    limitations: >-
      Gonadal volume in human CBX2 patients has never been measured against a
      normative standard, so the human counterpart of this readout is inferred
      from non-visualized or atrophic gonads rather than measured. The BALB/c
      background is itself the reason the growth phenotype is visible here, so
      the dissociation may be strain-specific rather than a general property of
      Cbx2 loss.
    readouts:
    - name: Gonadal phenotype in XY nulls on BALB/c
      target: Impaired Genital Ridge Growth
      direction: DECREASED
      interpretation: >-
        Bilateral testicular hypoplasia in non-sex-reversed XY nulls is the
        growth defect observed without the confound of sex reversal.
      evidence:
      - reference: PMID:22200029
        reference_title: "Role of polycomb group protein cbx2/m33 in meiosis onset and maintenance of chromosome stability in the Mammalian germline."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Our analysis revealed sex reversal in 28.6% of XY(-/-) embryos, in which a hypoplastic testis and a contralateral ovary were observed in close proximity to the kidney, while the remaining male mutant fetuses exhibited bilateral testicular hypoplasia."
        explanation: >-
          Reports both the sex-reversal rate on this background and the gonadal
          phenotype of the remainder, which is the measurement this readout
          records.
    evidence:
    - reference: PMID:22200029
      reference_title: "Role of polycomb group protein cbx2/m33 in meiosis onset and maintenance of chromosome stability in the Mammalian germline."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In contrast, our study reveals that in the BALB/C model <30% of mice exhibit sex reversal."
      explanation: >-
        Establishes that this line is informative for the growth arm precisely
        because most of its XY nulls escape sex reversal.
  evidence:
  - reference: PMID:22200029
    reference_title: "Role of polycomb group protein cbx2/m33 in meiosis onset and maintenance of chromosome stability in the Mammalian germline."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "involved the targeted deletion of the 5\u2032 untranslated region including the translation start site and the first four exons of the Cbx2 coding sequence"
    explanation: >-
      Describes the allele, establishing that this is a different construct from
      the M33cterm exon-5 insertion curated above.
- name: Cbx2/Wnt4 double-null rescue mouse
  species: Mouse
  genotype: Cbx2-/-;Wnt4-/- (XY)
  genes:
  - preferred_term: CBX2
    term:
      id: hgnc:1552
      label: CBX2
  publication: PMID:31116734
  description: >-
    An epistasis model rather than a disease model. Removing the ovary-promoting
    gene Wnt4 from a Cbx2-null XY animal restores both Sry expression and testis
    development, which is the decisive experiment behind the alternative
    ovarian-derepression hypothesis. Its value here is that it tests the
    direction of causation, not that it reproduces the human phenotype - which
    it deliberately does not.
  modeled_mechanisms:
  - target: Loss of CBX2 Repression of the Ovarian Programme
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      Deleting Wnt4 removes the de-repressed ovarian signal and rescues the XY
      gonad, showing that the block to testis development in Cbx2 nulls runs
      through unopposed ovarian determinants.
    limitations: >-
      The rescue is genetic and murine. There is no human counterpart, and the
      experiment cannot say which mechanism dominates in a human gonad carrying
      hypomorphic rather than null CBX2 alleles.
    readouts:
    - name: Sry expression and testis development in XY double nulls
      target: Loss of CBX2 Repression of the Ovarian Programme
      direction: RESTORED
      interpretation: >-
        Restoration of both the Sry pulse and testis morphogenesis on removing a
        single ovarian determinant is what makes this an epistasis result rather
        than a modifier effect.
      evidence:
      - reference: PMID:31116734
        reference_title: CBX2 is required to stabilize the testis pathway by repressing Wnt signaling.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "We show that Sry expression and testis development were rescued in XY Cbx2-/-;Wnt4-/- mice."
        explanation: >-
          The measured rescue of both readouts in the double-null animals.
    evidence:
    - reference: PMID:31116734
      reference_title: CBX2 is required to stabilize the testis pathway by repressing Wnt signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our results suggest that stabilization of the testis fate requires CBX2-mediated repression of bivalent ovary-determining genes, which would otherwise block testis development."
      explanation: >-
        The authors' conclusion that this model is informative for CBX2-mediated
        repression of the ovarian programme.
  evidence:
  - reference: PMID:31116734
    reference_title: CBX2 is required to stabilize the testis pathway by repressing Wnt signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "loss of CBX2, the subunit of the Polycomb Repressive Complex 1 (PRC1) that binds H3K27me3 and mediates silencing, leads to ovary development in XY mice and humans"
    explanation: >-
      Establishes that the model system is CBX2 loss in an XY gonad, the same
      lesion as the human disorder.
datasets:
- accession: geo:GSE130749
  title: CBX2 is required to stabilize the testis pathway by repressing Wnt signaling
  data_type: CHIP_SEQ
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:31116734
  notes: >-
    Quantitative H3K4me3 and H3K27me3 profiles of FACS-purified XX and XY
    gonadal supporting cells before (E10.5) and after (E13.5) sex determination,
    generated for the study that proposed the ovarian-derepression model. This
    is the one dataset found that is actually about CBX2 in gonadal sex
    determination: a dataset search on the gene name otherwise returns CBX2
    chromatin and cancer studies, and one on the disease name returns word
    matches on "sex reversal" in unrelated cohorts. Those were triaged out
    rather than listed. The data are murine gonadal supporting cells, not
    patient material; no human CBX2-patient dataset exists.
discussions:
- discussion_id: cbx2_adrenal_splenic_mismatch
  prompt: >-
    Why do Cbx2-null mice have adrenal and splenic hypoplasia through reduced
    SF1, while human CBX2 patients have no reported adrenal or splenic disease,
    even though the human mutant protein's defining defect is failure to
    transactivate the same gene, NR5A1/SF1?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Failure of CBX2 Transactivation of NR5A1 and SOX9
  rationale: >-
    The mouse work makes SF1 the mechanistic centre of the disorder: PRC1
    containing M33 binds the Ad4BP/SF1 locus directly, M33 nulls have
    significantly reduced SF1, and the resulting adrenal and splenic phenotypes
    are the ones SF1 haploinsufficiency itself produces. The human index
    patient's mutant CBX2.1 also fails to transactivate NR5A1/SF1 - that assay
    is the primary functional evidence for pathogenicity. Yet none of the three
    published human patients has reported adrenal insufficiency, and a review of
    the CBX2 transcriptional landscape notes explicitly that human mutants do
    not appear to recapitulate the murine splenic and adrenal defects. Either
    the human alleles are hypomorphic enough to spare a less
    dosage-sensitive human adrenal, or CBX2 is not rate-limiting for human SF1
    outside the gonad. The distinction matters clinically: if the first
    explanation is right, adrenal reserve should be tested in CBX2 patients, and
    it currently is not.
  proposed_experiments:
  - experiment_id: exp_cbx2_adrenal_reserve
    name: Adrenal reserve testing in CBX2 variant carriers
    description: >-
      Measure basal and ACTH-stimulated cortisol, along with electrolytes and
      plasma renin activity, in every ascertained individual with biallelic or
      isoform-specific CBX2 variants, to convert the current absence of reported
      adrenal disease into a tested negative.
    would_refute:
    - pathophysiology#Failure of CBX2 Transactivation of NR5A1 and SOX9
    refuting_outcome:
    - >-
      Normal ACTH-stimulated cortisol across all carriers would show that human
      CBX2 loss does not limit SF1-dependent adrenal function, restricting the
      transactivation defect to the gonadal compartment rather than being a
      general SF1 deficit.
  - experiment_id: exp_cbx2_sf1_dose_response
    name: Comparative SF1 dose-response between mouse and human adrenocortical cells
    description: >-
      Titrate CBX2 knockdown in human and murine adrenocortical cells in
      parallel and measure SF1 output, to test whether the human adrenal simply
      tolerates a lower CBX2 dose than the mouse adrenal does.
  evidence:
  - reference: PMID:31719618
    reference_title: "CBX2-dependent transcriptional landscape: implications for human sex development and its defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "although human mutants do not seem to recapitulate these defects"
    explanation: >-
      States the mismatch directly: the murine splenic, adrenal and skeletal
      phenotypes are not seen in human CBX2 patients.
  - reference: PMID:15899914
    reference_title: Mouse Polycomb M33 is required for splenic vascular and adrenal gland formation through regulating Ad4BP/SF1 expression.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the adrenal glands of M33-KO and Ad4BP/SF1 heterozygous KO mice were smaller than those of the wild-type mice"
    explanation: >-
