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Definitions

1

46,XY sex reversal 11 case definition

A 46,XY individual with a difference of testicular development and a pathogenic or likely pathogenic DHX37 variant consistent with the phenotype and inheritance. Most established alleles are heterozygous missense changes in conserved helicase domains. A rare variant or an in silico damaging prediction alone does not establish the diagnosis. A homozygous missense case has also been reported, so heterozygosity is not an absolute requirement.

CASE_DEFINITION This gene-defined entry spans gonadal dysgenesis and testicular regression because recurrent alleles produce both presentations within and across families. Other genetic and non-genetic causes of those clinical phenotypes require separate diagnosis. The allelic DHX37 neurodevelopmental disorder NEDBAVC is distinct and can involve biallelic or de novo heterozygous variants.

Show evidence (2 references)

PMID:34293745 SUPPORT DIRECT BACKGROUND Human Clinical

"Missense variants in the RNA-helicase DHX37 are associated with either 46,XY gonadal dysgenesis or 46,XY testicular regression syndrome (TRS). DHX37 is required for ribosome biogenesis, and this subgroup of XY DSD is a new human ribosomopathy."

States the gene-anchored scope of this entry and the two clinical poles it spans.

PMID:35835064 SUPPORT DIRECT REVIEW SYNTHESIS Other

"compound heterozygous as well as de novo heterozygous missense variants in DHX37 are also associated with a complex congenital developmental syndrome (NEDBAVC, neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies; OMIM 618731)"

Establishes NEDBAVC as a distinct allelic DHX37 disorder, supporting its exclusion from this entry's scope.

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Inheritance

1

Autosomal dominant, sex-limited, with incomplete penetrance HP:0000006

Specific heterozygous DHX37 variants show sex-limited autosomal dominant inheritance with variable expression and incomplete penetrance in 46,XY carriers. Unaffected 46,XX carriers, unaffected or mildly affected fertile fathers, and de novo variants are reported. Maternal transmission predominates in some family series, whereas five of six parentally tested cases in the 2019 discovery cohort were de novo; these ascertained series do not establish a population penetrance or de novo fraction.

sex-limited autosomal dominant inheritance Penetrance: INCOMPLETE

Show evidence (3 references)

url:https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the presence of the p.Arg308Gln variant in the asymptomatic father"

The familial cohort documents an unaffected father transmitting the recurrent allele; the surrounding segregation analysis also records maternal and de novo inheritance.

PMID:31337883 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Where tested, all pathogenic variants are de novo with one exception, which was inherited from the phenotypically normal mother."

The discovery cohort had parental data for six of thirteen children; this is a cohort-specific observation, not a general de novo frequency.

PMID:40026690 SUPPORT DIRECT REVIEW SYNTHESIS Other

"The gonadal development and fertility of female (46,XX) carriers with DHX37 gene mutations are not affected; however, incomplete penetrance may be observed in males (46,XY)."

Directly states both the sex-limited expression and the incomplete penetrance in 46,XY carriers.

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Discussions and Knowledge Gaps

6

How does disruption of DHX37, a housekeeping nucleolar helicase needed for ribosome biogenesis in every cell, produce a phenotype restricted to the gonad and expressed only in 46,XY individuals?

KNOWLEDGE GAP OPEN dhx37_tissue_specificity

Attached to

pathophysiology#Impaired Small Ribosomal Subunit Biogenesis pathophysiology#Nucleolar Structural Disruption

DHX37 has broad cellular roles, while specific variants are associated with testicular-development disease. The clinical genetic evidence is stronger than the proposed universal ribosome-stress mechanism. Selected variants alter protein abundance or beta-catenin in overexpression systems, whereas Ser408Leu does not increase p53 or apoptosis relative to wild type. The Glu257Lys VUS was functionally negative in the reported assays and co-occurred with a likely pathogenic NR5A1 variant; that case does not demonstrate an undetectable disease mechanism. Patient gonadal pre-rRNA/40S measurements and allele-matched developmental models remain gaps.

Show evidence (3 references)

PMID:38142677 SUPPORT DIRECT REVIEW SYNTHESIS Other

"The trick question regarding DHX37 is how a helicase involved in basic cell function could have a specific role in testis development."

States this knowledge gap as the field's central open question.

PMID:37065748 REFUTE DIRECT PRIMARY RESULT In Vitro

"there is no difference in p53 expression among cells transfected with empty expressing vector, wt-DHX37, or mutant DHX37."

The Ser408Leu assay does not support a universal variant-induced increase in p53. It does not refute the distinct conditional-null mouse result.

PMID:42057034 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The other c.769G > A variant of DHX37 had no significant effect on the expression level and cellular localization of DHX37, and the downstream signaling pathway of DHX37."

The tested Glu257Lys VUS showed no change in protein abundance/localization or beta-catenin/p53 readouts. This does not establish pathogenicity or test every possible function.

How do developmental stage and assay influence the observed testicular distribution of DHX37?

KNOWLEDGE GAP OPEN dhx37_expression_compartment

Attached to

genetic#DHX37 animal_models#Sertoli-cell conditional Dhx37 knockout mouse

The apparent disagreement is partly resolved by the full texts. McElreavey and colleagues report fetal somatic-cell localization and explicitly report adult spermatogonial expression. The da Silva series includes late fetal, neonatal and adult specimens and observes germ-cell/Leydig staining with rare weak Sertoli staining. These stage- and assay-dependent observations do not establish a mutually exclusive somatic-versus-germ-cell mechanism. Expression outside the gonad also precludes interpreting fetal somatic localization as whole-body gonad specificity.

Show evidence (2 references)

PMID:31337883 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Although expression was not observed in germ cells in fetal gonads, in adult human testes the protein is mainly localized in spermatogonia"

Immunolocalization in normal fetal versus adult human testis demonstrates a developmental-stage difference; this is not a measurement in affected patient gonads.

PMID:31287541 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Immunohistochemistry analysis in human testis showed that DHX37 is mainly expressed in germ cells at different stages of testis maturation, in Leydig cells, and rarely in Sertoli cells."

The study examined later fetal, neonatal and adult specimens; its compartment findings are interpreted alongside early fetal localization rather than as a direct contradiction.

How do dysgenesis and subsequent tissue regression overlap across DHX37-related disease?

KNOWLEDGE GAP OPEN dhx37_regression_versus_dysgenesis

Attached to

pathophysiology#Testicular Regression pathophysiology#Impaired Testicular Development

Cohort definitions differ. The Belgian histology supports early dysgenesis with Müllerian remnants, while other series enroll individuals without Müllerian derivatives. Neither observation excludes a shared developmental-and-maintenance spectrum. A pathogenic-variant carrier with loss of palpable testes during childhood provides direct longitudinal evidence for postnatal regression. Hormone action, anatomy and histology need to be interpreted together rather than assigning a universal gestational timing from a diagnostic label.

Show evidence (3 references)

PMID:39659563 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Histological analysis confirmed DHX37 as a gonadal development, rather than a BTR-related, gene."

The histology-based argument that DHX37 disease is developmental rather than regressive.

PMID:38359811 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"DHX37 variant is one of the common genetic causes in Japanese patients with TRS/PGD without Müllerian derivatives."

An ascertainment-defined series without Müllerian derivatives demonstrates another part of the clinical spectrum, not a refutation of the Belgian histology.

PMID:40916030 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"However, patient 1 exhibited progressive postnatal gonadal disappearance."

A patient with pathogenic Arg334Trp had palpable inguinal testes in early childhood followed by their disappearance, demonstrating that regression is not confined to fetal life.

Which consequences of a Sertoli-cell conditional null model also occur with heterozygous human DHX37 missense variants?

HUMAN MODEL MISMATCH OPEN dhx37_allele_mechanism_model_mismatch

Attached to

animal_models#Sertoli-cell conditional Dhx37 knockout mouse pathophysiology#DHX37 Missense Variation

Amh-Cre deletion begins after initial sex determination and adult knockout findings test maintenance of a formed testis. The model does not establish early human sex reversal, a shared missense mechanism or p53 necessity. Variant-specific abundance and signaling assays also differ from null perturbations. A heterozygous allele-matched developmental model with appropriate dosage controls would help test which pathways mediate the human phenotype.

Proposed experiments

Knock-in of a recurrent human DHX37 missense allele in mouse

dhx37_r308q_knockin_mouse

Generate a mouse carrying the orthologue of p.Arg308Gln or p.Arg674Trp in the heterozygous state and assess fetal gonadal development, Müllerian regression, external genital masculinization, and postnatal gonadal presence, alongside nucleolar integrity and p53 activation in gonadal supporting cells.

Would support

pathophysiology#DHX37 Missense Variation pathophysiology#Nucleolar Structural Disruption

Supporting outcome

A heterozygous allele reproduces a gonadal phenotype together with the proposed cellular change; comparison with heterozygous null animals and pathway rescue helps distinguish dosage effects from other mechanisms.

Refuting outcome

Absence of the proposed molecular change or failure of pathway rescue would weaken that particular mechanism. A phenotypically normal mouse would limit this model without excluding human pathogenicity or proving a species-specific mechanism.

Show evidence (1 reference)

PMID:41535247 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"In the Dhx37-/- mice, we observed pronounced defects, including diminished testicular volume, lower testosterone levels, and marked vacuolization of the seminiferous tubules."

The knockout phenotype is a hypoplastic but formed testis with spermatogenic failure, not the failed determination or fetal gonadal loss seen in humans — which is the mismatch this discussion records.

What are the long-term outcomes of DHX37-related 46,XY DSD — germ-cell tumour risk in retained dysgenetic tissue, bone and cardiovascular health on lifelong replacement, and gender-identity trajectories?

KNOWLEDGE GAP OPEN dhx37_long_term_outcomes

Attached to

pathophysiology#Reduced Functional Testicular Tissue

Published case-level follow-up now documents hormone replacement, postnatal regression, azoospermia and a germ-cell-neoplasia-in-situ observation. These findings do not supply a genotype-specific tumor-risk estimate or robust comparative treatment outcomes. General DSD guidance informs care, with clear separation from DHX37-specific observations. The three gender-identity observations in the Belgian series should not be used as predictive proportions.

Show evidence (1 reference)

PMID:40026690 SUPPORT DIRECT REVIEW SYNTHESIS Other

"The treatments are primarily surgical intervention and hormone replacement therapy administered at appropriate times; however, the long-term prognosis remains unknown."

A review identifies limited long-term outcome knowledge; this does not mean that no case-level follow-up exists.

Do the uncertain variants reported with mild gynecomastia or another established DSD genotype contribute to disease?

KNOWLEDGE GAP OPEN dhx37_uncertain_mild_phenotypes

Attached to

genetic#DHX37

Five of six variants in the 2026 series were VUS. Its gynecomastia observations include a patient who did not meet DSD criteria, and the Gly478Arg case repeats a previously published individual. The 2023 double-variant series includes NR5A1 loss-of-function alleles with DHX37 Leu467Val (VUS) or Val999Met (likely benign), so co-occurrence does not establish digenic causation. These observations are retained as interpretation gaps instead of established phenotype frequencies.

Show evidence (2 references)

PMID:42510869 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"According to ACMG/AMP guidelines, p.Arg334Trp was classified as pathogenic, and the remaining five as variants of uncertain significance."

The classifications limit what can be attributed to the gene from this six-case series.

url:https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867 SUPPORT DIRECT REVIEW SYNTHESIS Other

"no in vitro studies have been performed to determine its pathogenicity and possible correlation with DSD."

The full discussion cautions about Val999Met; no measured synergistic effect with NR5A1 was demonstrated.

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Pathophysiology

14

DHX37 Missense Variation

Specific germline missense variants in DHX37 cause the testicular-development spectrum. Many cluster in the RecA-like helicase domains. Their shared biochemical effect is unresolved: domain location and enrichment establish a genetic association without proving decreased ATPase activity, dominant-negative action, gain of function or haploinsufficiency. Reports of variants of uncertain significance require separate interpretation.

Genetic context DHX37 hgnc:17210 allele_type: MISSENSE variant_origin: GERMLINE zygosity: HETEROZYGOUS

Downstream

Reduced DHX37 Abundance Selected variant constructs have reduced protein abundance in cultured cells; this has not been established for every disease allele.

Impaired Small Ribosomal Subunit Biogenesis A proposed consequence of altered DHX37 function; direct DSD-allele ribosome-output measurements remain unavailable.

Altered Beta-Catenin Abundance Variant-specific cell-culture evidence informs this candidate branch.

Impaired Testicular Development Human genetic and histological evidence establishes the disease association while the molecular intermediates remain unresolved.

Testicular Regression The human phenotype includes prenatal or postnatal regression; the mechanism of tissue loss is unresolved.

Altered RNA Splicing Knockdown data motivate a candidate role for altered RNA processing; equivalent changes have not been demonstrated for the established human DSD alleles.

Show evidence (1 reference)

PMID:31337883 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Twelve variants are clustered in two highly conserved functional domains and were specifically associated with gonadal dysgenesis and TRS."

Establishes enrichment and helicase-domain clustering of specific missense variants in the gonadal dysgenesis and regression spectrum; it does not measure helicase activity.

Reduced DHX37 Abundance

Mechanism confidence: Provisional

Arg308Gln and Arg671Thr constructs produce less DHX37 protein than wild type in HEK293T cells. Ser408Leu overexpression in a human Sertoli cell line reduces both transcript and protein abundance. Localization remains similar to wild type. These are construct-specific observations; protein stability, helicase activity and patient gonadal abundance were not directly measured.

Experimental models

DHX37 variant transfection in HEK293T and COS7 cells CELL LINE Provides a defined experimental readout relevant to this candidate mechanism.

Show evidence (2 references)

PMID:38769888 SUPPORT DIRECT PRIMARY RESULT In Vitro

"compared with the cells transfected with pcDNA3.1‐WT, those with pcDNA3.1‐Arg308Gln and pcDNA3.1‐Arg671Thr displayed a lower level of DHX37"

Western blots in transfected HEK293T cells show reduced protein abundance for these constructs; enzymatic activity and patient gonadal abundance were not measured. The paper inconsistently labels Arg671Thr pathogenic in prose and VUS in Table 1.

PMID:37065748 SUPPORT DIRECT PRIMARY RESULT In Vitro

"compared with the cells transfected with pcDNA3.1-WT, those with pcDNA3.1-S408L displayed decreased DHX37 expression both at the mRNA and protein levels."

The human Sertoli cell-line overexpression experiment supports a variant-specific abundance effect, not general loss of helicase function.

Impaired Small Ribosomal Subunit Biogenesis

Mechanism confidence: Hypothetical

DHX37 normally supports small-subunit maturation. Human HeLa-cell depletion reduces 18S rRNA and 40S output and impairs conversion of 21S pre-rRNA to 18SE. Wild-type DHX37 rescues processing defects in HEK293 complementation assays, whereas engineered catalytic T282A does not and causes retention of U3 snoRNA on pre-ribosomes. T282A is not a patient DSD allele; ribosome processing/output has not been demonstrated to fail in affected human gonads, so the SRXY11 mechanism remains hypothetical. Yeast experiments on neurological or zebrafish ortholog substitutions do not fill this gap.

ribosomal small subunit biogenesis GO:0042274 ↓ DECREASED

Experimental models

Human DHX37 depletion and catalytic-mutant complementation CELL LINE Depletion and catalytic perturbation impair small-subunit maturation; complementation with wild-type DHX37 reverses the processing defect.

Downstream

Nucleolar Structural Disruption Ribosome-assembly defects are a proposed contributor to the nucleolar phenotype after mouse Dhx37 deletion; this intermediate has not been isolated experimentally.

Show evidence (5 references)

PMID:30582406 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Using an in vivo crosslinking approach, we show that DHX37 binds directly to the U3 small nucleolar RNA (snoRNA) and demonstrate that the catalytic activity of the helicase is required for dissociation of the U3 snoRNA from pre-ribosomal complexes."