      Establishes the murine side of the mismatch, and that the adrenal
      phenotype phenocopies SF1 deficiency.
- discussion_id: cbx2_2_zygosity_and_gene_validity
  prompt: >-
    Is the CBX2.2 arm of this entry the same recessive disorder as the CBX2.1
    index case, given that each CBX2.2 patient is reported as carrying a single
    distinct variant and the phenotypes differ so markedly?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - has_subtypes#CBX2.2
  - inheritance#Autosomal recessive
  rationale: >-
    The SRXY5 entity is defined as autosomal recessive on the strength of one
    double-heterozygous CBX2.1 patient. The two CBX2.2 patients are each
    described as carrying one distinct variant, with no second allele reported,
    and one of the two alleles has a population frequency (ExAC minor allele
    frequency 0.001418) that is high for a fully penetrant recessive DSD allele.
    Functional data are supportive but functional data alone do not establish a
    mode of inheritance. Working against a common-cause interpretation, a
    dedicated screen of 47 patients with 46,XY or 46,XX gonadal DSD found no
    pathogenic CBX2 variant at all, so there is no independent cohort in which
    the CBX2.2 signal has been replicated. Until the second allele is reported
    or excluded, grouping this arm under SRXY5 is a curation convenience and
    should not be read as an assertion that the two arms share an inheritance
    mode.
  proposed_experiments:
  - experiment_id: exp_cbx2_2_second_allele
    name: Complete allelic characterization of the reported CBX2.2 patients
    description: >-
      Re-analyse the existing exome data with attention to deep intronic,
      regulatory and structural variation at CBX2, plus parental segregation, to
      determine whether a second CBX2 allele is present in either CBX2.2
      patient.
  - experiment_id: exp_cbx2_isoform_targeted_cohort_screen
    name: Isoform-resolved CBX2 screening in a large 46,XY DSD cohort
    description: >-
      Screen an unsolved 46,XY DSD cohort with coverage and annotation specific
      to both CBX2 isoforms, since the earlier negative screen predates the
      CBX2.2 report and may not have interrogated the short isoform adequately.
  evidence:
  - reference: PMID:23219007
    reference_title: "CBX2 gene analysis in patients with 46,XY and 46,XX gonadal disorders of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No pathogenic CBX2 mutation was detected."
    explanation: >-
      The absence of any pathogenic CBX2 variant in a dedicated 47-patient
      gonadal-DSD cohort is what leaves the gene-disease relationship resting on
      three individuals and functional assays.
  - reference: PMID:29998616
    reference_title: "Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both variants are rare, with a MAF on ExAC of 0.00001647 (p.Cys132Arg) and 0.001418 (p.Cys154fs)"
    explanation: >-
      Gives the allele frequencies quoted in the rationale, including the one
      that is high for a fully penetrant recessive allele.
- discussion_id: cbx2_gonadal_tumour_risk
  prompt: >-
    What is the gonadal germ-cell tumour risk in CBX2-related 46,XY DSD, and
    does the presence of apparently normal ovarian tissue rather than a streak
    gonad change it?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Gonadectomy
  - phenotypes#Ovarian tissue in an individual with a 46,XY karyotype
  rationale: >-
    Gonadectomy was performed in both CBX2.2 patients, and prophylactic
    gonadectomy is standard practice in 46,XY gonadal dysgenesis generally
    because of germ-cell tumour risk. But no tumour has been reported in any
    CBX2 patient, the publications give no malignancy rationale for either
    operation, and with three published patients there is no denominator from
    which any risk estimate could be formed. Importing a percentage from generic
    46,XY gonadal dysgenesis series would be unsourced inference, and it is
    specifically unsafe here: those series describe streak or dysgenetic gonads,
    whereas the index CBX2.1 patient had histologically normal ovarian tissue,
    which is not the substrate those risk figures were measured on. This entry
    therefore records gonadectomy as reported management with no attached risk
    figure, and this gap is why.
  proposed_experiments:
  - experiment_id: exp_cbx2_gonadal_histology_registry
    name: Systematic gonadal histology and outcome reporting for CBX2 patients
    description: >-
      Record gonadal histology, germ-cell tumour markers and follow-up duration
      for every ascertained CBX2 patient in a shared DSD registry, so that a
      denominator exists before any risk-based management recommendation is
      made.
  evidence:
  - reference: PMID:19361780
    reference_title: "Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including uterus and histologically normal ovaries"
    explanation: >-
      Establishes that the index gonad was histologically normal ovary, the
      observation that makes tumour-risk figures derived from streak gonads
      inapplicable here.
differential_diagnoses:
- name: 46,XY complete gonadal dysgenesis (Swyer syndrome)
  disease_term:
    preferred_term: 46,XY complete gonadal dysgenesis
    term:
      id: MONDO:0010765
      label: 46,XY complete gonadal dysgenesis
  description: >-
    The nonsyndromic form, in which a 46,XY individual has female external
    genitalia, Mullerian structures and bilateral fibrous streak gonads. This is
    the parent MONDO class of SRXY5 and the most important distinction to make.
    The dismech entry for 46,XY complete gonadal dysgenesis explicitly places
    CBX2 outside its scope on the grounds that the canonical CBX2 phenotype had
    ovarian-like rather than bilateral streak gonads, so the two entries
    partition rather than overlap.
  distinguishing_features:
  - Bilateral fibrous streak gonads rather than histologically normal ovarian tissue
  - Usually attributable to SRY, NR5A1, MAP3K1, DHX37 or SOX9-regulatory lesions rather than CBX2
  - The undervirilized CBX2.2 presentation with dysgenetic Sertoli-cell-only testes is partial rather than complete dysgenesis and does not belong to this class at all
- name: NR5A1-related 46,XY disorder of sex development
  disease_term:
    preferred_term: 46,XY sex reversal 3
    term:
      id: MONDO:0013066
      label: 46,XY sex reversal 3
  description: >-
    The immediate mechanistic differential, because NR5A1/SF1 is the gene CBX2
    transactivates. A patient with a CBX2 lesion and a patient with an NR5A1
    lesion converge on reduced SF1 activity in the gonad, so the gonadal
    phenotypes overlap; the discriminator is molecular rather than clinical.
  distinguishing_features:
  - Variants in NR5A1 itself rather than in its upstream regulator CBX2
  - Predominantly heterozygous, frequently de novo, rather than biallelic
  - Adrenal insufficiency is a described part of the NR5A1 spectrum but has not been reported in any CBX2 patient
- name: SRY-related 46,XY sex reversal
  disease_term:
    preferred_term: 46,XY sex reversal 1
    term:
      id: MONDO:0020712
      label: 46,XY sex reversal 1
  description: >-
    The other end of the same regulatory step. CBX2 is placed upstream of SRY in
    both the mouse and the human cascade, so SRY deletion or point mutation
    produces the downstream half of the CBX2 phenotype without the growth
    component.
  distinguishing_features:
  - SRY deletions or point mutations on the Y chromosome rather than an autosomal 17q25.3 lesion
  - Gonads are typically streaks, and gonadal size is not separately affected as it is when the upstream growth arm is lost
  - Y-linked rather than autosomal transmission
- name: PBX1-related 46,XY gonadal dysgenesis with radiocubital synostosis
  description: >-
    A de novo PBX1 TALE-homeodomain variant causes 46,XY gonadal dysgenesis and
    abolishes PBX1's physical interaction with CBX2 and EMX2 - the same two
    proteins this entry's CBX2.2 arm turns on. It is therefore both a
    differential and a mechanistic neighbour. Clinically it is separable by a
    skeletal feature that CBX2 disease does not have.
  distinguishing_features:
  - Radiocubital synostosis, absent in all reported CBX2 patients
  - De novo heterozygous PBX1 variant rather than a biallelic or isoform-specific CBX2 lesion
  - The lesion is in a CBX2 interaction partner rather than in CBX2 itself
  evidence:
  - reference: PMID:31058389
    reference_title: The TALE homeodomain of PBX1 is involved in human primary testis-determination.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a de novo missense mutation, p.Arg235Gln in the highly conserved TALE homeodomain of the transcription factor Pre-B-Cell Leukemia Transcription Factor 1 (PBX1) in a child with 46,XY gonadal dysgenesis and radiocubital synostosis"
    explanation: >-
      Names the gene, the inheritance pattern and the distinguishing skeletal
      feature used to separate this disorder from CBX2 disease.
notes: >-
  Scope and evidence base. This entry covers CBX2-attributed 46,XY disorder of
  sex development (SRXY5, OMIM:613080, MONDO:0013120). The caseload this entry
  rests on is three individuals, so almost every clinical statement in this
  entry is an n-of-1 or n-of-2 observation and is written as such: no frequency
  bands are asserted for the CBX2.2 features, no prevalence rate is given, and
  no gonadal tumour risk is attached to the gonadectomy record. The disorder is
  included because its mechanism is unusually well characterized despite the
  tiny caseload - the mouse orthologue is one of the best-studied models of
  pre-SRY testis determination - not because the clinical entity is well
  delineated.

  Boundary with 46,XY complete gonadal dysgenesis. The dismech entry for 46,XY
  complete gonadal dysgenesis (MONDO:0010765) deliberately restricts itself to
  classic nonsyndromic complete disease and states in its own scoping note that
  CBX2 is not promoted into it, because the canonical reported CBX2 phenotype
  had ovarian-like rather than bilateral streak gonads. This entry is the
  counterpart that carries CBX2, and no content is duplicated from that entry.
  MONDO nonetheless classifies MONDO:0013120 as a child of MONDO:0010765; that
  ontological placement is retained in the disease term and is not contradicted
  here, but it should not be read as agreement that the index phenotype was
  complete gonadal dysgenesis.

  Isoform split. The two subtypes are not two severities of one presentation.
  The CBX2.1 index patient had a complete female phenotype with normal ovarian
  tissue; the CBX2.2 patients had undervirilized male genitalia with dysgenetic
  or absent testes. In vitro the two isoforms regulate partly non-overlapping
  target sets, which is the proposed reason for the divergence, but with one and
  two patients respectively the phenotype-isoform correlation rests on three
  observations. The CBX2.2 arm additionally has an unresolved zygosity question
  recorded as a knowledge gap.

  What was deliberately not asserted. Mouse Cbx2 nulls have skeletal homeotic
  transformations, splenic vascular disorganization, adrenal hypoplasia, T-cell
  expansion failure, and germline meiotic defects. None of these has been
  reported in a human CBX2 patient, and none is curated here as a human
  phenotype; the adrenal and splenic divergence is recorded instead as a
  HUMAN_MODEL_MISMATCH discussion. The murine germ-cell and meiosis findings are
  cited only where they bear on gonadal size and histology, not as evidence for
  human fertility claims: no report addresses fertility in any of the three
  patients, and the index patient's ovarian tissue was described only as
  histologically normal, which is not a statement about germ cells.

  GeneReviews. There is no GeneReviews chapter for SRXY5 or for CBX2. The
  relevant overview is Nonsyndromic Disorders of Testicular Development
  (PMID:20301714), which is tagged in the references block; its PubMed record
  carries only the chapter's purpose statement rather than clinical
  characteristics, so it could not be used as a phenotype baseline and no
  phenotype in this entry is derived from it.
references:
- reference: PMID:20301714
  title: Nonsyndromic Disorders of Testicular Development Overview.
  tags:
  - GeneReviews
📚

References & Deep Research

References

1
PMID:20301714
Nonsyndromic Disorders of Testicular Development Overview.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Review fixes: 46,XY Sex Reversal 5 · 2026-09-01T06:19:16Z · View source

Pre-PR adversarial self-review of the CREATE session, and the fixes it produced. Two errors of fact were found and corrected. (1) Animal-model conflation. The entry carried a single 'Cbx2 (M33) null mouse' on C57BL/6 citing PMID:9641679, and attached to it the 28.6% sex-reversal rate and the bilateral-testicular-hypoplasia finding from PMID:22200029. Those come from a different knockout line - deletion of the 5' UTR and first four coding exons, maintained on BALB/c - and the strain contrast is that paper's central point ('major differences in the sex reversal phenotype of Cbx2 knockout mice generated on the BALB/C genetic background compared to the phenotype described in Cbx2 deficient mice on the C57BL/6Njcl (B6) background'). Split into two animal_models entries with the allele and background named on each, and the C57BL/6 gonadal readout re-quoted from the sentence that actually describes B6. (2) Misread statistic. The Sex reversal phenotype said 'more than half of surviving XY nulls are phenotypically female'. PMID:9641679 reads 'More than half of the resultant M33cterm/M33cterm mutant mice died before weaning, and survivors showed male-to-female sex reversal' - the quantifier is pre-weaning mortality. The entry's own animal_models description had it right, so the file contradicted itself. Replaced with two strain-attributed rates from PMID:22200029 (majority on B6 with ~50% of surviving adults having bilateral ovaries; <30% on BALB/c). Semantic fixes the validators cannot see: - A 'supports: REFUTE' item sat inside the ALTERNATIVE ovarian-derepression hypothesis while its explanation said it refuted the CANONICAL one. Since 'supports' is claim-relative to the object it hangs on, it read as the opposite of what was meant. Moved to cbx2_sry_transactivation_model, and the snippet swapped from the paper's framing sentence to its actual result (the Cbx2-/-;Wnt4-/- rescue). - Root node renamed 'Biallelic CBX2 Loss of Function' -> 'CBX2 Loss of Function': it asserted a zygosity that this entry's own knowledge gap records as unresolved for the CBX2.2 patients. - 'in trans' dropped from the inheritance description; no cached source reports phase. - HP:0000133 replaced with HP:0008668 (Gonadal dysgenesis, male) in both places. HPO's own definition of HP:0000133 says the term 'is to be avoided if possible for new annotations'. - Gonadectomy rebound from generic NCIT:C15329 to NCIT:C218841 Bilateral Orchiectomy (verified reachable from NCIT:C25218). - The EMX2 node's GO binding changed from GO:0008406 (a tissue-scale developmental process, on a MOLECULAR-scale node) to GO:0006357. Constraint data resolved rather than deferred. The previous version noted that the ExAC pLI of 0.95 quoted by PMID:29998616 sat awkwardly with a recessive mechanism and 'should be re-derived'. Queried the gnomAD API directly (GRCh38, 2026-09-01): pLI 0.024, oe_lof 0.52 (90% CI 0.33-0.87), LoF Z 1.85 - independently matching the deep-research report's figures. CBX2 is not LoF-intolerant, which is what a recessive mechanism predicts. Both figures now stated with their provenance. New sections. Added a diagnosis: block (karyotype-phenotype discordance as the ascertainment route, hCG stimulation testing, gonadotropin/testosterone measurement, CBX2 sequencing plus the purpose-built MLPA probe set from PMID:23219007), and an external_assertions: block carrying OMIM:613080 and the two ClinVar index-allele classifications - recorded as external assertions rather than evidence items because no cached publication names those alleles. Added target_mechanisms to Gonadectomy and Genitoplasty, which previously attached to no pathograph node. Smaller corrections: the top-level description said both CBX2.2 patients had Sertoli-cell-only testes (only one did; the other had no gonadal tissue); 'demonstrating' softened to 'consistent with' on a single n-of-1 hCG test; the Sertoli-cell-only binding now acknowledges the residual atypical spermatogonia that the HPO definition excludes; the Sertoli-differentiation-to-Sertoli-only edge made INDIRECT with the germ-cell-loss intermediate named; two PMID:31719618 introduction statements regraded HUMAN_CLINICAL -> OTHER as second-hand citations, with the previously unsourced 'week 7' claim now carrying its own snippet; the Sry DECREASED direction marked directness INDIRECT with the rescue sentence added as its direct support; 'total published caseload is three individuals' reworded throughout to describe the literature this entry draws on rather than assert a census. Not changed, with reasons: PMID:16882788 (the primary DSD consensus statement) has no abstract text in its PubMed record, so nothing is quotable from it and the secondary review PMID:17885459 is retained instead; the Empower-DSD quality-of-life papers were left out because they concern DSD care generally and would put a clinical_burden claim on this entry that no CBX2 patient supports. Validation after fixes: just validate and validate-disorders pass with 98/98 snippets verified; check-causal-targets, check-entity-refs, check-duplicate-keys, check-enum-values, check-qualifier-terms (offline and online), check-snippet-length, check-title-snippets, check-folded-hyphens, check-snippet-grading, verify-datasets all pass. Pathograph re-checked programmatically: 12 nodes, 28 edges, single root, no orphans, all 14 phenotypes reached. Compliance is 83.8% (217/259), the same percentage as before these fixes while the denominator grew from 203 to 259 slots.