Human cultured-cell experiments establish the normal ribosome-assembly role. The disease connection remains indirect because DSD alleles and affected gonads were not assayed.

PMID:31188444 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Finally, we have functionally characterized three mutations identified in an animal model or in human patients suffering from neurological disease and showed that one (L639P) impairs ribosome biogenesis severely"

Yeast Dhr1 ortholog substitutions modeled neurological alleles and a zebrafish allele, not human DSD variants. These results cannot establish ribosome failure in SRXY11.

PMID:30582406 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"depletion of DHX37 does not affect production of 60S subunits but leads to a significant decrease in the abundance of 40S particles as well as a decrease in the amount of 80S monosomes"

Sucrose-gradient analysis of DHX37-depleted human cultured cells directly measures reduced small-subunit abundance; the experiments do not test a human DSD allele. Application to heterozygous DHX37-related DSD remains indirect.

+ 2 more references

Nucleolar Structural Disruption

Mechanism confidence: Provisional

Sertoli-cell Dhx37 knockout mice show fragmented, smaller nucleoli by electron microscopy and reduced fibrillarin staining in adult testes. This supports nucleolar disruption following substantial experimental loss of Dhx37. The corresponding change in heterozygous human DSD remains provisional.

Sertoli cell CL:0000216

Animal models

Sertoli-cell conditional Dhx37 knockout mouse Mouse recapitulates Demonstrates this experimental consequence of conditional Dhx37 loss in the testicular supporting-cell compartment.

Downstream

p53 Accumulation Nucleolar disruption and increased p53 coexist in knockout testes. Proposed ribosomal-protein/MDM2 intermediates were not directly tested.

Show evidence (1 reference)

PMID:41535247 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"Dhx37 deficiency caused nucleolar fragmentation, rupture, and marked size reduction in Sertoli cells"

Transmission electron microscopy directly demonstrates nucleolar structural disruption in the Sertoli-targeted knockout mouse.

p53 Accumulation

Mechanism confidence: Provisional

Mouse knockout testes show increased p53 and p21, together with changes in apoptosis-associated proteins. These observations support p53-associated stress signaling but do not establish its necessity for tissue loss. In contrast, Ser408Leu overexpression did not increase p53 in the human Sertoli-cell assay.

Animal models

Sertoli-cell conditional Dhx37 knockout mouse Mouse recapitulates Demonstrates this experimental consequence of conditional Dhx37 loss in the testicular supporting-cell compartment.

Downstream

Sertoli Cell Apoptosis A candidate p53-mediated contribution is supported by concomitant signaling and apoptosis markers; no p53-inhibition or genetic-rescue experiment establishes mediation.

Show evidence (2 references)

PMID:41535247 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"p53 and its downstream effector p21 were up-regulated, while the pro-apoptotic markers BAX and cleaved caspase-3 accumulated"

Protein measurements support p53-associated stress signaling in knockout testes. Neither p53 rescue nor requirement for the phenotype was tested.

PMID:37065748 REFUTE DIRECT PRIMARY RESULT In Vitro

"there is no difference in p53 expression among cells transfected with empty expressing vector, wt-DHX37, or mutant DHX37."

The Ser408Leu assay does not support a universal variant-induced increase in p53. It does not refute the distinct conditional-null mouse result.

Sertoli Cell Apoptosis

Mechanism confidence: Provisional

Adult Sertoli-targeted Dhx37 knockout testes have increased TUNEL staining in the supporting-cell compartment. A role in human testicular regression is plausible but unproven. The Ser408Leu overexpression experiment instead showed more apoptosis with wild-type than mutant DHX37, so it cannot be cited as variant-induced apoptosis.

Sertoli cell CL:0000216

apoptotic process GO:0006915 ↑ INCREASED

Animal models

Sertoli-cell conditional Dhx37 knockout mouse Mouse recapitulates Demonstrates this experimental consequence of conditional Dhx37 loss in the testicular supporting-cell compartment.

Downstream

Testicular Regression Experimental supporting-cell loss is a candidate route to reduced tissue maintenance; extrapolation to human prenatal or postnatal regression remains hypothetical.

Show evidence (2 references)

PMID:41535247 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"TUNEL assay (green) combined with SOX9 immunostaining (red) demonstrates a pronounced increase in apoptotic cells in Dhx37−/− testes."

Adult P60 mouse testis sections document increased apoptosis in the Sertoli-cell compartment after conditional deletion. This is not an observation in fetal human variant-bearing gonads.

PMID:37065748 REFUTE DIRECT PRIMARY RESULT In Vitro

"Furthermore, cells that expressed wt-DHX37 showed an even higher apoptosis rate than the mutant."

Both constructs increased apoptosis relative to empty vector; the variant did not produce an excess over wild type.

Reduced Sertoli Cell Proliferation

Mechanism confidence: Provisional

Ki67 staining is reduced in the Sertoli-cell compartment of adult conditional-knockout testes. This is separate from apoptosis and does not measure a fetal human progenitor defect. In the Ser408Leu cell assay, mutant and wild-type overexpression did not differ in their effect on proliferation.

Sertoli cell CL:0000216

Animal models

Sertoli-cell conditional Dhx37 knockout mouse Mouse recapitulates Demonstrates this experimental consequence of conditional Dhx37 loss in the testicular supporting-cell compartment.

Downstream

Reduced Functional Testicular Tissue Reduced supporting-cell renewal may contribute to knockout testis dysfunction; the human developmental connection is indirect.

Show evidence (1 reference)

PMID:41535247 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"we observed a marked attenuation of Sertoli proliferation in Dhx37 mice"

Ki67 staining supports reduced proliferative activity in the knockout Sertoli-cell compartment, distinct from increased cell death.

Altered RNA Splicing

Mechanism confidence: Provisional

Dhx37 depletion in mouse TM4 Sertoli cells alters exon usage and intron retention. This provides an experimental RNA-processing branch distinct from ribosome assembly. The affected transcripts include cell-cycle and stress-associated genes, but the causal contribution of these changes to human DSD variants is unresolved.

Experimental models

Dhx37 knockdown in mouse TM4 Sertoli cells CELL LINE Dhx37 RNAi alters transcript splicing in a mouse Sertoli-cell line.

Show evidence (2 references)

PMID:41535247 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Dhx37 KD triggered 949 significant AS events"

RNA-seq after Dhx37 knockdown in mouse TM4 cells identifies alternative-splicing changes; their contribution to human variant-associated gonadal disease remains untested.

PMID:41535247 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Sashimi plots corroborated Dhx37-dependent alterations in exon usage and intron retention"

The primary analysis documents altered exon use and intron retention, not merely pathway enrichment.

Altered Beta-Catenin Abundance

Mechanism confidence: Hypothetical

In a human Sertoli cell line, wild-type DHX37 overexpression lowers beta-catenin protein and the Ser408Leu construct restores it toward the empty-vector condition. The assay does not establish beta-catenin stabilization, nuclear transcriptional activity or canonical WNT activation in patient gonads. A connection to testis determination remains hypothetical.

Experimental models

DHX37 Ser408Leu human Sertoli-cell overexpression CELL LINE Provides a defined experimental readout relevant to this candidate mechanism.

Downstream

Impaired Testicular Development A proposed effect on sex-development signaling, not a demonstrated fate switch in the variant-bearing cells.

Show evidence (1 reference)

PMID:37065748 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"transfection with wt-DHX37 led to a significant decrease of the β-catenin protein, which was rescued by the mutant DHX37."

In an overexpression assay, Ser408Leu fails to reproduce the wild-type reduction in beta-catenin abundance. This is not direct evidence of canonical WNT activation or ovarian fate in an embryonic gonad.

Impaired Testicular Development

Testicular differentiation is variably impaired, yielding dysgenetic or undifferentiated tissue. Gonadal dysgenesis and subsequent regression can overlap. Retained Müllerian structures indicate incomplete fetal hormone action but are not a binary discriminator separating every case of dysgenesis from regression.

male gonad development GO:0008584 ↓ DECREASED

testis UBERON:0000473

Downstream

Gonadal dysgenesis

Reduced Functional Testicular Tissue

Deficient Fetal Anti-Mullerian Hormone Action

Deficient Fetal Androgen Exposure

Germ cell neoplasia Retained dysgenetic tissue may contain neoplastic germ cells; the genotype-specific risk and molecular intermediates are unknown.

Show evidence (1 reference)

PMID:39659563 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Histological analysis of two participants with DHX37 variants suggested early disruption of gonadal development due to the presence of Müllerian remnants in both and undifferentiated gonadal tissue in one."

Human gonadal histology supports impaired differentiation. Müllerian remnants in this cohort were fallopian tubes, not proof of a retained uterus in every carrier.

Testicular Regression

Testicular tissue can be lost after some differentiation and hormone production. The timing and degree of prior function vary: atypical genitalia and Müllerian remnants can accompany early regression, while a pathogenic-variant carrier also had progressive disappearance of palpable testes during childhood. Definitions of regression and anorchia differ between cohorts.

Downstream

Reduced Functional Testicular Tissue

Absent testis

Show evidence (2 references)

PMID:40916030 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"However, patient 1 exhibited progressive postnatal gonadal disappearance."

A patient with pathogenic Arg334Trp had palpable inguinal testes in early childhood followed by their disappearance, demonstrating that regression is not confined to fetal life.

PMID:38359811 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The testicular regression syndrome (TRS) is a form of differences of sex development (DSD) in which the testes differentiate and function during early embryonic development, but subsequently regress."

Defines the form-then-regress sequence that distinguishes this node from failure of determination.

Deficient Fetal Anti-Mullerian Hormone Action

Insufficient fetal Sertoli-cell AMH action permits persistence of Müllerian structures. Fallopian remnants and a uterus are distinct anatomical observations. In SRXY11 the fetal hormonal deficit is inferred from anatomy; low postnatal AMH does not directly measure fetal exposure.

Sertoli cell CL:0000216

Downstream

Presence of uterus in 46,XY individual

Show evidence (1 reference)

PMID:31337883 SUPPORT INDIRECT BACKGROUND Other

"46,XY partial gonadal dysgenesis is characterized by partially developed internal ducts usually consisting of a mixture of Wolffian (epididymis, vas deferens, and seminal vesicle) and Müllerian ducts (fallopian tube, uterus, and upper third of the vagina) with varying degrees of virilization of..."

Developmental context supports the consequences of variable testicular differentiation. Fetal AMH concentrations were not measured in the affected individuals.

Deficient Fetal Androgen Exposure

Reduced fetal androgen exposure provides a developmental explanation for variable undervirilization, micropenis and hypospadias. Anatomical severity depends on timing and residual testicular function; fetal testosterone was not measured in the reported carriers.

Leydig cell CL:0000178

Downstream

Undervirilized external genitalia

Female external genitalia in individual with 46,XY karyotype

Micropenis

Hypospadias

Show evidence (1 reference)

PMID:31337883 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Four of the 13 children had virilized external genitalia and were raised as male suggesting that functional Leydig cells were present during fetal development."

The authors infer prior fetal androgen production from anatomy. Variable fetal androgen exposure is inferred, not directly measured.

Reduced Functional Testicular Tissue

Dysgenesis or regression reduces gonadal endocrine and reproductive capacity to a variable degree. Low testosterone, AMH and inhibin B and elevated gonadotropins can occur, but residual hormone secretion and spontaneous pubertal onset are possible. Low markers do not prove total absence of tissue. Fertility is impaired in severe disease, while some variant-bearing fathers are fertile.

testis UBERON:0000473

Downstream

Hypergonadotropic hypogonadism

Delayed puberty

Primary amenorrhea

Decreased circulating antimullerian hormone

Decreased serum testosterone concentration

Infertility

Azoospermia

Show evidence (3 references)

PMID:37717579 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Endocrinological tests indicated hypergonadotropic hypogonadism with remarkably elevated gonadotropins"

Elevated gonadotropins indicate deficient gonadal feedback. The variants in this report were classified VUS, so this observation is supporting clinical context rather than independent proof of their pathogenicity.

PMID:37717579 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The administration of hCG (1,500 IU/day, intramuscular injection for 3 days) slightly increased testosterone levels (0.16–0.73 nmol/L), suggesting that the gonads had poor testicular function."

A blunted but detectable testosterone response indicates poor residual gonadal function; it does not establish complete absence of Leydig cells or testicular tissue.

PMID:37717579 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Anti-Müllerian hormone and inhibin B levels were also below the normal reference range"

Low AMH and inhibin B support impaired Sertoli-cell function. Below-reference values are not synonymous with undetectable concentrations or absent gonads.

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Histopathology

3

Fibrotic gonadal remnant with undifferentiated sex cords

A DHX37 Arg308Gln-positive participant had a largely fibrotic gonadal remnant containing a small area of undifferentiated sex cords in gonadal stroma, without germ cells. This documents residual dysgenetic tissue rather than complete absence of all gonadal material.

Show evidence (1 reference)

PMID:39659563 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"a small area of undifferentiated gonadal tissue, containing sex cords in a background of gonadal stroma, an absence of germ cells, and fat infiltration"

Histological description of participant 2’s left gonadal remnant.

Residual immature seminiferous tubules and Leydig-cell groups

The Gly478Arg VUS carrier had sparse immature seminiferous tubules and Leydig-cell groups in a hypoplastic spermatic-cord specimen with dystrophic calcification. The observation supports residual tissue within the reported regression phenotype, but does not independently establish variant pathogenicity.

Show evidence (1 reference)

PMID:37717579 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The histologic examination revealed hypoplastic spermatic cord, focal dystrophic calcification, with sparse immature seminiferous tubules and Leydig cell groups in the stoma, confirming the diagnosis of TRS."

Primary case histology; the paper classifies Gly478Arg as VUS.

Germ cell neoplasia in situ in dysgenetic testis

The original familial cohort documents GCNIS in an Arg674Trp-positive member’s left dysgenetic testis. The isolated observation supports tumor surveillance/management considerations without quantifying genotype-specific risk.

Show evidence (1 reference)

url:https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Left dysgenetic testis with GCNIS*"

Table 1, family member F4:II-4; the table footnote expands GCNIS as germ cell neoplasia in situ.

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Pathograph

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Phenotypes

16

Endocrine 4

Hypergonadotropic hypogonadism HP:0000815

Show evidence (1 reference)

PMID:37717579 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Endocrinological tests indicated hypergonadotropic hypogonadism with remarkably elevated gonadotropins"

Directly reports hypergonadotropic hypogonadism in a DHX37 carrier.

Decreased circulating antimullerian hormone Decreased circulating antimullerian hormone circulation HP:0031103

Show evidence (1 reference)

PMID:37717579 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Anti-Müllerian hormone and inhibin B levels were also below the normal reference range"

Reports the low AMH and inhibin B this phenotype describes.

Decreased serum testosterone concentration HP:0040171

Show evidence (1 reference)

PMID:37717579 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The administration of hCG (1,500 IU/day, intramuscular injection for 3 days) slightly increased testosterone levels (0.16–0.73 nmol/L), suggesting that the gonads had poor testicular function."

Reports the blunted hCG-stimulated testosterone response in a DHX37 carrier.

Delayed puberty HP:0000823

Show evidence (2 references)

PMID:38769888 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The patient was a 14‐year‐old male with pubertal retardation and partial gonadal dysgenesis."

Reports delayed puberty in an Arg671Thr carrier; the paper has conflicting variant classification between text and Table 1.

url:https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The patient developed normal puberty at 12 years old but presented with low testosterone levels at 17 years old."

The pathogenic Arg308Gln carrier demonstrates spontaneous onset followed by insufficient sustained endocrine function.

Genitourinary 12

Gonadal dysgenesis HP:0000133

Show evidence (2 references)

PMID:39659563 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Histological analysis confirmed DHX37 as a gonadal development, rather than a BTR-related, gene."