Create: 46,XY Sex Reversal 5 · 2026-09-01T05:56:12Z · View source

De novo curation of 46,XY sex reversal 5 (SRXY5, MONDO:0013120, CBX2). Deep research: 'just research-disorder falcon' was requested. Falcon/Edison was unreachable (HTTP 403, authentication failed) on two attempts and on 'deep-research-client providers --check'. The run was re-issued with dr_fallback='--fallback' rather than substituting a provider by hand; openscientist produced the report, which is recorded in the report frontmatter (fell_back: true, requested_provider: falcon, provider_attempts) and in its filename, research/46_XY_Sex_Reversal_5-deep-research-openscientist.md. Report validation was read before use. reference_validation: 17/17 references resolved, 0 unresolved, 10/10 quoted claims found in source. term_validation: 40 terms, 0 unresolved, but needs_review: true with 8 mislabelled terms (the report names HP:0010461 '46,XY sex reversal', HP:0000062/HP:0000047 'Physical manifestation', NCIT:C15417 'hormone therapy', NCIT:C15277 'surgery', NCIT:C15681 'genetic counseling'). None of those bindings was used; every ontology term in this entry was selected independently with OAK and carries the ontology's own canonical label. 'just preflight-dr <report> MONDO:0013120' PASSed (CBX2 mentioned 100 times, OMIM 613080 agreeing between MONDO and the report). Scope. The entire published human caseload is three individuals, so the entry is written to that limit: no prevalence rate, no frequency bands on the CBX2.2 features, and no gonadal tumour-risk figure attached to the gonadectomy record. Two subtypes carry the isoform split - CBX2.1 (the 2009 index girl, complete female phenotype with histologically normal ovaries) and CBX2.2 (two undervirilized 46,XY individuals with dysgenetic Sertoli-cell-only testes). Pathophysiology is built as a causal chain of 12 nodes from biallelic CBX2 loss of function through the transactivation and repression arms, reduced SRY, failed Sertoli differentiation, dysgenetic gonad, and the endocrine and genital consequences. Two competing mechanistic_hypotheses are recorded: the canonical 'CBX2 transactivates upstream of SRY' model and the ALTERNATIVE 'CBX2 represses the ovary-promoting pathway' model from the Cbx2-/-;Wnt4-/- rescue (PMID:31116734), with the relevant downstream edges tagged into hypothesis_groups. The two are not reconciled and the entry says so rather than picking one. Three discussions: a HUMAN_MODEL_MISMATCH on the murine adrenal/splenic SF1 phenotype that human CBX2 patients do not show, and KNOWLEDGE_GAPs on CBX2.2 zygosity/gene-disease validity (a 47-patient screen found no pathogenic CBX2, PMID:23219007) and on the absent tumour-risk denominator. Key references: PMID:19361780 (index case), PMID:29998616 (CBX2.2 patients), PMID:31719618 and PMID:25569159 (target landscape), PMID:31116734 (Wnt4 rescue), PMID:9641679, PMID:22186409, PMID:15899914, PMID:22200029 (mouse), PMID:23219007 (negative screen), PMID:31058389 (PBX1-CBX2-EMX2), PMID:17885459 (DSD management). PMID:20301714 (Nonsyndromic Disorders of Testicular Development) is tagged GeneReviews in the references block; there is no GeneReviews chapter for SRXY5 or CBX2, and that record's PubMed abstract carries only the chapter purpose statement, so no phenotype was derived from it. One correction made against the sources: the CBX2 pLI of 0.95 quoted by PMID:29998616 is an ExAC-era figure that sits awkwardly with a recessive mechanism, and the deep-research report's gnomAD lookup gives a much lower value. The entry reports the published figure with that attribution and flags it rather than asserting either number as current constraint. Datasets: geo:GSE130749 added and verified with 'just verify-datasets'. Every other candidate from 'just discover-datasets' was a GENE_ONLY match on CBX2 chromatin/cancer biology or a word match on 'sex reversal' in an unrelated cohort, and was triaged out; the reason is recorded in the dataset notes. Validation: 'just validate' passes with 85/85 snippets verified against the reference cache; 'just validate-terms' passes; check-causal-targets, check-entity-refs, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-snippet-length, check-title-snippets, check-folded-hyphens, check-snippet-grading all pass. 'just compliance' reports 83.8%. The stub stubs/46_XY_Sex_Reversal_5.yaml was deleted.

OpenScientist ▸
Key Findings
openscientist-autonomous 17 citations 2026-09-01T05:47:39.997872

Key Findings

Finding 1 — SRXY5 is caused by biallelic loss-of-function mutations in CBX2, placing CBX2 upstream of SRY

The defining discovery of SRXY5 came from a single, unusually informative index case. Biason-Lauber et al. (2009) described a prenatally karyotyped 46,XY girl born with completely normal female external genitalia, a uterus, and histologically normal ovaries. Whole-gene analysis of CBX2 — the human ortholog of mouse M33 — revealed compound-heterozygous loss-of-function mutations. This case defines the OMIM entry #613080 (46,XY sex reversal 5).

Crucially, the discovery added a new, higher tier to the human sex-determination cascade. As the authors state:

"The analysis of the human homolog of M33, Chromobox homolog 2 (CBX2), in this girl revealed loss-of-function mutations that allowed us, by placing CBX2 upstream of SRY, to add an additional component to the still incomplete cascade of human sex development." — PMID: 19361780

This is the single most important mechanistic anchor for the disease: CBX2 is not merely another testis gene but an upstream enabler of the SRY-initiated switch.

Finding 2 — Mouse M33/Cbx2 knockout recapitulates XY sex reversal via loss of upstream regulation of Sry and Nr5a1/SF-1

The human finding rests on a robust animal foundation predating it by more than a decade. Katoh-Fukui et al. (1998) showed that M33-null mice display XY male-to-female sex reversal with retarded genital ridge formation and gonadal growth defects arising near the time of Sry expression:

"survivors showed male-to-female sex reversal" — PMID: 9641679

"Gonadal growth defects appeared near the time of expression of the Y-chromosome-specific Sry gene, suggesting that M33 deficiency may cause sex reversal by interfering with steps upstream of Sry." — PMID: 9641679

A subsequent study connected M33 to the nuclear receptor SF-1: M33-knockout adrenal/splenic phenotypes mirror those of Nr5a1 (Ad4BP/SF-1) knockouts, and M33-KO gonads/adrenals showed significantly reduced Ad4BP/SF-1 expression with ChIP evidence of direct regulation:

"indicating that M33 is an essential upstream regulator of Ad4BP/SF1" — PMID: 15899914

Sex-reversal penetrance is incomplete in mice: one study reported reversal in ~28.6% of XY−/− embryos, with the remainder showing bilateral testicular hypoplasia (PMID: 22200029).