The authors' histology-based conclusion that DHX37 carriers have a gonadal developmental defect.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells"

The overview describes the broader dysgenetic-testis histological spectrum; not every component is established in every DHX37 carrier.

Absent testis HP:0010469

Show evidence (1 reference)

url:https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"No gonadal tissue No gonadal tissue"

Table 2 documents absent gonadal tissue in DHX37-positive sporadic regression cases; other columns document residual dysgenetic gonads.

Undervirilized external genitalia Ambiguous genitalia HP:0000062

Show evidence (1 reference)

PMID:31337883 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The external genitalia of children carrying DHX37 pathogenic variants ranged from completely female to male with bilateral cryptorchidism."

Direct clinical spectrum in the pathogenic-variant discovery cohort.

Female external genitalia in individual with 46,XY karyotype HP:0008730

Show evidence (1 reference)

PMID:31337883 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The external genitalia of children carrying DHX37 pathogenic variants ranged from completely female to male with bilateral cryptorchidism."

Direct clinical spectrum in the pathogenic-variant discovery cohort.

Micropenis HP:0000054

Show evidence (1 reference)

PMID:39659563 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All three participants with a DHX37 variant had a microphallus at birth (leading to female sex assignment in one), while only six of the remaining 31 participants without a DHX37 variant (19.4%) had a microphallus at birth"

Quantifies microphallus in DHX37 carriers against the non-DHX37 comparator within the same cohort.

Cryptorchidism HP:0000028

Show evidence (1 reference)

url:https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"both gonads palpable in the inguinal canal"

The Arg308Gln-positive patient had bilateral inguinal testes and biopsy-confirmed partial gonadal dysgenesis.

Presence of uterus in 46,XY individual HP:0034546

Show evidence (1 reference)

PMID:40916030 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Present (residual) (5 y 11 m)"

Table 2, patient 3 (pathogenic Arg674Trp), uterus column records a residual uterus at age 5 years 11 months. The adjacent fallopian-tube and gonadal findings are distinct columns.

Germ cell neoplasia HP:0100728

No genotype-specific tumor-risk estimate is established by these sources. A small negative regression subgroup in a general DSD cohort does not exclude risk in retained dysgenetic tissue.

Show evidence (2 references)

url:https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Left dysgenetic testis with GCNIS*"

The primary cohort Table 1 identifies germ-cell neoplasia in situ in the left dysgenetic testis of family member F4:II-4, who carried Arg674Trp.

PMID:27862157 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"The overall GCTs risk was 15·41% and 46, XY pure gonadal dysgenesis (46, XY PGD) carried the highest risk up to 23·33%"

This non-DHX37-genotyped DSD cohort supplies background risk context only; its percentage must not be assigned to SRXY11.

Hypospadias HP:0000047

Show evidence (2 references)

PMID:40916030 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Patient 3 had a phallus with severe perineal hypospadias and was raised as a female."

Patient 3 carried the pathogenic Arg674Trp allele.

PMID:38769888 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"including perineal hypospadias, micropenis (53.0 × 10.0 mm), and bilateral inguinal cryptorchidism."

The reported Arg671Thr carrier had perineal hypospadias; interpretation retains the paper’s internal variant-classification uncertainty.

Primary amenorrhea HP:0000786

Show evidence (1 reference)

PMID:31337883 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"five children carried the recurrent p.R308Q pathogenic variant with a phenotype that varied from female with primary amenorrhea to male with micropenis and bilateral cryptorchidism."

Directly reports primary amenorrhea in the recurrent pathogenic-variant spectrum.

Infertility HP:0000789

Show evidence (1 reference)

url:https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"has high levels of FSH (34.5 IU/L) and LH (12 IU/L) and presented with azoospermia."

The Arg308Gln-positive patient had azoospermia at age 21, supporting impaired sperm production; infertility is not inferred for every carrier.

Azoospermia HP:0000027

Show evidence (1 reference)

url:https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"has high levels of FSH (34.5 IU/L) and LH (12 IU/L) and presented with azoospermia."

Direct semen finding in the pathogenic Arg308Gln patient; the other azoospermic case in the paper carried a likely benign DHX37 allele and is not pooled here.

🧬

Genetic Associations

1

DHX37

Gene: DHX37 hgnc:17210 relationship_type: CAUSATIVE variant_origin: GERMLINE

Sex-limited autosomal dominant, incomplete penetrance in 46,XY

Show evidence (3 references)

PMID:31337883 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Thirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis."

The foundational cohort establishing DHX37 as causative in this phenotype.

PMID:40916030 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"we identified two pathogenic DEAH-box helicase 37 (DHX37) variants in three patients. We also identified a patient with a likely pathogenic variant in SOX9 and a rare likely benign variant in DHX37."

A caution for variant interpretation: not every rare DHX37 variant found in a 46,XY DSD patient is causal — one in this cohort was likely benign and sat alongside a likely pathogenic SOX9 variant that better explained the phenotype.

PMID:31287541 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The frequency of rare, predicted-to-be-deleterious DHX37 variants in this cohort (14%) is significantly higher than that observed in the Genome Aggregation Database (0.4%; P < 0.001)."

Case-versus-population-control enrichment against gnomAD — a roughly thirty-five-fold excess of rare deleterious DHX37 variants in 46,XY DSD. This is the population-genetic argument that the gene is causal rather than incidentally variable, independent of the separate enrichment test in PMID:31337883.

🔬

Variants

5

DHX37 p.Arg308Gln Pathogenic

Gene: DHX37 hgnc:17210

Recurrent pathogenic allele observed across unrelated families and at both dysgenesis and regression presentations. A 2025 literature review counted it in 36.67% of its 60 reported cases, a literature-selected set that includes uncertain variants rather than a population frequency.

Identifiers: c.923G>A

Show evidence (3 references)

PMID:40026690 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Sixty patients were reported to have DHX37-related 46,XY DSD, with p.R308Q, p.R674W variants being the two most common mutation hotspots, accounting for 36.67% and 11.67% of cases respectively."

Quantifies p.Arg308Gln as the leading recurrent allele.

PMID:38359811 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"we identified two heterozygous rare variants of DHX37 in four families: a previously reported pathogenic variant (c.923G>A, p.Arg308Gln) in three and a novel likely pathogenic variant (c.1882A>C, p.Thr628Pro) in one"

Independent recurrence of the same allele in a Japanese cohort, with the cDNA change quoted.

url:https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The p.Arg308Gln variant is classified as pathogenic"

The primary manuscript explicitly assigns pathogenic status to Arg308Gln, unlike the likely-pathogenic classifications assigned to its other three variants.

DHX37 p.Arg674Trp Pathogenic

Gene: DHX37 hgnc:17210

Recurrent helicase-domain allele seen in familial and sporadic dysgenesis or regression. The original cohort classified it as likely pathogenic; a later Japanese series classified it as pathogenic. The disease severity is variable across carriers.

Identifiers: c.2020C>T

Show evidence (3 references)

PMID:31287541 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Two variants were recurrent: p.Arg308Gln (in two families and in three sporadic cases) and p.Arg674Trp (in two families and in two sporadic cases)."

Establishes p.Arg674Trp as a recurrent allele in familial and sporadic cases.

PMID:31287541 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We identified four heterozygous missense rare variants, classified as pathogenic or likely pathogenic in the Asp-Glu-Ala-His-box (DHX) helicase 37 (DHX37) gene in five families (n = 11 patients) and in six sporadic cases."

The original cohort grouped pathogenic and likely pathogenic alleles; this broad quote alone does not establish the individual classification. The later Japanese report below explicitly calls Arg674Trp pathogenic.

PMID:40916030 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Three patients (patients 1–3) harbored previously reported pathogenic DHX37 variants (NM_032656; c.1000C>T; p.(Arg334Trp) and c.2020C>T;p.(Arg674Trp))"

Source for the cDNA identifier on this record, against transcript NM_032656, and an independent Japanese cohort observation of the allele.

DHX37 p.Arg334Trp Pathogenic

Gene: DHX37 hgnc:17210

Recurrent RecA1-domain allele classified as pathogenic in the cited later series. It occurs in the Belgian multicenter regression cohort and in a Japanese patient with postnatal loss of palpable testes.

Identifiers: c.1000C>T

Show evidence (2 references)

PMID:39659563 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Heterozygous (likely) pathogenic missense variants in DHX37 (p.Arg334Trp and p.Arg308Gln) were found in three participants."

Documents the allele in a selected multicenter bilateral-regression cohort, not population screening.

PMID:42510869 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"According to ACMG/AMP guidelines, p.Arg334Trp was classified as pathogenic,"

Source for the PATHOGENIC clinical_significance on this record.

DHX37 p.Gly478Arg Uncertain Significance

Gene: DHX37 hgnc:17210

Variant of uncertain significance reported in a boy with a regression phenotype and inherited from an unaffected mother. The later six-case series includes the same patient and is not an independent recurrence. Computational predictions do not resolve pathogenicity.

Identifiers: c.1432G>A

Show evidence (2 references)

PMID:37717579 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Both variants were classified as VUS (PM1 + PM2 + PP3) according to the recommendation of the ACMG guidelines."

Source for the UNCERTAIN_SIGNIFICANCE on this record, with the ACMG criteria applied.

PMID:42510869 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Of these, p.Arg334Trp is an established pathogenic variant; p.Gly478Arg has been reported previously, albeit in the same patient included in the present study; and the remaining four were novel."

Bears on the weight of evidence rather than on the allele's existence: the later series reporting it turned out to include the same patient as the original report, so the apparent second observation is not an additional family. INDIRECT because the count of independent families follows from the sentence rather than being stated by it.

DHX37 p.Arg390His Uncertain Significance

Gene: DHX37 hgnc:17210

RecA1-domain variant reported in an individual with complete gonadal dysgenesis. Later variant summaries classify it as uncertain significance; a rare-variant observation and computational prediction alone are insufficient to establish pathogenicity.

Show evidence (2 references)

PMID:34293745 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A novel p.R390H variant within the RecA1 domain was identified in a girl with complete gonadal dysgenesis."

The single reported observation of this allele, at the complete-dysgenesis pole.

PMID:38769888 SUPPORT DIRECT REVIEW SYNTHESIS Other

Table 1 classifies Arg390His as VUS in a literature variant summary.

💊

Medical Actions

6

Testosterone Replacement Therapy

Category: Therapeutic Action: Hormone Replacement Therapy NCIT:C15599

Agent: testosterone CHEBI:17347

Platform: Small molecule

For individuals seeking androgen-mediated puberty, incremental testosterone replacement can induce and sustain pubertal development when endogenous production is inadequate. Dose and timing follow growth, hormone results, clinical response and individual goals. Penile response varies; the Belgian series documents limited growth in two DHX37 carriers at Tanner G3 and does not establish universal adult failure. Short courses in infancy for micropenis are a separate individualized decision. Adequate sex-steroid replacement supports adolescent bone accrual. Follow pubertal progression, growth, skeletal maturation, hormone results and adverse effects during induction; the Endo-ERN guideline describes clinical review every three to six months.

Mechanism Target:

Reduced Functional Testicular Tissue — Replaces deficient sex-steroid output according to the individual’s pubertal and longer-term goals; it does not restore gonadal tissue.

Target Phenotypes: Hypergonadotropic hypogonadism HP:0000815 Hypogonadism HP:0000135

Show evidence (4 references)

PMID:39659563 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Statural growth and pubertal development are adequate with incremental doses of testosterone replacement therapy (TRT); however, penile growth is often suboptimal"

Summarizes the entire bilateral-regression cohort, most of whom did not have a DHX37 variant. Genotype-specific numbers and maturational stages require separate interpretation.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Testosterone therapy is typically required to initiate and sustain puberty."

Family-level care guidance applies to those with deficient androgen production and corresponding pubertal goals.

PMID:35353710 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"We found no studies on treatment to induce or sustain puberty in male patients with partial gonadal dysgenesis."

The guideline’s systematic review found no male-PGD induction studies; treatment recommendations therefore draw on broader hypogonadism evidence and expert practice.

+ 1 more reference

Estrogen Replacement Therapy

Category: Therapeutic Action: Estrogen Replacement Therapy NCIT:C15231

Agent: estradiol CHEBI:23965

Platform: Small molecule

For individuals seeking estrogen-mediated puberty, gradual estrogen replacement induces breast development and supports bone accrual when gonadal steroid production is inadequate. If a uterus is present, progesterone is added after puberty has progressed. Treatment follows the individual’s goals and anatomy. Direct DHX37 observations include estradiol induction at age 11.3 years in an Arg308Gln carrier and estrogen at age 12 years 2 months in an Arg674Trp carrier; these are case-level observations rather than comparative trials. The broader Endo-ERN guideline favors 17β-estradiol and gradual dose escalation with clinical monitoring; much of its evidence derives from other forms of gonadal insufficiency.

Mechanism Target:

Reduced Functional Testicular Tissue — Replaces deficient sex-steroid output according to the individual’s pubertal and longer-term goals; it does not restore gonadal tissue.

Target Phenotypes: Hypergonadotropic hypogonadism HP:0000815 Hypogonadism HP:0000135

Show evidence (3 references)

PMID:39659563 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"At the age of 11.3 years, puberty induction was started with incremental estradiol doses."

The sentence describes DHX37-positive participant 2, who carried maternally inherited Arg308Gln.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"If the affected individual has a uterus, progesterone will be added once puberty has progressed in order to promote menstrual cycles."

The full overview supplies the anatomy- and puberty-dependent progestogen guidance.

PMID:35353710 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"We recommend to use 17β-oestradiol for puberty induction or to sustain puberty in girls"

Endo-ERN recommends physiologic estradiol for those pursuing estrogen-mediated puberty. Much of the supporting evidence comes from Turner syndrome rather than DHX37-related disease.

Gonadal Surgery

Category: Therapeutic Action: gonadectomy (bilateral orchiectomy) Ontology label: Orchiectomy NCIT:C15288

Platform: Surgery

Decisions depend on gonadal function, histology, location and tumor concern. Removal of nonfunctioning dysgenetic gonads may be appropriate; potentially functioning retained gonads may instead be positioned for examination and monitored after individualized counseling. Surveillance has limitations and no validated DHX37-specific protocol. Management of a fibrotic regression remnant is a separate question from a retained dysgenetic testis. Prostheses are optional and discussed according to the individual’s preferences.

Target Phenotypes: Germ cell neoplasia HP:0100728

Show evidence (3 references)

PMID:39659563 SUPPORT DIRECT REVIEW SYNTHESIS Other

"we would propose planning resection of gonadal remnants only in cases where gonadal dysgenesis is suspected, due to the risk for gonadal germ cell cancer."

The cohort authors distinguish suspected dysgenesis from a typically virilized regression presentation. This is a clinical recommendation, not a trial result.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Depending on the specific diagnosis, potentially functional gonads may be retained with appropriate surveillance for tumor development."

The overview supports individualized preservation of potentially functioning gonads.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"There are no current guidelines on surveillance; one option would be yearly ultrasound of the gonad."

The chapter presents ultrasound as an option without an established surveillance guideline; this must not be represented as a validated DHX37 screening protocol.

Genetic Counseling

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

Explain sex-limited expression, variable severity, incomplete penetrance in 46,XY carriers and the distinction between an established variant and a VUS. A heterozygous parent has a 50% chance of transmitting the allele in each pregnancy, which is not a 50% chance of an affected child. Parental testing informs recurrence counseling; negative blood testing cannot exclude germline mosaicism. Once a familial pathogenic variant is established, testing of relatives and reproductive testing options can be discussed. NEDBAVC is a distinct allelic disorder with variant-dependent inheritance.

Show evidence (3 references)

url:https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the presence of the p.Arg308Gln variant in the asymptomatic father"

The familial cohort documents an unaffected father transmitting the recurrent allele; the surrounding segregation analysis also records maternal and de novo inheritance.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"the risk to sibs of inheriting the genetic alteration is 50%."

This is the transmission probability in a heterozygous family, modified by sex-limited expression and incomplete penetrance documented in DHX37-specific cohorts.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"to sibs is low but greater than that of the general population"

In the GeneReviews paragraph on a variant not detected in either parent’s leukocyte DNA, this clause describes residual sibling recurrence risk; the surrounding paragraph attributes it to possible parental germline mosaicism.

Multidisciplinary DSD Supportive Care

Category: Therapeutic Action: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Provide ongoing endocrine, urologic/gynecologic, genetics and psychological care, with age-appropriate explanation and active participation in decisions. Sex of rearing does not determine later identity or treatment preferences. Three DHX37 carriers in one selected cohort reported male, female and non-binary identities; these observations are not predictive probabilities. Discuss sex-steroid effects, fertility implications, body image and transition to adult care. Nonessential irreversible genital procedures should be considered in a process that enables the affected individual to participate.

Show evidence (3 references)

PMID:39659563 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The three participants with a DHX37 variant developed a male, female, and non-binary gender identity, respectively; all other participants identified as males."

Documents the heterogeneous gender-identity outcomes in DHX37 carriers relative to the rest of the cohort.

PMID:39659563 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"sufficient and understandable information regarding the effects and side effects of TRT is required throughout the management of these patients"

The authors' explicit care recommendation arising from their quality-of-care findings.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Many surgeries are not medically necessary and thus consideration should be given to delaying surgery in order to allow the affected individual to participate in the decision-making process."

The overview supports participation in decisions about nonessential irreversible procedures.

Fertility counseling

Category: Counseling / Informational Action: Fertility and Reproductive Counseling NCIT:C171451

Assess reproductive potential according to residual gonadal tissue and function, without assuming infertility in every variant carrier. Azoospermia is documented in a pathogenic-variant carrier. For individuals with a uterus, pregnancy through oocyte donation is a broader DSD care option rather than a demonstrated DHX37-specific treatment outcome.

Show evidence (2 references)

url:https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"has high levels of FSH (34.5 IU/L) and LH (12 IU/L) and presented with azoospermia."

The Arg308Gln-positive patient had azoospermia at age 21, supporting impaired sperm production; infertility is not inferred for every carrier.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"may become pregnant through oocyte donation."

Family-level reproductive option dependent on anatomy; no DHX37-specific outcome is asserted.

🔬

Diagnosis

5

Karyotype

Chromosome analysis establishes a 46,XY complement and evaluates a possible sex-chromosome mosaic differential. The sensitivity for low-level or tissue-limited mosaicism depends on the specimen, cell count and method. Cytogenetic or genomic follow-up is guided by the presentation.

Karyotyping NCIT:C16768

Show evidence (1 reference)

PMID:37717579 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Case 2 (13.5-year-old girl) had a 46,XY karyotype with female external genitalia and was diagnosed as GD."

The case evaluation documents karyotyping in a patient with a DHX37 VUS; the test establishes chromosome complement rather than variant pathogenicity.

Gonadal function testing

Interpret FSH, LH, testosterone, AMH and inhibin B against age-appropriate ranges and the clinical examination. Selected hCG testing can characterize Leydig-cell function but is not required in every case. Low markers or a blunted response indicate impaired function without necessarily proving absent tissue; hormonal testing cannot distinguish one from two functioning gonads. NCIT search for "hormone stimulation test" found no fitting specific term; this entry also includes basal hormone assays, so the broader diagnostic-procedure binding is retained.

Diagnostic Procedure NCIT:C18020

Show evidence (2 references)

PMID:37717579 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The administration of hCG (1,500 IU/day, intramuscular injection for 3 days) slightly increased testosterone levels (0.16–0.73 nmol/L), suggesting that the gonads had poor testicular function."

The response in this VUS carrier indicates poor residual testicular function, not complete absence of tissue.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"this test is not always necessary, particularly if there is other evidence that a gonad is nonfunctional."

GeneReviews qualifies use of hCG stimulation within the broader evaluation.

Pelvic and inguinal imaging

Pelvic and inguinal ultrasound assesses Müllerian structures and gonadal position, with MRI or selected exploration when anatomy remains unclear. Small dysgenetic gonads may not be visualized. Absence of a uterus does not by itself distinguish regression from partial dysgenesis.

Ultrasound Imaging NCIT:C17230

Show evidence (1 reference)

PMID:37717579 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"No obvious gonadal structure was identified on abdominal-pelvic and inguinal US. Pelvic US demonstrated no evidence of uterine structures."

Shows the imaging findings used to characterize gonadal and Müllerian status in a DHX37 carrier.

Molecular genetic testing

A DSD gene panel including DHX37, or exome/genome analysis with appropriate variant interpretation, can establish the gene-defined diagnosis. Clinical findings guide interpretation and the differential. A VUS or a likely benign DHX37 allele alongside a pathogenic variant in another gene does not confirm SRXY11. Segregation studies and later reanalysis can clarify uncertain findings.

Genetic Testing NCIT:C15709

Show evidence (3 references)

PMID:38359811 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Genetic test is helpful in detecting DHX37-related TRS/PGD because of the phenotypic diversity of the external genitalia in this disorder."

States that molecular testing rather than phenotype is what identifies DHX37-related disease.

PMID:41466375 SUPPORT INDIRECT PRIMARY RESULT Other

"Genome-wide sequencing should be prioritized in VSC/DSD diagnostics, consistent with current best practices, to improve diagnostic yield"

Supports genome-wide rather than targeted sequencing as the diagnostic route. INDIRECT because it is a cross-OMIM recommendation for DSD generally, not a DHX37-specific finding.

PMID:40916030 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the SOX9 p.(Arg437Cys) and DHX37 p.(Pro428Leu) variants were assessed as likely pathogenic and likely benign, respectively"

Demonstrates why identifying a rare DHX37 allele is not sufficient to establish causation.

Selected surgical exploration and gonadal histology

Exploration and histology may define tissue that remains anatomically or functionally uncertain and inform management of a retained dysgenetic gonad. They are individualized procedures rather than mandatory tests in every carrier. Biopsy has sampling limitations and may compromise future gonadal function. NCIT "testicular biopsy" resolves to C51894 (Biopsy of Testis), but this combined assessment includes exploration and sampling of potentially nontesticular dysgenetic tissue; the broader procedure binding preserves that scope.

Surgical Procedure NCIT:C15329

Show evidence (2 references)

PMID:39659563 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Histological analysis of two participants with DHX37 variants suggested early disruption of gonadal development due to the presence of Müllerian remnants in both and undifferentiated gonadal tissue in one."

Shows what gonadal histology contributes to classifying DHX37-related disease.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Results may be inaccurate because of biopsy sampling error; gonadal biopsy may harm the future growth and development of the gonad."

The overview explicitly qualifies diagnostic biopsy.

📈

Progression

3

Variable prenatal testicular differentiation

Age: Fetal development

Early differentiation and hormone production vary, producing a spectrum of genital anatomy and Müllerian retention. Diagnostic labels do not establish an exact gestational time of tissue loss in every patient.

Show evidence (1 reference)

PMID:31337883 SUPPORT INDIRECT BACKGROUND Other

"The genital phenotype may range predominantly from male to female, including marked sex ambiguity depending on the duration of normal testicular function prior to the loss of testicular tissue."

The clinical interpretation relates anatomy to timing of fetal function rather than directly measuring fetal hormone production.

Possible postnatal regression

Age: Childhood

In a pathogenic Arg334Trp carrier, inguinal gonads were palpable at about two years but not at six years two months; later imaging showed rudimentary tissue. This supports longitudinal assessment rather than assuming all regression is prenatal.

Show evidence (1 reference)

PMID:40916030 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The inguinal gonads, which were palpable at 2 years of age, were not palpable at 6 years and 2 months of age, with only rudimentary gonads detected via echography."

Direct longitudinal observation in patient 1.

Variable pubertal function and adult reproductive impairment

Age: Adolescence and adulthood

Puberty may require induction, or may start spontaneously and subsequently stall. A pathogenic Arg308Gln carrier entered puberty at twelve, began testosterone at seventeen and had azoospermia at twenty-one. These outcomes are variable and should not be assigned as universal carrier features.

Show evidence (2 references)

url:https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The patient developed normal puberty at 12 years old but presented with low testosterone levels at 17 years old."

Primary Arg308Gln case follow-up.

url:https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"has high levels of FSH (34.5 IU/L) and LH (12 IU/L) and presented with azoospermia."

Direct semen finding in the pathogenic Arg308Gln patient; the other azoospermic case in the paper carried a likely benign DHX37 allele and is not pooled here.

📊

Prevalence

1

General population

Not yet documented

Population prevalence has not been established in the reviewed sources. Referral-cohort diagnostic yields and literature-selected case fractions are not prevalence estimates.

🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from 46,XY Sex Reversal 11:

Non-genetic bilateral testicular regression (perinatal vascular accident)

Overlapping Features Bilateral testicular regression may have a non-genetic or unresolved cause. Gestational complications and discordant monozygotic twins support environmental contributions in some cases. Typical external virilization and less marked microphallus can be clues, but a negative DHX37 test does not prove a vascular cause or exclude another genetic etiology.

Show evidence (1 reference)

PMID:39659563 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"An environmental origin in some participants is supported by the high incidence of gestational complications (38.2%) and by the three monozygotic twin pregnancies discordant for the BTR phenotype."

The selected Belgian series supports environmental contributions in some participants; three of 34 analyzable participants carried a DHX37 variant.

46,XY gonadal dysgenesis due to other genes

Overlapping Features Variants involving SRY, NR5A1, DMRT1, MAP3K1, DHH, SOX9 and other genes can produce overlapping gonadal phenotypes. Molecular diagnosis can alter associated-risk assessment, for example renal and Wilms tumor risk in WT1-related disease. Adrenal insufficiency is rare in NR5A1-related DSD and is not assumed for every carrier.

Show evidence (1 reference)

PMID:38359811 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Previously described pathogenic variants or novel nonsense variants (SRY, NR5A1, and DMRT1) were observed in four out of 10 families."

Shows the alternative monogenic causes found in the same clinical population.

Bilateral cryptorchidism with viable testes

Overlapping Features Nonpalpable but retained testes can resemble anorchia at examination. Hormonal testing, imaging and selected exploration assess tissue location and function; present dysgenetic testes may also have low hormone output.

Show evidence (1 reference)

PMID:39659563 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"It has a similar presentation as the more common undescended testicles, which can pose difficulties for physicians in diagnosing the condition."

States that undescended testes are the clinically confusable alternative.

🧫

Experimental Models

4

DHX37 Ser408Leu human Sertoli-cell overexpression CELL_LINE

Transient wild-type or Ser408Leu DHX37 overexpression in a human Sertoli cell line, compared with empty vector. Variant RNA and protein are lower than wild type; localization is similar. Beta-catenin abundance is higher than with wild-type overexpression, p53 is unchanged, and variant-associated apoptosis is lower than with wild type.

Organism

human NCBITaxon:9606

Publication

PMID:37065748

Pathograph links

Altered Beta-Catenin Abundance recapitulates fidelity: low Provides a defined experimental readout relevant to this candidate mechanism.

Limitations: Overexpression is not a heterozygous patient-derived system. No direct helicase, ATPase, pre-rRNA, WNT-transcriptional or fetal-fate assay was performed. Later summaries classify Ser408Leu as VUS.

Readouts

Beta-catenin abundance relative to wild-type overexpression

Direction: INCREASED

Interpretation: The result is specific to the assayed perturbation and cell context.

Show evidence (1 reference)

PMID:37065748 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"transfection with wt-DHX37 led to a significant decrease of the β-catenin protein, which was rescued by the mutant DHX37."

In an overexpression assay, Ser408Leu fails to reproduce the wild-type reduction in beta-catenin abundance. This is not direct evidence of canonical WNT activation or ovarian fate in an embryonic gonad.

Show evidence (1 reference)

PMID:37065748 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"transfection with wt-DHX37 led to a significant decrease of the β-catenin protein, which was rescued by the mutant DHX37."

In an overexpression assay, Ser408Leu fails to reproduce the wild-type reduction in beta-catenin abundance. This is not direct evidence of canonical WNT activation or ovarian fate in an embryonic gonad.

DHX37 variant transfection in HEK293T and COS7 cells CELL_LINE

Arg308Gln and Arg671Thr constructs were tested for protein abundance in HEK293T cells and localization in COS7 cells. Both had reduced protein abundance and no detected localization change.

Organism

human NCBITaxon:9606

Publication

PMID:38769888

Pathograph links

Reduced DHX37 Abundance recapitulates fidelity: low Provides a defined experimental readout relevant to this candidate mechanism.

Limitations: HEK293T is human whereas COS7 is a nonhuman primate kidney-derived line; the organism annotation applies to the abundance assay. These are not gonadal or patient-derived cells. Arg671Thr is called pathogenic in the narrative but VUS in Table 1.

Readouts

DHX37 protein abundance

Direction: DECREASED

Interpretation: The result is specific to the assayed perturbation and cell context.

Show evidence (1 reference)

PMID:38769888 SUPPORT DIRECT PRIMARY RESULT In Vitro

"compared with the cells transfected with pcDNA3.1‐WT, those with pcDNA3.1‐Arg308Gln and pcDNA3.1‐Arg671Thr displayed a lower level of DHX37"

Western blots in transfected HEK293T cells show reduced protein abundance for these constructs; enzymatic activity and patient gonadal abundance were not measured. The paper inconsistently labels Arg671Thr pathogenic in prose and VUS in Table 1.

Show evidence (1 reference)

PMID:38769888 SUPPORT DIRECT PRIMARY RESULT In Vitro

"compared with the cells transfected with pcDNA3.1‐WT, those with pcDNA3.1‐Arg308Gln and pcDNA3.1‐Arg671Thr displayed a lower level of DHX37"

Western blots in transfected HEK293T cells show reduced protein abundance for these constructs; enzymatic activity and patient gonadal abundance were not measured. The paper inconsistently labels Arg671Thr pathogenic in prose and VUS in Table 1.

Dhx37 knockdown in mouse TM4 Sertoli cells CELL_LINE

Mouse TM4 RNAi, RNA-seq and RIP-seq assess transcript abundance, splicing and RNA associations after Dhx37 depletion. Enrichment of PI3K-AKT-associated transcripts is not a direct measurement of pathway activity. RIP-seq used one immunoprecipitate and matched input, limiting inference about binding reproducibility.

Organism

mouse NCBITaxon:10090

Publication

PMID:41535247

Pathograph links

Altered RNA Splicing perturbs fidelity: low Dhx37 RNAi alters transcript splicing in a mouse Sertoli-cell line.

Limitations: Culture findings inform candidate stress pathways; they do not reproduce a human missense genotype, test canonical AKT activation or establish MDM2-mediated p53 causality.

Readouts

Alternative splicing events after Dhx37 RNAi

Direction: ALTERED

Interpretation: Changed exon usage and intron retention are measured; functional consequences of individual splice changes remain untested.

Show evidence (2 references)

PMID:41535247 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Dhx37 KD triggered 949 significant AS events"

RNA-seq after Dhx37 knockdown in mouse TM4 cells identifies alternative-splicing changes; their contribution to human variant-associated gonadal disease remains untested.

+ 1 more reference

Show evidence (2 references)

PMID:41535247 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Dhx37 KD triggered 949 significant AS events"

RNA-seq after Dhx37 knockdown in mouse TM4 cells identifies alternative-splicing changes; their contribution to human variant-associated gonadal disease remains untested.

+ 1 more reference

Human DHX37 depletion and catalytic-mutant complementation CELL_LINE

HeLa RNAi and HEK293 complementation with RNAi-resistant wild-type or engineered T282A DHX37 define pre-rRNA processing and small-subunit assembly functions. Wild-type transgene rescues processing defects. Purified recombinant-protein experiments independently show RNA-dependent ATPase activity and stimulation by directly interacting UTP14A. The catalytic mutant retains the protein-presence function that prevents aberrant pre-rRNA turnover, separating that function from ATPase-dependent maturation.