Finding 3 — CBX2 is a PRC1 chromatin regulator that stimulates the male pathway and represses the female pathway; two isoforms have distinct DSD roles

Genome-wide DamID mapping in Sertoli-like NT-2D1 cells identified ~1,600 direct CBX2 targets and established CBX2's bistable, dual role:

"CBX2 role in the sex development cascade is to stimulate the male pathway and concurrently inhibit the female pathway" — PMID: 25569159

Mechanistically, CBX2 is an H3K27me3 "reader" within Polycomb Repressive Complex 1 (PRC1), where it associates with RING1B, PCGF2, and PHC2 and plays a structural role in the H2AK119 mono-ubiquitination machinery (PMID: 31093962; PMID: 32979540).

The gene encodes two functionally distinct isoforms. The shorter isoform, CBX2.2, has its own DSD-associated variants (p.Cys132Arg and p.Cys154fs) that cause 46,XY DSD, likely through defective regulation of EMX2:

"both CBX2.2 variants fail to regulate the expression of genes essential for sexual development, leading to a severe 46,XY DSD defect, likely because of a defective expression of EMX2 in the developing gonad" — PMID: 29998616

Finding 4 — Phenotypic spectrum ranges from complete female genitalia with ovaries to ambiguous genitalia

SRXY5 is phenotypically variable. The index case had a fully female phenotype with uterus and normal ovaries (PMID: 19361780). At the opposite end, CBX2.2-variant patients presented with:

"two patients with features of DSD i.e. atypical external genitalia, perineal hypospadias and no palpable gonads" — PMID: 29998616

Because 46,XY gonadal dysgenesis broadly carries elevated germ-cell-tumor/gonadoblastoma risk, gonadectomy is considered, and care follows the multidisciplinary DSD consensus framework:

"medical, surgical and psychological care and the decision regarding sex of rearing or gender assignment" — PMID: 18987491

Finding 5 — Gene annotation and gnomAD constraint support an autosomal-recessive mechanism

CBX2 identifiers: HGNC:1552, NCBI Gene 84733, Ensembl ENSG00000173894, UniProt Q14781, OMIM gene 602770*, cytoband 17q25.3 (chr17:79,778,135–79,788,394, GRCh38); aliases M33, CDCA6, SRXY5. gnomAD constraint metrics show CBX2 is not loss-of-function intolerant: pLI = 0.024, observed/expected LoF (oe_lof) = 0.52 (90% CI 0.33–0.87), lof_z = 1.85. Heterozygous LoF is therefore tolerated in the general population, consistent with a recessive disease requiring biallelic loss. ClinVar lists 224 CBX2 variants, predominantly benign/VUS.

Finding 6 — CBX2 acts upstream of SRY: rescue epistasis with Sry/Sox9

The decisive genetic proof of hierarchy comes from mouse rescue experiments. In Cbx2-KO gonads, expression of Sry, Sox9, Lhx9, Ad4BP/SF-1 (Nr5a1), Dax-1 (Nr0b1), Gata4, Arx, and Dmrt1 is disrupted:

"the expression of Sry, Sox9, Lhx9, Ad4BP/SF-1, Dax-1, Gata4, Arx, and Dmrt1, genes encoding transcription factors essential for gonadal development, is affected in Cbx2 KO gonads" — PMID: 22186409

Forced expression of Sry or Sox9 rescues the sex reversal but not the gonadal hypoplasia:

"Male-to-female sex reversal in Cbx2 KO mice was rescued by crossing them with transgenic mice displaying forced expression of Sry or Sox9." — PMID: 22186409

This dissociates two CBX2 functions: (i) controlling the sex-determining switch specifically through Sry, and (ii) governing gonad size via a separate downstream gene set.

Finding 7 — Disease and molecular ontology annotations

Disease IDs: OMIM #613080; MONDO:0013120 (confirmed via EBI OLS); Orphanet groups under 46,XY complete/partial gonadal dysgenesis (ORPHA:242, ORPHA:2138). Gene/protein: CBX2 (HGNC:1552, OMIM 602770, UniProt Q14781, 532 aa). Protein architecture (UniProt Q14781): N-terminal chromodomain (aa 12–70; H3K9me/H3K27me reader), nuclear localization signal (aa 163–168), and large disordered/AT-hook-containing C-terminal regions (aa 60–204, 296–348, 379–493). Notably, the index-case variants p.Pro98Leu and p.Arg443Pro fall in the disordered regions outside* the chromodomain.

Suggested GO terms: GO:0035102 (PRC1 complex), GO:0031519 (PcG protein complex), GO:0045137 (development of primary sexual characteristics), GO:0062072 (histone reader activity), GO:0000122/GO:0045892 (negative regulation of transcription), GO:0031507 (heterochromatin formation), GO:0005634 (nucleus).

Finding 8 — ClinVar confirms the two index-case alleles as Pathogenic

ClinVar (queried 2026-09-01) lists NM_005189.3(CBX2):c.293C>T (p.Pro98Leu) and NM_005189.3(CBX2):c.1328G>C (p.Arg443Pro), both classified Pathogenic for the condition "46,XY sex reversal 5" — precisely the compound-heterozygous genotype of the index patient (PMID: 19361780). Other CBX2 coding substitutions (p.His331Arg, p.Met404Leu, p.Val487Ile, p.Ala460Thr) are VUS. Pathogenic large 17q25.3 CNVs in ClinVar are contiguous-gene events rather than isolated CBX2-DSD.

Finding 9 — Mouse ortholog identifiers and completed model-organism annotation

Mouse ortholog Cbx2 (M33): NCBI Gene 12416, MGI:88289, Ensembl ENSMUSG00000025577, chromosome 11. The constitutive M33/Cbx2 knockout is the validated SRXY5 model recapitulating XY male-to-female sex reversal (PMID: 9641679, PMID: 22186409, PMID: 15899914, PMID: 22200029).

Section-by-Section Report

1. Disease Information

Overview. SRXY5 is a rare Mendelian 46,XY DSD in which a chromosomally male (46,XY) individual fails to complete testis determination because of loss of the Polycomb regulator CBX2. The result is dysgenetic gonads or ovaries, frequently with Müllerian (uterine) structures, and external genitalia ranging from typically female to ambiguous.

Key identifiers:

Resource Identifier
OMIM (phenotype) #613080
OMIM (gene) *602770 (CBX2)
MONDO MONDO:0013120
Orphanet (grouping) ORPHA:242, ORPHA:2138 (46,XY complete/partial gonadal dysgenesis)
Gene (HGNC) HGNC:1552
NCBI Gene 84733
Ensembl ENSG00000173894
UniProt Q14781
MeSH (broad) Disorders of Sex Development; Gonadal Dysgenesis, 46,XY

Synonyms / alternative names: 46,XY sex reversal 5; SRXY5; CBX2-related 46,XY DSD; gonadal dysgenesis due to CBX2 deficiency. Gene aliases: M33, CDCA6.

Information source. Disease-level knowledge derives primarily from aggregated resources (OMIM, ClinVar, Orphanet) built on a very small number of individual clinical case reports plus extensive mouse model data — not from EHR-scale datasets.

2. Etiology

Primary cause — genetic. SRXY5 is caused by biallelic (autosomal-recessive) loss-of-function mutations in CBX2. The index genotype is compound-heterozygous p.Pro98Leu / p.Arg443Pro (PMID: 19361780). Isoform-specific CBX2.2 variants (p.Cys132Arg, p.Cys154fs) cause a severe 46,XY DSD via defective EMX2 regulation (PMID: 29998616).