Organism

human NCBITaxon:9606

Publication

PMID:30582406

Pathograph links

Impaired Small Ribosomal Subunit Biogenesis perturbs fidelity: low Depletion and catalytic perturbation impair small-subunit maturation; complementation with wild-type DHX37 reverses the processing defect.

Limitations: HeLa and HEK293 cells are not fetal gonadal or patient-derived cells. T282A is engineered, not an SRXY11 allele. The study does not test human sex determination, p53 necessity or MDM2 binding. The exact stage of human U3 release remains unresolved, and UTP14A-depletion effects on U3 retention may be secondary to an earlier processing block.

Readouts

40S ribosomal subunit abundance

Direction: DECREASED

Interpretation: 40S and 18S output decline while 60S and 28S production are spared after DHX37 depletion.

Show evidence (1 reference)

PMID:30582406 SUPPORT DIRECT PRIMARY RESULT In Vitro

"depletion of DHX37 does not affect production of 60S subunits but leads to a significant decrease in the abundance of 40S particles as well as a decrease in the amount of 80S monosomes"

Sucrose-gradient analysis of DHX37-depleted human cultured cells directly measures reduced small-subunit abundance; the experiments do not test a human DSD allele.

21S-to-18SE pre-rRNA processing

Direction: DECREASED

Interpretation: 21S accumulates and 18SE falls after depletion or catalytic T282A complementation. Wild-type transgene rescues the processing defect.

Show evidence (2 references)

PMID:30582406 SUPPORT DIRECT PRIMARY RESULT In Vitro

"depletion of DHX37 caused accumulation of the 21S pre-rRNA and a concomitant decrease in the levels of the 18SE pre-rRNA"

Northern blots establish a pre-rRNA processing defect after experimental DHX37 depletion in human cells.

+ 1 more reference

U3 snoRNA retention on pre-ribosomal complexes

Direction: INCREASED

Interpretation: Catalytic T282A increases pre-ribosome-associated U3 relative to wild-type complementation. This supports a release defect without directly measuring duplex unwinding.

Show evidence (1 reference)

PMID:30582406 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Expression of DHX37T282A lead to a notable increase in the proportion of the U3 snoRNA associated with pre-ribosomal complexes"

Fractionation and northern blotting show U3 retention with engineered catalytic T282A after endogenous DHX37 depletion, rather than a direct purified U3-duplex unwinding assay.

Show evidence (2 references)

PMID:30582406 SUPPORT DIRECT PRIMARY RESULT In Vitro

"depletion of DHX37 caused accumulation of the 21S pre-rRNA and a concomitant decrease in the levels of the 18SE pre-rRNA"

Northern blots establish a pre-rRNA processing defect after experimental DHX37 depletion in human cells.

+ 1 more reference

🐁

Animal Models

1

Sertoli-cell conditional Dhx37 knockout mouse

Sertoli-cell conditional deletion with Amh-Cre beginning at embryonic day 12.5, after mouse male-sex determination. Adult P60/approximately eight-week readouts include smaller testes, reduced sperm and testosterone, infertility, seminiferous-tubule abnormalities, nucleolar fragmentation, altered junction proteins and increased apoptosis. Cell-culture RIP-seq and RNAi experiments from the same paper are recorded separately. No human-allele knock-in, fetal sex-reversal experiment or demonstration of absent testes was performed. Secondary Leydig-cell hormone changes in a Sertoli-targeted model do not establish Leydig-autonomous DHX37 deficiency.

Species

Mouse

Genotype

Dhx37 flox/flox; Amh-Cre (Sertoli-cell conditional knockout)

Publication

PMID:41535247

Pathograph links

Nucleolar Structural Disruption recapitulates fidelity: moderate Demonstrates this experimental consequence of conditional Dhx37 loss in the testicular supporting-cell compartment.

Limitations: Electron microscopy and fibrillarin staining measure architecture; they do not directly quantify pre-rRNA processing or 40S output.

Readouts

Sertoli-cell nucleolar architecture

Direction: ALTERED

Interpretation: Measured experimental phenotype; extrapolation to human SRXY11 is limited by allele, timing and species.

Show evidence (1 reference)

PMID:41535247 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Dhx37 deficiency caused nucleolar fragmentation, rupture, and marked size reduction in Sertoli cells"

Transmission electron microscopy directly demonstrates nucleolar structural disruption in the Sertoli-targeted knockout mouse.

Show evidence (1 reference)

PMID:41535247 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Dhx37 deficiency caused nucleolar fragmentation, rupture, and marked size reduction in Sertoli cells"

Transmission electron microscopy directly demonstrates nucleolar structural disruption in the Sertoli-targeted knockout mouse.

p53 Accumulation recapitulates fidelity: moderate Demonstrates this experimental consequence of conditional Dhx37 loss in the testicular supporting-cell compartment.

Limitations: No p53-inhibition or rescue experiment establishes necessity. Proposed FBL or ribosomal-protein interactions with MDM2 were not directly assayed.

Readouts

p53 and p21 abundance

Direction: INCREASED

Interpretation: Measured experimental phenotype; extrapolation to human SRXY11 is limited by allele, timing and species.

Show evidence (1 reference)

PMID:41535247 SUPPORT DIRECT PRIMARY RESULT Model Organism

"p53 and its downstream effector p21 were up-regulated, while the pro-apoptotic markers BAX and cleaved caspase-3 accumulated"

Protein measurements support p53-associated stress signaling in knockout testes. Neither p53 rescue nor requirement for the phenotype was tested.

Show evidence (1 reference)

PMID:41535247 SUPPORT DIRECT PRIMARY RESULT Model Organism

"p53 and its downstream effector p21 were up-regulated, while the pro-apoptotic markers BAX and cleaved caspase-3 accumulated"

Protein measurements support p53-associated stress signaling in knockout testes. Neither p53 rescue nor requirement for the phenotype was tested.

Sertoli Cell Apoptosis recapitulates fidelity: moderate Demonstrates this experimental consequence of conditional Dhx37 loss in the testicular supporting-cell compartment.

Limitations: Adult conditional-null tissue differs from heterozygous human missense disease; the model does not establish fetal regression.

Readouts

SOX9-associated TUNEL signal

Direction: INCREASED

Interpretation: Measured experimental phenotype; extrapolation to human SRXY11 is limited by allele, timing and species.

Show evidence (1 reference)

PMID:41535247 SUPPORT DIRECT PRIMARY RESULT Model Organism

"TUNEL assay (green) combined with SOX9 immunostaining (red) demonstrates a pronounced increase in apoptotic cells in Dhx37−/− testes."

Adult P60 mouse testis sections document increased apoptosis in the Sertoli-cell compartment after conditional deletion. This is not an observation in fetal human variant-bearing gonads.

Show evidence (1 reference)

PMID:41535247 SUPPORT DIRECT PRIMARY RESULT Model Organism

"TUNEL assay (green) combined with SOX9 immunostaining (red) demonstrates a pronounced increase in apoptotic cells in Dhx37−/− testes."

Adult P60 mouse testis sections document increased apoptosis in the Sertoli-cell compartment after conditional deletion. This is not an observation in fetal human variant-bearing gonads.

Reduced Sertoli Cell Proliferation recapitulates fidelity: moderate Demonstrates this experimental consequence of conditional Dhx37 loss in the testicular supporting-cell compartment.

Limitations: Adult proliferation markers do not measure initial fetal sex determination.

Readouts

Sertoli-compartment Ki67 staining

Direction: DECREASED

Interpretation: Measured experimental phenotype; extrapolation to human SRXY11 is limited by allele, timing and species.

Show evidence (1 reference)

PMID:41535247 SUPPORT DIRECT PRIMARY RESULT Model Organism

"we observed a marked attenuation of Sertoli proliferation in Dhx37 mice"

Ki67 staining supports reduced proliferative activity in the knockout Sertoli-cell compartment, distinct from increased cell death.

Show evidence (1 reference)

PMID:41535247 SUPPORT DIRECT PRIMARY RESULT Model Organism

"we observed a marked attenuation of Sertoli proliferation in Dhx37 mice"

Ki67 staining supports reduced proliferative activity in the knockout Sertoli-cell compartment, distinct from increased cell death.

{ }

Source YAML

click to show

name: 46,XY Sex Reversal 11
creation_date: "2026-09-01T00:00:00Z"
category: Mendelian
description: >-
  46,XY sex reversal 11 (SRXY11) is a DHX37-related difference of testicular development. Specific
  heterozygous missense variants cause a spectrum of complete or partial gonadal dysgenesis and testicular
  regression, with variable external genital anatomy, Müllerian derivatives and residual gonadal
  function. Transmission is usually sex-limited autosomal dominant with incomplete penetrance in
  46,XY carriers; de novo variants also occur. Regression may follow impaired fetal development,
  and postnatal loss of palpable testes has been documented. DHX37 participates in ribosome biogenesis,
  but a shared molecular mechanism linking the human variants to gonadal disease remains unresolved.
  Variant-specific protein-abundance and beta-catenin findings in cultured cells and nucleolar disruption
  after Sertoli-cell Dhx37 deletion in mice inform candidate mechanisms without establishing a universal
  ribosomopathy or p53-dependent fetal regression pathway.
disease_term:
  preferred_term: 46,XY sex reversal 11
  term:
    id: MONDO:8000015
    label: 46,XY sex reversal 11
synonyms:
- SRXY11
- DHX37-related 46,XY disorder of sex development
- DHX37-related gonadal dysgenesis
- DHX37-related testicular regression syndrome
parents:
- Disorder of sex development
- Gonadal development disorder
references:
- reference: PMID:20301714
  title: "Nonsyndromic Disorders of Testicular Development Overview."
  tags:
  - GeneReviews
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
  title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
- reference: PMID:35353710
  title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
definitions:
- name: 46,XY sex reversal 11 case definition
  definition_type: CASE_DEFINITION
  description: >-
    A 46,XY individual with a difference of testicular development and a pathogenic or likely pathogenic
    DHX37 variant consistent with the phenotype and inheritance. Most established alleles are heterozygous
    missense changes in conserved helicase domains. A rare variant or an in silico damaging prediction
    alone does not establish the diagnosis. A homozygous missense case has also been reported, so
    heterozygosity is not an absolute requirement.
  scope: >-
    This gene-defined entry spans gonadal dysgenesis and testicular regression because recurrent
    alleles produce both presentations within and across families. Other genetic and non-genetic
    causes of those clinical phenotypes require separate diagnosis. The allelic DHX37 neurodevelopmental
    disorder NEDBAVC is distinct and can involve biallelic or de novo heterozygous variants.
  evidence:
  - reference: PMID:34293745
    reference_title: "Expanding DSD Phenotypes Associated with Variants in the DEAH-Box RNA Helicase DHX37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Missense variants in the RNA-helicase DHX37 are associated with either
      46,XY gonadal dysgenesis or 46,XY testicular regression syndrome (TRS).
      DHX37 is required for ribosome biogenesis, and this subgroup of XY DSD is a
      new human ribosomopathy.
    explanation: >-
      States the gene-anchored scope of this entry and the two clinical poles it
      spans.
    quote_role: BACKGROUND
    directness: DIRECT
  - reference: PMID:35835064
    reference_title: "DHX37 and 46,XY DSD: A New Ribosomopathy?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      compound heterozygous as well as de novo heterozygous missense variants in
      DHX37 are also associated with a complex congenital developmental syndrome
      (NEDBAVC, neurodevelopmental disorder with brain anomalies and with or
      without vertebral or cardiac anomalies; OMIM 618731)
    explanation: >-
      Establishes NEDBAVC as a distinct allelic DHX37 disorder, supporting its
      exclusion from this entry's scope.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
inheritance:
- name: Autosomal dominant, sex-limited, with incomplete penetrance
  inheritance_term:
    preferred_term: sex-limited autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  description: >-
    Specific heterozygous DHX37 variants show sex-limited autosomal dominant inheritance with variable
    expression and incomplete penetrance in 46,XY carriers. Unaffected 46,XX carriers, unaffected
    or mildly affected fertile fathers, and de novo variants are reported. Maternal transmission
    predominates in some family series, whereas five of six parentally tested cases in the 2019 discovery
    cohort were de novo; these ascertained series do not establish a population penetrance or de
    novo fraction.
  evidence:
  - reference: url:https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf
    reference_title: https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      the presence of the p.Arg308Gln variant in the asymptomatic father
    explanation: >-
      The familial cohort documents an unaffected father transmitting the recurrent allele; the surrounding
      segregation analysis also records maternal and de novo inheritance.
  - reference: PMID:31337883
    reference_title: Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Where tested, all pathogenic variants are de novo with one exception, which was inherited from
      the phenotypically normal mother.
    explanation: >-
      The discovery cohort had parental data for six of thirteen children; this is a cohort-specific
      observation, not a general de novo frequency.
  - reference: PMID:40026690
    reference_title: "Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The gonadal development and fertility of female (46,XX) carriers with DHX37
      gene mutations are not affected; however, incomplete penetrance may be
      observed in males (46,XY).
    explanation: >-
      Directly states both the sex-limited expression and the incomplete
      penetrance in 46,XY carriers.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
pathophysiology:
- name: DHX37 Missense Variation
  description: >-
    Specific germline missense variants in DHX37 cause the testicular-development spectrum. Many
    cluster in the RecA-like helicase domains. Their shared biochemical effect is unresolved: domain
    location and enrichment establish a genetic association without proving decreased ATPase activity,
    dominant-negative action, gain of function or haploinsufficiency. Reports of variants of uncertain
    significance require separate interpretation.
  biological_scale: MOLECULAR
  genetic_context:
    gene:
      preferred_term: DHX37
      term:
        id: hgnc:17210
        label: DHX37
    allele_type: MISSENSE
    zygosity: HETEROZYGOUS
    variant_origin: GERMLINE
  downstream:
  - target: Reduced DHX37 Abundance
    causal_link_type: DIRECT
    description: >-
      Selected variant constructs have reduced protein abundance in cultured cells; this has not
      been established for every disease allele.
    evidence:
    - reference: PMID:38769888
      reference_title: Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders of sex development.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        compared with the cells transfected with pcDNA3.1‐WT, those with pcDNA3.1‐Arg308Gln and pcDNA3.1‐Arg671Thr
        displayed a lower level of DHX37
      explanation: >-
        Western blots in transfected HEK293T cells show reduced protein abundance for these constructs;
        enzymatic activity and patient gonadal abundance were not measured. The paper inconsistently
        labels Arg671Thr pathogenic in prose and VUS in Table 1.
    - reference: PMID:37065748
      reference_title: A novel DEAH-box helicase 37 mutation associated with differences of sex development.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        compared with the cells transfected with pcDNA3.1-WT, those with pcDNA3.1-S408L displayed
        decreased DHX37 expression both at the mRNA and protein levels.
      explanation: >-
        The human Sertoli cell-line overexpression experiment supports a variant-specific abundance
        effect, not general loss of helicase function.
  - target: Impaired Small Ribosomal Subunit Biogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A proposed consequence of altered DHX37 function; direct DSD-allele ribosome-output measurements
      remain unavailable.
    evidence:
    - reference: PMID:30582406
      reference_title: The human RNA helicase DHX37 is required for release of the U3 snoRNP from pre-ribosomal particles.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Using an in vivo crosslinking approach, we show that DHX37 binds directly to the U3 small
        nucleolar RNA (snoRNA) and demonstrate that the catalytic activity of the helicase is required
        for dissociation of the U3 snoRNA from pre-ribosomal complexes.
      explanation: >-
        Human cultured-cell experiments establish the normal ribosome-assembly role. The disease
        connection remains indirect because DSD alleles and affected gonads were not assayed.
    - reference: PMID:31188444
      reference_title: The DEAH-box RNA helicase Dhr1 contains a remarkable carboxyl terminal domain essential for small ribosomal subunit biogenesis.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Finally, we have functionally characterized three mutations identified in an animal model
        or in human patients suffering from neurological disease and showed that one (L639P) impairs
        ribosome biogenesis severely
      explanation: >-
        Yeast Dhr1 ortholog substitutions modeled neurological alleles and a zebrafish allele, not
        human DSD variants. These results cannot establish ribosome failure in SRXY11.
  - target: Altered Beta-Catenin Abundance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Variant-specific cell-culture evidence informs this candidate branch.
    evidence:
    - reference: PMID:37065748
      reference_title: A novel DEAH-box helicase 37 mutation associated with differences of sex development.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        transfection with wt-DHX37 led to a significant decrease of the β-catenin protein, which
        was rescued by the mutant DHX37.
      explanation: >-
        In an overexpression assay, Ser408Leu fails to reproduce the wild-type reduction in beta-catenin
        abundance. This is not direct evidence of canonical WNT activation or ovarian fate in an
        embryonic gonad.
  - target: Impaired Testicular Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Human genetic and histological evidence establishes the disease association while the molecular
      intermediates remain unresolved.
    evidence:
    - reference: PMID:39659563
      reference_title: "Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Histological analysis of two participants with DHX37 variants suggested
        early disruption of gonadal development due to the presence of Müllerian
        remnants in both and undifferentiated gonadal tissue in one.
      explanation: >-
        Human gonadal histology supports impaired differentiation. Müllerian remnants in this cohort
        were fallopian tubes, not proof of a retained uterus in every carrier.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
  - target: Testicular Regression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The human phenotype includes prenatal or postnatal regression; the mechanism of tissue loss
      is unresolved.
    evidence:
    - reference: PMID:40916030
      reference_title: DHX37 variants in patients with 46,XY disorders or differences of sex development.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        However, patient 1 exhibited progressive postnatal gonadal disappearance.
      explanation: >-
        A patient with pathogenic Arg334Trp had palpable inguinal testes in early childhood followed
        by their disappearance, demonstrating that regression is not confined to fetal life.
    - reference: PMID:38359811
      reference_title: "DHX37 Variant Is One of the Common Genetic Causes in Japanese Patients with Testicular Regression Syndrome/Partial Gonadal Dysgenesis without Müllerian Derivatives."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The testicular regression syndrome (TRS) is a form of differences of sex
        development (DSD) in which the testes differentiate and function during
        early embryonic development, but subsequently regress.
      explanation: >-
        Defines the form-then-regress sequence that distinguishes this node from
        failure of determination.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
  - target: Altered RNA Splicing
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Knockdown data motivate a candidate role for altered RNA processing; equivalent changes have
      not been demonstrated for the established human DSD alleles.
    evidence:
    - reference: PMID:41535247
      reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Dhx37 KD triggered 949 significant AS events
      explanation: >-
        RNA-seq after Dhx37 knockdown in mouse TM4 cells identifies alternative-splicing changes;
        their contribution to human variant-associated gonadal disease remains untested.
    - reference: PMID:41535247
      reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Sashimi plots corroborated Dhx37-dependent alterations in exon usage and intron retention
      explanation: >-
        The primary analysis documents altered exon use and intron retention, not merely pathway
        enrichment.
  evidence:
  - reference: PMID:31337883
    reference_title: "Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twelve variants are clustered in two highly conserved functional domains
      and were specifically associated with gonadal dysgenesis and TRS.
    explanation: >-
      Establishes enrichment and helicase-domain clustering of specific missense variants in the
      gonadal dysgenesis and regression spectrum; it does not measure helicase activity.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: Reduced DHX37 Abundance
  description: >-
    Arg308Gln and Arg671Thr constructs produce less DHX37 protein than wild type in HEK293T cells.
    Ser408Leu overexpression in a human Sertoli cell line reduces both transcript and protein abundance.
    Localization remains similar to wild type. These are construct-specific observations; protein
    stability, helicase activity and patient gonadal abundance were not directly measured.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:38769888
    reference_title: Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders of sex development.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      compared with the cells transfected with pcDNA3.1‐WT, those with pcDNA3.1‐Arg308Gln and pcDNA3.1‐Arg671Thr
      displayed a lower level of DHX37
    explanation: >-
      Western blots in transfected HEK293T cells show reduced protein abundance for these constructs;
      enzymatic activity and patient gonadal abundance were not measured. The paper inconsistently
      labels Arg671Thr pathogenic in prose and VUS in Table 1.
  - reference: PMID:37065748
    reference_title: A novel DEAH-box helicase 37 mutation associated with differences of sex development.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      compared with the cells transfected with pcDNA3.1-WT, those with pcDNA3.1-S408L displayed decreased
      DHX37 expression both at the mRNA and protein levels.
    explanation: >-
      The human Sertoli cell-line overexpression experiment supports a variant-specific abundance
      effect, not general loss of helicase function.
- name: Impaired Small Ribosomal Subunit Biogenesis
  description: >-
    DHX37 normally supports small-subunit maturation. Human HeLa-cell depletion reduces 18S rRNA
    and 40S output and impairs conversion of 21S pre-rRNA to 18SE. Wild-type DHX37 rescues processing
    defects in HEK293 complementation assays, whereas engineered catalytic T282A does not and causes
    retention of U3 snoRNA on pre-ribosomes. T282A is not a patient DSD allele; ribosome processing/output
    has not been demonstrated to fail in affected human gonads, so the SRXY11 mechanism remains hypothetical.
    Yeast experiments on neurological or zebrafish ortholog substitutions do not fill this gap.
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  biological_processes:
  - preferred_term: ribosomal small subunit biogenesis
    term:
      id: GO:0042274
      label: ribosomal small subunit biogenesis
    modifier: DECREASED
  downstream:
  - target: Nucleolar Structural Disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Ribosome-assembly defects are a proposed contributor to the nucleolar phenotype after mouse
      Dhx37 deletion; this intermediate has not been isolated experimentally.
    evidence:
    - reference: PMID:41535247
      reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        Dhx37 deficiency caused nucleolar fragmentation, rupture, and marked size reduction in Sertoli
        cells
      explanation: >-
        Transmission electron microscopy directly demonstrates nucleolar structural disruption in
        the Sertoli-targeted knockout mouse.
  evidence:
  - reference: PMID:30582406
    reference_title: The human RNA helicase DHX37 is required for release of the U3 snoRNP from pre-ribosomal particles.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Using an in vivo crosslinking approach, we show that DHX37 binds directly to the U3 small nucleolar
      RNA (snoRNA) and demonstrate that the catalytic activity of the helicase is required for dissociation
      of the U3 snoRNA from pre-ribosomal complexes.
    explanation: >-
      Human cultured-cell experiments establish the normal ribosome-assembly role. The disease connection
      remains indirect because DSD alleles and affected gonads were not assayed.
  - reference: PMID:31188444
    reference_title: The DEAH-box RNA helicase Dhr1 contains a remarkable carboxyl terminal domain essential for small ribosomal subunit biogenesis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Finally, we have functionally characterized three mutations identified in an animal model or
      in human patients suffering from neurological disease and showed that one (L639P) impairs ribosome
      biogenesis severely
    explanation: >-
      Yeast Dhr1 ortholog substitutions modeled neurological alleles and a zebrafish allele, not
      human DSD variants. These results cannot establish ribosome failure in SRXY11.
  - reference: PMID:30582406
    reference_title: The human RNA helicase DHX37 is required for release of the U3 snoRNP from pre-ribosomal particles.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      depletion of DHX37 does not affect production of 60S subunits but leads to a significant decrease
      in the abundance of 40S particles as well as a decrease in the amount of 80S monosomes
    explanation: >-
      Sucrose-gradient analysis of DHX37-depleted human cultured cells directly measures reduced
      small-subunit abundance; the experiments do not test a human DSD allele. Application to heterozygous
      DHX37-related DSD remains indirect.
  - reference: PMID:30582406
    reference_title: The human RNA helicase DHX37 is required for release of the U3 snoRNP from pre-ribosomal particles.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      depletion of DHX37 caused accumulation of the 21S pre-rRNA and a concomitant decrease in the
      levels of the 18SE pre-rRNA
    explanation: >-
      Northern blots establish a pre-rRNA processing defect after experimental DHX37 depletion in
      human cells. Application to heterozygous DHX37-related DSD remains indirect.
  - reference: PMID:30582406
    reference_title: The human RNA helicase DHX37 is required for release of the U3 snoRNP from pre-ribosomal particles.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      expression of wild-type DHX37 from a transgene can rescue these defects
    explanation: >-
      HEK293 complementation rescues pre-rRNA processing after endogenous DHX37 depletion; engineered
      T282A fails to rescue the 21S-to-18SE defect. This is not rescue of a patient variant or gonadal
      phenotype. Application to heterozygous DHX37-related DSD remains indirect.
- name: Nucleolar Structural Disruption
  description: >-
    Sertoli-cell Dhx37 knockout mice show fragmented, smaller nucleoli by electron microscopy and
    reduced fibrillarin staining in adult testes. This supports nucleolar disruption following substantial
    experimental loss of Dhx37. The corresponding change in heterozygous human DSD remains provisional.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  downstream:
  - target: p53 Accumulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Nucleolar disruption and increased p53 coexist in knockout testes. Proposed ribosomal-protein/MDM2
      intermediates were not directly tested.
    evidence:
    - reference: PMID:41535247
      reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        p53 and its downstream effector p21 were up-regulated, while the pro-apoptotic markers BAX
        and cleaved caspase-3 accumulated
      explanation: >-
        Protein measurements support p53-associated stress signaling in knockout testes. Neither
        p53 rescue nor requirement for the phenotype was tested.
  evidence:
  - reference: PMID:41535247
    reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Dhx37 deficiency caused nucleolar fragmentation, rupture, and marked size reduction in Sertoli
      cells
    explanation: >-
      Transmission electron microscopy directly demonstrates nucleolar structural disruption in the
      Sertoli-targeted knockout mouse.
- name: p53 Accumulation
  description: >-
    Mouse knockout testes show increased p53 and p21, together with changes in apoptosis-associated
    proteins. These observations support p53-associated stress signaling but do not establish its
    necessity for tissue loss. In contrast, Ser408Leu overexpression did not increase p53 in the
    human Sertoli-cell assay.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Sertoli Cell Apoptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A candidate p53-mediated contribution is supported by concomitant signaling and apoptosis markers;
      no p53-inhibition or genetic-rescue experiment establishes mediation.
    evidence:
    - reference: PMID:41535247
      reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        TUNEL assay (green) combined with SOX9 immunostaining (red) demonstrates a pronounced increase
        in apoptotic cells in Dhx37−/− testes.
      explanation: >-
        Adult P60 mouse testis sections document increased apoptosis in the Sertoli-cell compartment
        after conditional deletion. This is not an observation in fetal human variant-bearing gonads.
  evidence:
  - reference: PMID:41535247
    reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      p53 and its downstream effector p21 were up-regulated, while the pro-apoptotic markers BAX
      and cleaved caspase-3 accumulated
    explanation: >-
      Protein measurements support p53-associated stress signaling in knockout testes. Neither p53
      rescue nor requirement for the phenotype was tested.
  - reference: PMID:37065748
    reference_title: A novel DEAH-box helicase 37 mutation associated with differences of sex development.
    supports: REFUTE
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      there is no difference in p53 expression among cells transfected with empty expressing vector,
      wt-DHX37, or mutant DHX37.
    explanation: >-
      The Ser408Leu assay does not support a universal variant-induced increase in p53. It does not
      refute the distinct conditional-null mouse result.
- name: Sertoli Cell Apoptosis
  description: >-
    Adult Sertoli-targeted Dhx37 knockout testes have increased TUNEL staining in the supporting-cell
    compartment. A role in human testicular regression is plausible but unproven. The Ser408Leu overexpression
    experiment instead showed more apoptosis with wild-type than mutant DHX37, so it cannot be cited
    as variant-induced apoptosis.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  downstream:
  - target: Testicular Regression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Experimental supporting-cell loss is a candidate route to reduced tissue maintenance; extrapolation
      to human prenatal or postnatal regression remains hypothetical.
    evidence:
    - reference: PMID:41535247
      reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        TUNEL assay (green) combined with SOX9 immunostaining (red) demonstrates a pronounced increase
        in apoptotic cells in Dhx37−/− testes.
      explanation: >-
        Adult P60 mouse testis sections document increased apoptosis in the Sertoli-cell compartment
        after conditional deletion. This is not an observation in fetal human variant-bearing gonads.
  evidence:
  - reference: PMID:41535247
    reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      TUNEL assay (green) combined with SOX9 immunostaining (red) demonstrates a pronounced increase
      in apoptotic cells in Dhx37−/− testes.
    explanation: >-
      Adult P60 mouse testis sections document increased apoptosis in the Sertoli-cell compartment
      after conditional deletion. This is not an observation in fetal human variant-bearing gonads.
  - reference: PMID:37065748
    reference_title: A novel DEAH-box helicase 37 mutation associated with differences of sex development.
    supports: REFUTE
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Furthermore, cells that expressed wt-DHX37 showed an even higher apoptosis rate than the mutant.
    explanation: >-
      Both constructs increased apoptosis relative to empty vector; the variant did not produce an
      excess over wild type.
- name: Reduced Sertoli Cell Proliferation
  description: >-
    Ki67 staining is reduced in the Sertoli-cell compartment of adult conditional-knockout testes.
    This is separate from apoptosis and does not measure a fetal human progenitor defect. In the
    Ser408Leu cell assay, mutant and wild-type overexpression did not differ in their effect on proliferation.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  downstream:
  - target: Reduced Functional Testicular Tissue
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced supporting-cell renewal may contribute to knockout testis dysfunction; the human developmental
      connection is indirect.
    evidence:
    - reference: PMID:41535247
      reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        we observed a marked attenuation of Sertoli proliferation in Dhx37 mice
      explanation: >-
        Ki67 staining supports reduced proliferative activity in the knockout Sertoli-cell compartment,
        distinct from increased cell death.
  evidence:
  - reference: PMID:41535247
    reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      we observed a marked attenuation of Sertoli proliferation in Dhx37 mice
    explanation: >-
      Ki67 staining supports reduced proliferative activity in the knockout Sertoli-cell compartment,
      distinct from increased cell death.
- name: Altered RNA Splicing
  description: >-
    Dhx37 depletion in mouse TM4 Sertoli cells alters exon usage and intron retention. This provides
    an experimental RNA-processing branch distinct from ribosome assembly. The affected transcripts
    include cell-cycle and stress-associated genes, but the causal contribution of these changes
    to human DSD variants is unresolved.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:41535247
    reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Dhx37 KD triggered 949 significant AS events
    explanation: >-
      RNA-seq after Dhx37 knockdown in mouse TM4 cells identifies alternative-splicing changes; their
      contribution to human variant-associated gonadal disease remains untested.
  - reference: PMID:41535247
    reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Sashimi plots corroborated Dhx37-dependent alterations in exon usage and intron retention
    explanation: >-
      The primary analysis documents altered exon use and intron retention, not merely pathway enrichment.
- name: Altered Beta-Catenin Abundance
  description: >-
    In a human Sertoli cell line, wild-type DHX37 overexpression lowers beta-catenin protein and
    the Ser408Leu construct restores it toward the empty-vector condition. The assay does not establish
    beta-catenin stabilization, nuclear transcriptional activity or canonical WNT activation in patient
    gonads. A connection to testis determination remains hypothetical.
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  downstream:
  - target: Impaired Testicular Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A proposed effect on sex-development signaling, not a demonstrated fate switch in the variant-bearing
      cells.
    evidence:
    - reference: PMID:37065748
      reference_title: A novel DEAH-box helicase 37 mutation associated with differences of sex development.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        transfection with wt-DHX37 led to a significant decrease of the β-catenin protein, which
        was rescued by the mutant DHX37.
      explanation: >-
        In an overexpression assay, Ser408Leu fails to reproduce the wild-type reduction in beta-catenin
        abundance. This is not direct evidence of canonical WNT activation or ovarian fate in an
        embryonic gonad.
  evidence:
  - reference: PMID:37065748
    reference_title: A novel DEAH-box helicase 37 mutation associated with differences of sex development.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      transfection with wt-DHX37 led to a significant decrease of the β-catenin protein, which was
      rescued by the mutant DHX37.
    explanation: >-
      In an overexpression assay, Ser408Leu fails to reproduce the wild-type reduction in beta-catenin
      abundance. This is not direct evidence of canonical WNT activation or ovarian fate in an embryonic
      gonad.
- name: Impaired Testicular Development
  description: >-
    Testicular differentiation is variably impaired, yielding dysgenetic or undifferentiated tissue.
    Gonadal dysgenesis and subsequent regression can overlap. Retained Müllerian structures indicate
    incomplete fetal hormone action but are not a binary discriminator separating every case of dysgenesis
    from regression.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: male gonad development
    term:
      id: GO:0008584
      label: male gonad development
    modifier: DECREASED
  downstream:
  - target: Gonadal dysgenesis
    causal_link_type: DIRECT
  - target: Reduced Functional Testicular Tissue
    causal_link_type: DIRECT
  - target: Deficient Fetal Anti-Mullerian Hormone Action
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31337883
      reference_title: Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: >-
        46,XY partial gonadal dysgenesis is characterized by partially developed internal ducts usually
        consisting of a mixture of Wolffian (epididymis, vas deferens, and seminal vesicle) and Müllerian
        ducts (fallopian tube, uterus, and upper third of the vagina) with varying degrees of virilization
        of the external genitalia depending on the amount of testicular tissue present.
      explanation: >-
        Developmental context supports the consequences of variable testicular differentiation. Fetal
        AMH concentrations were not measured in the affected individuals.
  - target: Deficient Fetal Androgen Exposure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31337883
      reference_title: Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Four of the 13 children had virilized external genitalia and were raised as male suggesting
        that functional Leydig cells were present during fetal development.
      explanation: >-
        The authors infer prior fetal androgen production from anatomy. Variable fetal androgen exposure
        is inferred, not directly measured.
  - target: Germ cell neoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Retained dysgenetic tissue may contain neoplastic germ cells; the genotype-specific risk and
      molecular intermediates are unknown.
    evidence:
    - reference: url:https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf
      reference_title: https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Left dysgenetic