Genetic risk factors. The disease requires two damaging CBX2 alleles; heterozygous carriers are unaffected (consistent with gnomAD tolerance of monoallelic LoF, pLI = 0.024). Consanguinity increases risk of biallelic recessive genotypes (a recurring theme in DSD cohorts generally, e.g., PMID: 42202777).

Environmental / infectious factors. None known to cause SRXY5. This is a monogenic developmental disorder; there is no evidence for toxin, infectious, or lifestyle etiology.

Protective factors and gene–environment interactions. Not applicable / none established. The only "protective" scenario is the absence of a second pathogenic allele.

3. Phenotypes

Phenotype Type Suggested HPO Frequency / notes
46,XY complete gonadal dysgenesis / sex reversal Clinical sign HP:0010461 (46,XY sex reversal) Core; variable
Female external genitalia in 46,XY individual Physical manifestation HP:0000812 (abnormal external genitalia) Index case
Ambiguous genitalia Physical manifestation HP:0000062 CBX2.2-variant patients
Hypospadias (perineal) Physical manifestation HP:0000047 CBX2.2 cases (PMID: 29998616)
Presence of uterus / Müllerian derivatives Clinical sign HP:0000130 (abnormal uterus) Index case had uterus
Ovarian or dysgenetic gonadal tissue Histology HP:0000138 / HP:0000133 Index case: normal ovaries
Cryptorchidism / no palpable gonads Clinical sign HP:0000028 CBX2.2 cases
Germ-cell tumor / gonadoblastoma risk Neoplasm (risk) HP:0100728 / HP:0100729 Elevated in 46,XY GD generally
Primary amenorrhea / delayed puberty (potential) Lab/clinical HP:0000132 / HP:0000823 Depends on gonadal function

Characteristics. Onset is congenital (determined during embryonic gonadal development, ~gestational weeks 6–8 in humans). Severity is variable (from typically female to ambiguous). Course is stable/non-progressive structurally, though tumor risk accrues over time and pubertal hormone deficits emerge with age. Frequency data are limited by the very small number of confirmed cases.

Quality-of-life impact. DSD conditions carry documented psychosocial and quality-of-life burdens; a multidisciplinary education/empowerment program (Empower-DSD) improved or stabilized health-related quality of life in >66% of children and parents (PMID: 42597469) and improved diagnosis-specific knowledge (PMID: 41579703).

4. Genetic / Molecular Information

Causal gene. CBX2 (HGNC:1552; OMIM *602770; 17q25.3).

Pathogenic variants (ClinVar, Pathogenic for SRXY5):

Variant (NM_005189.3) Protein Type Classification Domain location
c.293C>T p.Pro98Leu Missense Pathogenic Disordered region (outside chromodomain)
c.1328G>C p.Arg443Pro Missense Pathogenic Disordered C-terminal region
(CBX2.2) p.Cys132Arg Missense Reported pathogenic (PMID: 29998616) Isoform-specific
(CBX2.2) p.Cys154fs Frameshift Reported pathogenic Isoform-specific

Allele frequency. Pathogenic alleles are ultra-rare/private; gnomAD shows CBX2 is LoF-tolerant at the heterozygous level (oe_lof 0.52). Origin: germline. Functional consequence: loss of function (biallelic).

Modifier genes / epigenetics. CBX2 itself is an epigenetic effector (H3K27me3 reader, H2AK119ub machinery). Downstream network members (SRY, SOX9, NR5A1/SF-1, EMX2, DMRT1, GATA4, DAX1/NR0B1, LHX9, ARX) are candidate modifiers of expressivity. No formal modifier locus is established.

Chromosomal abnormalities. Large 17q25.3 CNVs in ClinVar are contiguous-gene deletions/duplications, not isolated CBX2-DSD events. A 47-patient DSD MLPA study found no CBX2 copy-number changes and no additional pathogenic point mutations (PMID: 23219007), underscoring rarity.

5. Environmental Information

Not applicable. SRXY5 is a monogenic developmental disorder with no established environmental, lifestyle, toxicological, or infectious contribution.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

  1. Biallelic loss-of-function mutation in CBX2 (e.g., p.Pro98Leu + p.Arg443Pro) results in a non-functional CBX2 protein in the bipotential gonad (genital ridge). (Demonstrated — human PMID: 19361780; ClinVar Pathogenic.)
  2. Loss of CBX2 impairs assembly/function of the PRC1 chromatin-modifying complex (CBX2 is a structural H3K27me3 reader supporting H2AK119 mono-ubiquitination). (Demonstrated in vitro — PMID: 31093962, PMID: 32979540.)
  3. Defective CBX2/PRC1 activity fails to establish the chromatin state that stimulates male-pathway genes and represses female-pathway genes across ~1,600 direct targets. (Demonstrated — DamID, PMID: 25569159.)
  4. As an upstream node, CBX2 loss fails to permit/activate SRY (and NR5A1/SF-1) expression in pre-Sertoli somatic cells at the critical window (~gestational week 6–7; in mouse, near the time of Sry onset). (Demonstrated — mouse PMID: 9641679, PMID: 15899914, PMID: 22186409.)
  5. Absent SRY fails to activate SOX9, the master Sertoli-cell determinant. Branch: without SOX9-driven Sertoli differentiation, the supporting-cell lineage defaults toward the granulosa (ovarian) program; de-repressed pro-ovarian genes (e.g., via impaired EMX2 regulation in the CBX2.2 isoform axis) reinforce this. (Demonstrated/inferred — PMID: 22186409, PMID: 29998616.)
  6. Failure of Sertoli-cell determination results in gonadal dysgenesis or ovarian development in a 46,XY gonad. (Demonstrated — human/mouse.)
  7. Absent/deficient testicular Sertoli and Leydig function leads to loss of anti-Müllerian hormone and androgen output, which results in retention of Müllerian structures (uterus) and undervirilized/female external genitalia. (Inferred from endocrine physiology; consistent with index-case uterus + female genitalia.)
  8. In parallel, a separate CBX2-dependent gene set governs gonad size, so dysgenetic/hypoplastic gonads persist even when the sex-fate switch is rescued. (Demonstrated — Sry/Sox9 rescue corrects sex reversal but not hypoplasia, PMID: 22186409.)
CBX2 biallelic LOF
│ (results in)
▼
PRC1/H2AK119ub chromatin regulation impaired
│ (fails to set)
▼
Male genes not stimulated / female genes de-repressed
│ (fails to activate)
▼
SRY not expressed ──► SOX9 not activated
│                         │
│ (branch)                ▼
▼               Sertoli differentiation fails
Pro-ovarian program        │
(EMX2 axis) reinforced     ▼
└────────► Gonadal dysgenesis / ovary in 46,XY
          │ (leads to)
          ▼
↓ AMH, ↓ androgens ► uterus retained + female/ambiguous genitalia
          │
(parallel) separate gene set ► persistent gonadal hypoplasia

Upstream vs downstream. CBX2 is the most upstream demonstrated node (above SRY). SRY→SOX9→Sertoli differentiation and the NR5A1/SF-1, DMRT1, GATA4, DAX1, LHX9, ARX network are downstream.

Cell types / processes. Key cell type: bipotential/pre-Sertoli somatic supporting cell of the genital ridge (suggested CL: CL:0000216 Sertoli cell; CL:0000670 primordial germ cell; CL:0000501 granulosa cell). Processes: GO:0007530 sex determination, GO:0008584 male gonad development, GO:0045137 development of primary sexual characteristics, GO:0031507 heterochromatin formation.

Molecular profiling. DamID identified ~1,600 direct CBX2 targets in Sertoli-like cells (PMID: 25569159). No SRXY5-specific human metabolomic/proteomic/single-cell datasets are available given case rarity.

7. Anatomical Structures Affected

  • Primary organ: gonad (bipotential gonad / genital ridge) — UBERON:0000991 gonad; UBERON:0000992 ovary; UBERON:0000473 testis.
  • Secondary / body systems: reproductive/endocrine system (UBERON:0000990); Müllerian derivatives — uterus UBERON:0000995, external genitalia. Adrenal gland and spleen are affected in the mouse M33 model (via SF-1) but adrenal disease is not a prominent human SRXY5 feature.
  • Tissue/cell level: gonadal somatic supporting cells (Sertoli/granulosa) and germ cells; germline meiotic defects in the mouse model (PMID: 22200029).
  • Subcellular: nucleus / chromatin (GO:0005634 nucleus; GO:0035102 PRC1 complex; GO:0000785 chromatin).
  • Lateralization: typically bilateral gonadal involvement; asymmetric gonads (one hypoplastic testis + contralateral ovary/ovotestis) occur in the mouse model.

8. Temporal Development

  • Onset: congenital — the lesion acts during embryonic sex determination (human ~6–8 weeks gestation).
  • Onset pattern: insidious/developmental; often first detected at birth (ambiguous genitalia), prenatally (karyotype–phenotype discordance, as in the index case), or at puberty (delayed puberty/primary amenorrhea).
  • Progression: structurally stable/non-progressive; lifelong. Germ-cell-tumor risk accrues over time, and hypogonadism manifests at expected puberty.
  • Critical period: the sex-determination window is the intervention-relevant developmental window mechanistically, though no in-utero therapy exists.

9. Inheritance and Population

  • Inheritance: autosomal recessive (biallelic CBX2 LoF). Consistent with gnomAD LoF tolerance (pLI 0.024).
  • Prevalence/incidence: not precisely established — ultra-rare; only a handful of molecularly confirmed cases worldwide. A dedicated 47-patient DSD cohort found no additional pathogenic CBX2 mutations (PMID: 23219007), and the authors concluded the study "does not support CBX2 gene disruption as a common cause of gonadal DSD."
  • Penetrance/expressivity: variable expressivity (female to ambiguous phenotype); mouse penetrance of overt sex reversal is incomplete (~28.6% of XY−/−, PMID: 22200029).
  • Consanguinity/founder effects: consanguinity raises recessive-genotype probability (general DSD context); no CBX2 founder allele is established.
  • Carrier frequency: unknown; individual pathogenic alleles are private/ultra-rare in gnomAD.
  • Sex ratio / affected population: by definition affects 46,XY (chromosomally male) individuals who may present or be reared as female; no ethnic predilection established.

10. Diagnostics

Recommended approach: karyotype (46,XY) with phenotype–karyotype discordance triggers molecular workup.

  • Genetic testing: karyotyping (confirms 46,XY); DSD gene panels including CBX2 alongside SRY, SOX9, NR5A1, MAP3K1, WT1, GATA4, DHH, DMRT1; WES/WGS for gene-agnostic diagnosis (essential given rarity); single-gene CBX2 sequencing for targeted confirmation; chromosomal microarray/MLPA to detect CBX2 CNVs (MLPA probe set developed in PMID: 23219007). Confirm variants against ClinVar (both index alleles are Pathogenic).
  • Laboratory tests: gonadotropins (LH/FSH), testosterone, AMH, inhibin B, hCG stimulation test to assess gonadal function.
  • Imaging: pelvic/abdominal ultrasound and MRI to identify Müllerian structures (uterus) and locate gonads.
  • Histopathology: gonadal biopsy — ovarian, dysgenetic, or streak tissue; surveillance for gonadoblastoma/germ-cell neoplasia.
  • Differential diagnosis: other 46,XY complete/partial gonadal dysgenesis (SRY, NR5A1/SF-1, MAP3K1, WT1, SOX9, DHH, PBX1), androgen insensitivity syndrome, 17α-/11β-hydroxylase and steroidogenic defects, and Swyer syndrome. Distinguishing features: CBX2-related cases show early upstream failure with possible normal ovaries; PBX1 disease adds radioulnar/radiocubital synostosis (PMID: 31058389).
  • Screening: no population newborn screen; cascade genetic testing of relatives after a proband is identified.

11. Outcome / Prognosis

  • Survival/mortality: SRXY5 is not intrinsically life-limiting; life expectancy is normal. Principal medical risk is germ-cell tumor/gonadoblastoma in dysgenetic gonads, mitigated by surveillance/gonadectomy.
  • Morbidity/function: infertility is typical; hypogonadism requires lifelong hormone replacement; psychosocial burden is significant.
  • Complications: gonadal neoplasia; osteoporosis and metabolic effects of untreated hypogonadism; surgical and psychological sequelae.
  • Prognostic factors: phenotype severity, gonadal histology/position, and timing of diagnosis/intervention. No molecular prognostic biomarker beyond genotype is established.
  • Quality of life: improvable with structured multidisciplinary support (PMID: 42597469, PMID: 41579703).

12. Treatment

No disease-modifying/curative therapy exists (no gene, cell, or RNA therapy; not applicable). Management is supportive and individualized within the international DSD consensus framework (PMID: 16882788, PMID: 18987491, PMID: 17885459):

Modality Detail Suggested NCIT
Hormone replacement Estrogen (± progestin) or testosterone per sex of rearing/gonadal status NCIT:C15417 (hormone therapy)
Gonadectomy For germ-cell-tumor risk in dysgenetic gonads NCIT:C15277 (surgery) / gonadectomy
Genital / reconstructive surgery Individualized; deferred until autonomous consent where legally required (e.g., Germany) NCIT:C15329 (reconstructive surgery)
Psychological support DSD-specialized counseling; peer/empowerment programs supportive care
Genetic counseling Recurrence-risk (25% for AR), cascade testing NCIT:C15681 (genetic counseling)

Sex-of-rearing decisions should be based on the most likely adult gender identity, diagnosis, genital appearance, fertility potential, and psychosocial context (PMID: 17885459). No pharmacogenomic or experimental targeted therapy is specific to SRXY5.

13. Prevention

  • Primary prevention: not possible for a congenital monogenic disorder; genetic counseling and reproductive options (PGT/prenatal testing) for at-risk (carrier) couples.
  • Secondary prevention: early molecular diagnosis; gonadal tumor surveillance and timely gonadectomy where indicated.
  • Tertiary prevention: hormone replacement to prevent osteoporosis/metabolic complications; psychosocial support to reduce stigma-related morbidity.
  • Counseling: autosomal-recessive recurrence risk 25% per pregnancy for carrier couples; cascade carrier testing. Immunization/public-health/environmental measures: not applicable.

14. Other Species / Natural Disease

  • Taxonomy / ortholog: mouse Cbx2 (NCBI Gene 12416, MGI:88289, Ensembl ENSMUSG00000025577, chromosome 11); NCBI Taxon 10090 (Mus musculus).
  • Natural disease: no well-documented naturally occurring CBX2 sex-reversal disease in companion animals/wildlife is recorded here; the phenotype is known from engineered knockouts. (OMIA not confirmed for a spontaneous CBX2 DSD in this investigation.)
  • Comparative biology: the CBX2→Sry/SF-1 hierarchy is conserved between mouse and human, validating cross-species inference; mouse recapitulates XY male-to-female sex reversal and gonadal hypoplasia.
  • Zoonotic potential: not applicable.

15. Model Organisms

  • Primary model: constitutive M33/Cbx2-knockout mouse (mammalian; Alliance/MGI:88289).
  • Model types available: knockout (constitutive); the field also uses transgenic rescue lines (forced Sry or Sox9 expression) demonstrating epistasis (PMID: 22186409). In-vitro human models: NT-2D1 Sertoli-like cells (DamID target mapping, PMID: 25569159); gonadal fibroblasts and EBV-transformed lymphocytes express both CBX2 isoforms (PMID: 23219007).
  • Phenotype recapitulation: high — XY male-to-female sex reversal, gonadal hypoplasia, reduced SF-1, disrupted downstream TF network; additional homeotic skeletal transformations and germline/meiotic defects (broader Polycomb roles).
  • Limitations: incomplete penetrance (~28.6%); pleiotropic phenotypes (skeletal, splenic, adrenal) beyond the human DSD focus; isoform biology (CBX2.1 vs CBX2.2) is human-relevant and less fully modeled in mouse.
  • Resources: MGI, IMPC/IMSR for allele availability.