        testis with GCNIS*
      explanation: >-
        Table 1 records germ-cell neoplasia in situ in the left dysgenetic testis of the Arg674Trp-positive
        family member F4:II-4. This is a direct observation, not a risk estimate.
  evidence:
  - reference: PMID:39659563
    reference_title: "Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histological analysis of two participants with DHX37 variants suggested
      early disruption of gonadal development due to the presence of Müllerian
      remnants in both and undifferentiated gonadal tissue in one.
    explanation: >-
      Human gonadal histology supports impaired differentiation. Müllerian remnants in this cohort
      were fallopian tubes, not proof of a retained uterus in every carrier.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  locations:
  - preferred_term: testis
    term:
      id: UBERON:0000473
      label: testis
- name: Testicular Regression
  description: >-
    Testicular tissue can be lost after some differentiation and hormone production. The timing and
    degree of prior function vary: atypical genitalia and Müllerian remnants can accompany early
    regression, while a pathogenic-variant carrier also had progressive disappearance of palpable
    testes during childhood. Definitions of regression and anorchia differ between cohorts.
  biological_scale: TISSUE
  downstream:
  - target: Reduced Functional Testicular Tissue
    causal_link_type: DIRECT
  - target: Absent testis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:40916030
    reference_title: DHX37 variants in patients with 46,XY disorders or differences of sex development.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      However, patient 1 exhibited progressive postnatal gonadal disappearance.
    explanation: >-
      A patient with pathogenic Arg334Trp had palpable inguinal testes in early childhood followed
      by their disappearance, demonstrating that regression is not confined to fetal life.
  - reference: PMID:38359811
    reference_title: "DHX37 Variant Is One of the Common Genetic Causes in Japanese Patients with Testicular Regression Syndrome/Partial Gonadal Dysgenesis without Müllerian Derivatives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The testicular regression syndrome (TRS) is a form of differences of sex
      development (DSD) in which the testes differentiate and function during
      early embryonic development, but subsequently regress.
    explanation: >-
      Defines the form-then-regress sequence that distinguishes this node from
      failure of determination.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: Deficient Fetal Anti-Mullerian Hormone Action
  description: >-
    Insufficient fetal Sertoli-cell AMH action permits persistence of Müllerian structures. Fallopian
    remnants and a uterus are distinct anatomical observations. In SRXY11 the fetal hormonal deficit
    is inferred from anatomy; low postnatal AMH does not directly measure fetal exposure.
  biological_scale: ORGANISM
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  downstream:
  - target: Presence of uterus in 46,XY individual
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:31337883
    reference_title: Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      46,XY partial gonadal dysgenesis is characterized by partially developed internal ducts usually
      consisting of a mixture of Wolffian (epididymis, vas deferens, and seminal vesicle) and Müllerian
      ducts (fallopian tube, uterus, and upper third of the vagina) with varying degrees of virilization
      of the external genitalia depending on the amount of testicular tissue present.
    explanation: >-
      Developmental context supports the consequences of variable testicular differentiation. Fetal
      AMH concentrations were not measured in the affected individuals.
- name: Deficient Fetal Androgen Exposure
  description: >-
    Reduced fetal androgen exposure provides a developmental explanation for variable undervirilization,
    micropenis and hypospadias. Anatomical severity depends on timing and residual testicular function;
    fetal testosterone was not measured in the reported carriers.
  biological_scale: ORGANISM
  cell_types:
  - preferred_term: Leydig cell
    term:
      id: CL:0000178
      label: Leydig cell
  downstream:
  - target: Undervirilized external genitalia
    causal_link_type: DIRECT
  - target: Female external genitalia in individual with 46,XY karyotype
    causal_link_type: DIRECT
  - target: Micropenis
    causal_link_type: DIRECT
  - target: Hypospadias
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:31337883
    reference_title: Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Four of the 13 children had virilized external genitalia and were raised as male suggesting
      that functional Leydig cells were present during fetal development.
    explanation: >-
      The authors infer prior fetal androgen production from anatomy. Variable fetal androgen exposure
      is inferred, not directly measured.
- name: Reduced Functional Testicular Tissue
  description: >-
    Dysgenesis or regression reduces gonadal endocrine and reproductive capacity to a variable degree.
    Low testosterone, AMH and inhibin B and elevated gonadotropins can occur, but residual hormone
    secretion and spontaneous pubertal onset are possible. Low markers do not prove total absence
    of tissue. Fertility is impaired in severe disease, while some variant-bearing fathers are fertile.
  biological_scale: ORGANISM
  downstream:
  - target: Hypergonadotropic hypogonadism
    causal_link_type: DIRECT
  - target: Delayed puberty
    causal_link_type: DIRECT
  - target: Primary amenorrhea
    causal_link_type: DIRECT
  - target: Decreased circulating antimullerian hormone
    causal_link_type: DIRECT
  - target: Decreased serum testosterone concentration
    causal_link_type: DIRECT
  - target: Infertility
    causal_link_type: DIRECT
  - target: Azoospermia
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:37717579
    reference_title: "Two Novel Heterozygous Variants in RecA2 Domain of DHX37 Cause 46,XY Gonadal Dysgenesis and Testicular Regression Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Endocrinological tests indicated hypergonadotropic hypogonadism with
      remarkably elevated gonadotropins
    explanation: >-
      Elevated gonadotropins indicate deficient gonadal feedback. The variants in this report were
      classified VUS, so this observation is supporting clinical context rather than independent
      proof of their pathogenicity.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:37717579
    reference_title: "Two Novel Heterozygous Variants in RecA2 Domain of DHX37 Cause 46,XY Gonadal Dysgenesis and Testicular Regression Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The administration of hCG (1,500 IU/day, intramuscular injection for 3
      days) slightly increased testosterone levels (0.16–0.73 nmol/L), suggesting
      that the gonads had poor testicular function.
    explanation: >-
      A blunted but detectable testosterone response indicates poor residual gonadal function; it
      does not establish complete absence of Leydig cells or testicular tissue.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:37717579
    reference_title: "Two Novel Heterozygous Variants in RecA2 Domain of DHX37 Cause 46,XY Gonadal Dysgenesis and Testicular Regression Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anti-Müllerian hormone and inhibin B levels were also below the normal
      reference range
    explanation: >-
      Low AMH and inhibin B support impaired Sertoli-cell function. Below-reference values are not
      synonymous with undetectable concentrations or absent gonads.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  locations:
  - preferred_term: testis
    term:
      id: UBERON:0000473
      label: testis
phenotypes:
- category: Reproductive
  name: Gonadal dysgenesis
  phenotype_term:
    preferred_term: Dysgenetic or undifferentiated gonadal tissue
    term:
      id: HP:0000133
      label: Gonadal dysgenesis
  description: >-
    At the determination pole of the spectrum the gonad is dysgenetic or
    undifferentiated rather than an organized testis. Centralized histological
    review of DHX37 carriers within a bilateral-testicular-regression cohort
    found undifferentiated gonadal tissue and retained Müllerian remnants,
    evidence that DHX37 disease involves early developmental failure rather than
    pure late regression.
  evidence:
  - reference: PMID:39659563
    reference_title: "Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histological analysis confirmed DHX37 as a gonadal development, rather than
      a BTR-related, gene.
    explanation: >-
      The authors' histology-based conclusion that DHX37 carriers have a gonadal
      developmental defect.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      decreased size and number of seminiferous tubules, reduced number or absence of germ cells,
      peritubular fibrosis, and hyperplasia of Leydig cells
    explanation: >-
      The overview describes the broader dysgenetic-testis histological spectrum; not every component
      is established in every DHX37 carrier.
- category: Reproductive
  name: Absent testis
  phenotype_term:
    preferred_term: Bilateral anorchia (vanishing testis)
    term:
      id: HP:0010469
      label: Absent testis
  description: >-
    Complete absence of a testis is reported in severe regression, while other patients retain dysgenetic
    tissue or a fibrotic remnant. Sparse seminiferous tubules and Leydig-cell groups in a surgical
    specimen indicate residual tissue and should not be interpreted as histological proof of complete
    agenesis.
  evidence:
  - reference: url:https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf
    reference_title: https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      No gonadal
       tissue No gonadal tissue
    explanation: >-
      Table 2 documents absent gonadal tissue in DHX37-positive sporadic regression cases; other
      columns document residual dysgenetic gonads.
- category: Reproductive
  name: Undervirilized external genitalia
  phenotype_term:
    preferred_term: Ambiguous genitalia
    term:
      id: HP:0000062
      label: Ambiguous genitalia
  description: >-
    Atypical external genitalia span a continuum between female-appearing and male-appearing anatomy.
    The phenotype varies even among carriers of the same recurrent allele.
  evidence:
  - reference: PMID:31337883
    reference_title: Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The external genitalia of children carrying DHX37 pathogenic variants ranged from completely
      female to male with bilateral cryptorchidism.
    explanation: >-
      Direct clinical spectrum in the pathogenic-variant discovery cohort.
- category: Reproductive
  name: Female external genitalia in individual with 46,XY karyotype
  phenotype_term:
    preferred_term: Female external genitalia in a 46,XY individual
    term:
      id: HP:0008730
      label: Female external genitalia in individual with 46,XY karyotype
  description: >-
    Female-appearing external genitalia can accompany DHX37-related gonadal dysgenesis. External
    appearance alone does not establish complete dysgenesis; assessment of internal anatomy, hormones
    and gonadal tissue is required.
  evidence:
  - reference: PMID:31337883
    reference_title: Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The external genitalia of children carrying DHX37 pathogenic variants ranged from completely
      female to male with bilateral cryptorchidism.
    explanation: >-
      Direct clinical spectrum in the pathogenic-variant discovery cohort.
- category: Reproductive
  name: Micropenis
  phenotype_term:
    preferred_term: Micropenis / microphallus
    term:
      id: HP:0000054
      label: Micropenis
  description: >-
    Micropenis is reported from infancy. All three DHX37-positive participants in the selected Belgian
    bilateral-regression series had microphallus at birth. Testosterone response varied; penile growth
    remained limited in the two treated DHX37 carriers described at Tanner G3. These small observations
    do not establish universal adult treatment failure.
  evidence:
  - reference: PMID:39659563
    reference_title: "Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three participants with a DHX37 variant had a microphallus at birth
      (leading to female sex assignment in one), while only six of the remaining
      31 participants without a DHX37 variant (19.4%) had a microphallus at birth
    explanation: >-
      Quantifies microphallus in DHX37 carriers against the non-DHX37 comparator
      within the same cohort.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Reproductive
  name: Cryptorchidism
  phenotype_term:
    preferred_term: Undescended testes
    term:
      id: HP:0000028
      label: Cryptorchidism
  description: >-
    Retained testes may lie in the inguinal canal. Nonpalpable gonads alone cannot distinguish cryptorchidism
    from dysgenesis or absent testes; hormone assessment and imaging or selected exploration characterize
    the anatomy.
  evidence:
  - reference: url:https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867
    reference_title: https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      both gonads palpable in the inguinal canal
    explanation: >-
      The Arg308Gln-positive patient had bilateral inguinal testes and biopsy-confirmed partial gonadal
      dysgenesis.
- category: Endocrine
  name: Hypergonadotropic hypogonadism
  phenotype_term:
    preferred_term: Hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  description: >-
    Reduced gonadal function can produce elevated FSH and LH with low sex-steroid concentrations.
    Values depend on age and residual tissue and do not by themselves distinguish complete anorchia
    from a poorly functioning dysgenetic testis.
  evidence:
  - reference: PMID:37717579
    reference_title: "Two Novel Heterozygous Variants in RecA2 Domain of DHX37 Cause 46,XY Gonadal Dysgenesis and Testicular Regression Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Endocrinological tests indicated hypergonadotropic hypogonadism with
      remarkably elevated gonadotropins
    explanation: >-
      Directly reports hypergonadotropic hypogonadism in a DHX37 carrier.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Endocrine
  name: Decreased circulating antimullerian hormone
  phenotype_term:
    preferred_term: Undetectable or low anti-Müllerian hormone
    term:
      id: HP:0031103
      label: Decreased circulating antimullerian hormone circulation
  description: >-
    Low or undetectable AMH indicates reduced Sertoli-cell function in affected individuals. Low
    inhibin B may accompany it, but below-reference concentrations are not proof that all testicular
    tissue is absent.
  evidence:
  - reference: PMID:37717579
    reference_title: "Two Novel Heterozygous Variants in RecA2 Domain of DHX37 Cause 46,XY Gonadal Dysgenesis and Testicular Regression Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anti-Müllerian hormone and inhibin B levels were also below the normal
      reference range
    explanation: >-
      Reports the low AMH and inhibin B this phenotype describes.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Endocrine
  name: Decreased serum testosterone concentration
  phenotype_term:
    preferred_term: Low serum testosterone
    term:
      id: HP:0040171
      label: Decreased serum testosterone concentration
  description: >-
    Basal testosterone may be low for age, with an absent or blunted hCG-stimulated increase. Detectable
    responses occur and indicate some residual endocrine activity.
  evidence:
  - reference: PMID:37717579
    reference_title: "Two Novel Heterozygous Variants in RecA2 Domain of DHX37 Cause 46,XY Gonadal Dysgenesis and Testicular Regression Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The administration of hCG (1,500 IU/day, intramuscular injection for 3
      days) slightly increased testosterone levels (0.16–0.73 nmol/L), suggesting
      that the gonads had poor testicular function.
    explanation: >-
      Reports the blunted hCG-stimulated testosterone response in a DHX37
      carrier.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Endocrine
  name: Delayed puberty
  phenotype_term:
    preferred_term: Delayed or incomplete puberty
    term:
      id: HP:0000823
      label: Delayed puberty
  description: >-
    Severe gonadal dysfunction may prevent spontaneous puberty. Other carriers enter puberty spontaneously
    but subsequently require sex-steroid replacement, so absent pubertal onset is not universal.
  evidence:
  - reference: PMID:38769888
    reference_title: Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders of sex development.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The patient was a 14‐year‐old male with pubertal retardation and partial gonadal dysgenesis.
    explanation: >-
      Reports delayed puberty in an Arg671Thr carrier; the paper has conflicting variant classification
      between text and Table 1.
  - reference: url:https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867
    reference_title: https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The patient developed normal