Mechanistic Model / Interpretation

SRXY5 is best understood as a failure of the upstream "permissive" chromatin switch that normally licenses the male genetic program. CBX2, as a PRC1 reader of H3K27me3, sets the chromatin landscape that (a) permits/activates SRY and NR5A1/SF-1 and (b) represses the ovarian program. Because CBX2 sits above SRY, its biallelic loss is functionally equivalent — at the level of outcome — to SRY loss, but it acts one tier higher and simultaneously de-represses female genes. The mouse rescue experiments provide the cleanest logic: restoring Sry or Sox9 downstream corrects the sex-fate decision, proving CBX2's role in that decision is transmitted through SRY/SOX9; yet gonad size remains hypoplastic, revealing a second, parallel CBX2 output. This two-arm model (fate switch vs. growth) explains the clinical spectrum: patients can have ovaries with a uterus (fate fully flipped) or dysgenetic/ambiguous gonads (partial), depending on residual function and isoform involvement (CBX2.2→EMX2).

Node Role Direction Evidence
CBX2 (PRC1) Chromatin permissive switch Most upstream Human [19361780]; mouse [9641679]
SRY Testis-determining trigger Downstream of CBX2 Rescue [22186409]
SOX9 Master Sertoli determinant Downstream of SRY Rescue [22186409]
NR5A1/SF-1 Steroidogenic/gonadal TF Downstream target [15899914]
EMX2 (via CBX2.2) Ovarian/gonadal regulator Branch [29998616]

Evidence Base

PMID Title (abbrev.) Evidence type Role
19361780 Ovaries/female phenotype in 46,XY girl with CBX2 mutations Human clinical (index case) Defines SRXY5; CBX2 upstream of SRY
22186409 Cbx2 required for Sry expression Mouse genetic Epistasis: Sry/Sox9 rescue
9641679 Male-to-female sex reversal in M33 mutants Mouse Founding model; upstream of Sry
15899914 M33 regulates Ad4BP/SF1 Mouse/ChIP SF-1 link
25569159 Genome-wide CBX2 targets In vitro (DamID) Dual stimulate/repress role
29998616 CBX2 isoform 2 targets in DSD Human/functional CBX2.2 variants; EMX2
31093962 PRC1 topology/enzymology In vitro biochemistry CBX2 structural role in PRC1
32979540 CBX protein functions review Review CBX2 as H3K27me3 reader in PRC1
22200029 Cbx2 in meiosis/germline Mouse Penetrance ~28.6%; germline role
23219007 CBX2 in 46,XY/46,XX DSD cohort Human cohort (n=47) CBX2 not a common DSD cause; rarity
31058389 PBX1 in testis-determination Human CBX2 protein-interaction partner; DDx
18987491 / 16882788 / 17885459 DSD consensus statements Clinical guideline Management framework
42597469 / 41579703 Empower-DSD program Clinical (QoL/education) Quality-of-life/support evidence

Challenging/tempering evidence: PMID: 23219007 explicitly found no pathogenic CBX2 mutations in 47 DSD patients — a key check on over-attribution: CBX2 is a rare cause, not a common one.

Limitations and Knowledge Gaps

  1. Extreme rarity / small N. The human disease is defined by very few molecularly confirmed cases; genotype–phenotype correlations, penetrance, and prevalence are consequently imprecise.
  2. Mechanistic gaps in humans. The full downstream target set and the precise chromatin logic (which male genes are directly activated vs. which female genes de-repressed) are best characterized in cell lines and mouse, not patient gonads.
  3. Isoform biology. The distinct contributions of CBX2.1 vs CBX2.2 (and the EMX2 axis) are incompletely resolved and may explain phenotypic variability.
  4. No prevalence/epidemiology data, no natural-history cohort, and no SRXY5-specific omics datasets.
  5. No SRXY5-specific therapy or biomarker; management is generic to 46,XY gonadal dysgenesis.
  6. Domain location paradox. The pathogenic index missense variants (p.Pro98Leu, p.Arg443Pro) lie outside the chromodomain in disordered regions — the structural basis of their loss of function is not fully explained.

Proposed Follow-up Experiments / Actions

  1. Establish an SRXY5 patient registry and pursue GeneMatcher/international case aggregation to define penetrance, expressivity, and gonadal-tumor risk quantitatively.
  2. Functional characterization of p.Pro98Leu and p.Arg443Pro (and CBX2.2 variants) in isogenic gonadal-somatic iPSC-derived models to map how disordered-region substitutions disrupt PRC1 assembly and target regulation.
  3. Single-cell / spatial transcriptomics of patient or knockout gonadal ridge to resolve the Sertoli-vs-granulosa fate branch and validate the CBX2→SRY→SOX9 and CBX2.2→EMX2 arms in situ.
  4. Systematic reclassification of the many CBX2 VUS in ClinVar using calibrated functional assays to improve diagnostic yield.
  5. Comparative-genomics / OMIA search for spontaneous CBX2-related DSD in domestic species to add natural-disease models.
  6. Formalize a DSD-panel diagnostic algorithm ensuring CBX2 (with CNV/MLPA coverage) is included and cross-referenced to ClinVar, and integrate multidisciplinary psychosocial support (Empower-DSD-type programs) into standard care.

Report compiled from 9 confirmed findings and 21 reviewed papers, integrating human clinical, in-vitro/functional, model-organism, and computational-database evidence. Ontology suggestions (MONDO:0013120, HGNC:1552, GO:0007530/0008584/0035102, UBERON:0000991/0000992, CL:0000216, NCIT clinical-intervention terms) are provided for knowledge-base ingestion.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 17
Resolved 17
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 10
Quoted claims found in source 10
Quoted claims not found in source 0
References weighed for topical relevance 17
On topic 9
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 40
Resolved 36
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 4
Terms whose name was checked 18
Terms named correctly 5
Terms named as a different term 8
Terms whose name is worth a second look 5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0013120 (4 mentions) - the report calls it "confirmed via EBI OLS", "MONDO"; MONDO calls it 46,XY sex reversal 5
  • HP:0010461 (1 mention) - the report calls it "46,XY sex reversal"; HP calls it Abnormality of the male genitalia
  • HP:0000062 (1 mention) - the report calls it "Physical manifestation"; HP calls it Ambiguous genitalia
  • HP:0000047 (1 mention) - the report calls it "Physical manifestation"; HP calls it Hypospadias
  • HP:0000028 (1 mention) - the report calls it "Clinical sign"; HP calls it Cryptorchidism
  • NCIT:C15417 (1 mention) - the report calls it "hormone therapy"; NCIT calls it Randomized Clinical Trial
  • NCIT:C15277 (1 mention) - the report calls it "surgery"; NCIT calls it Mastectomy
  • NCIT:C15681 (1 mention) - the report calls it "genetic counseling"; NCIT calls it Cytotoxic Chemotherapy

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0062072 (1 mention) - the report calls it "histone reader activity"; GO calls it histone H3K9me2/3 reader activity, and lists "histone H3K9me2 reader activity" among its other names
  • GO:0045892 (1 mention) - the report calls it "negative regulation of transcription"; GO calls it negative regulation of DNA-templated transcription
  • HP:0000812 (1 mention) - the report calls it "abnormal external genitalia"; HP calls it Abnormal internal genitalia
  • HP:0000130 (1 mention) - the report calls it "abnormal uterus"; HP calls it Abnormality of the uterus
  • NCIT:C15329 (1 mention) - the report calls it "reconstructive surgery"; NCIT calls it Surgical Procedure, and lists "Type of Surgery" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • MONDO:0013120 - called "confirmed via EBI OLS", "MONDO"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.