      puberty at 12 years old but presented with low testosterone levels at 17 years old.
    explanation: >-
      The pathogenic Arg308Gln carrier demonstrates spontaneous onset followed by insufficient sustained
      endocrine function.
- category: Reproductive
  name: Presence of uterus in 46,XY individual
  phenotype_term:
    preferred_term: Presence of uterus in a 46,XY individual
    term:
      id: HP:0034546
      label: Presence of uterus in 46,XY individual
  description: >-
    A uterus is present in some affected individuals, whereas others have only fallopian remnants
    or no Müllerian structures. The finding reflects incomplete fetal AMH action and does not define
    every gonadal-dysgenesis or regression presentation.
  evidence:
  - reference: PMID:40916030
    reference_title: DHX37 variants in patients with 46,XY disorders or differences of sex development.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Present (residual) (5 y 11 m)
    explanation: >-
      Table 2, patient 3 (pathogenic Arg674Trp), uterus column records a residual uterus at age 5
      years 11 months. The adjacent fallopian-tube and gonadal findings are distinct columns.
- category: Neoplastic
  name: Germ cell neoplasia
  phenotype_term:
    preferred_term: Germ cell neoplasia in retained dysgenetic testis
    term:
      id: HP:0100728
      label: Germ cell neoplasia
  description: >-
    Germ-cell neoplasia in situ was documented in a retained dysgenetic testis of an Arg674Trp-positive
    family member. General 46,XY gonadal-dysgenesis cohorts also establish tumor susceptibility,
    but they do not provide a DHX37-specific risk estimate. Management depends on retained tissue,
    location, function and histology rather than the gene result alone.
  evidence:
  - reference: url:https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf
    reference_title: https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Left dysgenetic

      testis with GCNIS*
    explanation: >-
      The primary cohort Table 1 identifies germ-cell neoplasia in situ in the left dysgenetic testis
      of family member F4:II-4, who carried Arg674Trp.
  - reference: PMID:27862157
    reference_title: "Gonadal tumour risk in 292 phenotypic female patients with disorders of sex development containing Y chromosome or Y-derived sequence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The overall GCTs risk was 15·41% and 46, XY pure gonadal dysgenesis (46, XY
      PGD) carried the highest risk up to 23·33%
    explanation: >-
      This non-DHX37-genotyped DSD cohort supplies background risk context only; its percentage must
      not be assigned to SRXY11.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
  notes: >-
    No genotype-specific tumor-risk estimate is established by these sources. A small negative regression
    subgroup in a general DSD cohort does not exclude risk in retained dysgenetic tissue.
- category: Reproductive
  name: Hypospadias
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  description: >-
    Hypospadias occurs within the DHX37-associated dysgenesis spectrum. Its exclusion from selected
    bilateral-regression cohorts is an ascertainment criterion, not a rule that applies to every
    paper using the term testicular regression.
  evidence:
  - reference: PMID:40916030
    reference_title: DHX37 variants in patients with 46,XY disorders or differences of sex development.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Patient 3 had a phallus with severe perineal hypospadias and was raised as a female.
    explanation: >-
      Patient 3 carried the pathogenic Arg674Trp allele.
  - reference: PMID:38769888
    reference_title: Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders of sex development.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      including perineal hypospadias, micropenis (53.0 × 10.0 mm), and bilateral inguinal cryptorchidism.
    explanation: >-
      The reported Arg671Thr carrier had perineal hypospadias; interpretation retains the paper’s
      internal variant-classification uncertainty.
- category: Reproductive
  name: Primary amenorrhea
  phenotype_term:
    preferred_term: Primary amenorrhea
    term:
      id: HP:0000786
      label: Primary amenorrhea
  description: >-
    Primary amenorrhea may prompt evaluation in individuals with female-appearing anatomy. It can
    reflect gonadal steroid deficiency and/or absent Müllerian anatomy; it is not restricted to a
    single histological subtype.
  evidence:
  - reference: PMID:31337883
    reference_title: Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      five children carried the recurrent p.R308Q pathogenic variant with a phenotype that varied
      from female with primary amenorrhea to male with micropenis and bilateral cryptorchidism.
    explanation: >-
      Directly reports primary amenorrhea in the recurrent pathogenic-variant spectrum.
- category: Reproductive
  name: Infertility
  phenotype_term:
    preferred_term: Infertility
    term:
      id: HP:0000789
      label: Infertility
  description: >-
    Absent gonads or severe dysgenesis can compromise fertility. A pathogenic Arg308Gln carrier had
    azoospermia in young adulthood, whereas some variant-bearing fathers remain fertile; infertility
    is not universal across carriers.
  evidence:
  - reference: url:https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867
    reference_title: https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      has high levels of FSH (34.5 IU/L) and LH (12 IU/L) and presented with azoospermia.
    explanation: >-
      The Arg308Gln-positive patient had azoospermia at age 21, supporting impaired sperm production;
      infertility is not inferred for every carrier.
- name: Azoospermia
  category: Reproductive
  phenotype_term:
    preferred_term: Azoospermia
    term:
      id: HP:0000027
      label: Azoospermia
  description: >-
    A pathogenic Arg308Gln carrier with residual dysgenetic testes had azoospermia at age 21 after
    spontaneous pubertal onset and subsequent testosterone replacement. This single observation does
    not establish a frequency or an isolated drug-independent mechanism.
  evidence:
  - reference: url:https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867
    reference_title: https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      has high levels of FSH (34.5 IU/L) and LH (12 IU/L) and presented with azoospermia.
    explanation: >-
      Direct semen finding in the pathogenic Arg308Gln patient; the other azoospermic case in the
      paper carried a likely benign DHX37 allele and is not pooled here.
genetic:
- name: DHX37
  gene_term:
    preferred_term: DHX37
    term:
      id: hgnc:17210
      label: DHX37
  presence: "Missense variant, heterozygous in the great majority of cases"
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  frequency: >-
    Diagnostic yields vary with ascertainment. The discovery cohort found variants in 9/81 unexplained
    gonadal-dysgenesis cases and 4/16 testicular-regression cases. A Japanese series selected for
    TRS/PGD without Müllerian derivatives found DHX37 variants in four of ten families. The Belgian
    series identified three carriers among 34 successfully analyzed participants. These are selected
    cohort fractions, not disease prevalence or penetrance.
  inheritance:
  - name: Sex-limited autosomal dominant, incomplete penetrance in 46,XY
    inheritance_term:
      preferred_term: sex-limited autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
  notes: >-
    Established congenital DSD-associated variants are predominantly missense alleles affecting conserved
    helicase regions. The molecular mechanism is unresolved; variant class alone does not establish
    gain of function, dominant-negative action or haploinsufficiency. Co-occurring variants in NR5A1
    or SOX9 do not establish digenic inheritance, particularly when the DHX37 allele is uncertain
    or likely benign. A frameshift described in an infertility context should not be generalized
    to the congenital SRXY11 phenotype.
  case_fractions:
  - population: Japanese TRS/PGD cohort without Müllerian derivatives
    case_fraction_percent: 40.0
    cohort_size: 10
    notes: >-
      Four of ten families among eleven selected Japanese individuals with TRS/PGD and no Müllerian
      derivatives. The denominator is families, not unrelated unselected DSD patients.
    evidence:
    - reference: PMID:38359811
      reference_title: "DHX37 Variant Is One of the Common Genetic Causes in Japanese Patients with Testicular Regression Syndrome/Partial Gonadal Dysgenesis without Müllerian Derivatives."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Eighty percent of Japanese patients with TRS/PGD had monogenic disorders
        including DHX37 variant being the most commonly identified (40%).
      explanation: >-
        Reports the DHX37 share of this cohort.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
  - population: Brazilian 46,XY DSD referral cohort, embryonic testicular regression subgroup
    notes: >-
      The primary abstract and author manuscript report 7/14 ETRS index cases (50%). The methods
      describe ten affected members of five ETRS families plus eight sporadic cases, yielding thirteen
      apparent index families; that accounting does not reconcile cleanly with fourteen. Preserve
      the authors’ numerator/denominator in prose and omit a machine-readable fraction pending clarification.
      The separate overall yield is 11/78 index cases.
    evidence:
    - reference: PMID:31287541
      reference_title: "Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The variants were specifically associated with ETRS (7/14 index cases;
        50%).
      explanation: >-
        Reports the DHX37 share of the ETRS subgroup.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
  - population: Belgian bilateral testicular regression cohort
    case_fraction_percent: 8.8
    cohort_size: 34
    notes: >-
      Three carriers among 34 participants with analyzable DNA; one of the 35 recruited participants
      was excluded for suboptimal DNA quality. This was a retrospective multicenter clinical series,
      not population screening.
    evidence:
    - reference: PMID:39659563
      reference_title: 'Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series.'
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        DNA quality of one participant was suboptimal and was therefore excluded from further analysis.
        The results of the DSD-WES panels of the 34 remaining participants are presented in Table
        5. In three unrelated participants, heterozygous (likely) pathogenic variants were identified
        in DHX37.
      explanation: >-
        The full Results establish the analyzable denominator and three positive participants.
  - population: Previously unexplained 46,XY gonadal dysgenesis in the discovery cohort
    cohort_size: 81
    case_fraction_percent: 11.1
    notes: Nine of 81 gonadal-dysgenesis cases; complete and partial disease are not separated in this fraction.
    evidence:
    - reference: PMID:31337883
      reference_title: Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Pathogenic variants were specifically identified in children with 46,XY gonadal dysgenesis
        (9/81, 11%) and 46,XY TRS (4/16, 25%) but not in boys with either severe penoscrotal hypospadias
        or anorchia
      explanation: >-
        Source-specific yields in the selected discovery cohort.
  - population: Previously unexplained 46,XY testicular regression in the discovery cohort
    cohort_size: 16
    case_fraction_percent: 25.0
    notes: Four of sixteen clinically classified TRS cases; cohort definitions differ from later regression series.
    evidence:
    - reference: PMID:31337883
      reference_title: Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Pathogenic variants were specifically identified in children with 46,XY gonadal dysgenesis
        (9/81, 11%) and 46,XY TRS (4/16, 25%) but not in boys with either severe penoscrotal hypospadias
        or anorchia
      explanation: >-
        Source-specific TRS denominator, not the prevalence of SRXY11.
  evidence:
  - reference: PMID:31337883
    reference_title: "Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirteen children carried heterozygous missense pathogenic variants
      involving the RNA helicase DHX37, which is essential for ribosome
      biogenesis.
    explanation: >-
      The foundational cohort establishing DHX37 as causative in this phenotype.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:40916030
    reference_title: "DHX37 variants in patients with 46,XY disorders or differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified two pathogenic DEAH-box helicase 37 (DHX37) variants in
      three patients. We also identified a patient with a likely pathogenic
      variant in SOX9 and a rare likely benign variant in DHX37.
    explanation: >-
      A caution for variant interpretation: not every rare DHX37 variant found
      in a 46,XY DSD patient is causal — one in this cohort was likely benign
      and sat alongside a likely pathogenic SOX9 variant that better explained
      the phenotype.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:31287541
    reference_title: "Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The frequency of rare, predicted-to-be-deleterious DHX37 variants in this
      cohort (14%) is significantly higher than that observed in the Genome
      Aggregation Database (0.4%; P < 0.001).
    explanation: >-
      Case-versus-population-control enrichment against gnomAD — a roughly
      thirty-five-fold excess of rare deleterious DHX37 variants in 46,XY DSD.
      This is the population-genetic argument that the gene is causal rather
      than incidentally variable, independent of the separate enrichment test in
      PMID:31337883.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
variants:
- name: DHX37 p.Arg308Gln
  description: >-
    Recurrent pathogenic allele observed across unrelated families and at both dysgenesis and regression
    presentations. A 2025 literature review counted it in 36.67% of its 60 reported cases, a literature-selected
    set that includes uncertain variants rather than a population frequency.
  gene:
    preferred_term: DHX37
    term:
      id: hgnc:17210
      label: DHX37
  clinical_significance: PATHOGENIC
  identifiers:
  - "c.923G>A"
  evidence:
  - reference: PMID:40026690
    reference_title: "Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Sixty patients were reported to have DHX37-related 46,XY DSD, with p.R308Q,
      p.R674W variants being the two most common mutation hotspots, accounting
      for 36.67% and 11.67% of cases respectively.
    explanation: >-
      Quantifies p.Arg308Gln as the leading recurrent allele.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:38359811
    reference_title: "DHX37 Variant Is One of the Common Genetic Causes in Japanese Patients with Testicular Regression Syndrome/Partial Gonadal Dysgenesis without Müllerian Derivatives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified two heterozygous rare variants of DHX37 in four families: a
      previously reported pathogenic variant (c.923G>A, p.Arg308Gln) in three
      and a novel likely pathogenic variant (c.1882A>C, p.Thr628Pro) in one
    explanation: >-
      Independent recurrence of the same allele in a Japanese cohort, with the
      cDNA change quoted.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf
    reference_title: https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The p.Arg308Gln variant is classified as pathogenic
    explanation: >-
      The primary manuscript explicitly assigns pathogenic status to Arg308Gln, unlike the likely-pathogenic
      classifications assigned to its other three variants.
- name: DHX37 p.Arg674Trp
  description: >-
    Recurrent helicase-domain allele seen in familial and sporadic dysgenesis or regression. The
    original cohort classified it as likely pathogenic; a later Japanese series classified it as
    pathogenic. The disease severity is variable across carriers.
  gene:
    preferred_term: DHX37
    term:
      id: hgnc:17210
      label: DHX37
  clinical_significance: PATHOGENIC
  identifiers:
  - "c.2020C>T"
  evidence:
  - reference: PMID:31287541
    reference_title: "Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two variants were recurrent: p.Arg308Gln (in two families and in three
      sporadic cases) and p.Arg674Trp (in two families and in two sporadic
      cases).
    explanation: >-
      Establishes p.Arg674Trp as a recurrent allele in familial and sporadic
      cases.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:31287541
    reference_title: "Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified four heterozygous missense rare variants, classified as
      pathogenic or likely pathogenic in the Asp-Glu-Ala-His-box (DHX) helicase
      37 (DHX37) gene in five families (n = 11 patients) and in six sporadic
      cases.
    explanation: >-
      The original cohort grouped pathogenic and likely pathogenic alleles; this broad quote alone
      does not establish the individual classification. The later Japanese report below explicitly
      calls Arg674Trp pathogenic.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:40916030
    reference_title: "DHX37 variants in patients with 46,XY disorders or differences of sex development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients (patients 1–3) harbored previously reported pathogenic
      DHX37 variants (NM_032656; c.1000C>T; p.(Arg334Trp) and
      c.2020C>T;p.(Arg674Trp))
    explanation: >-
      Source for the cDNA identifier on this record, against transcript
      NM_032656, and an independent Japanese cohort observation of the allele.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: DHX37 p.Arg334Trp
  description: >-
    Recurrent RecA1-domain allele classified as pathogenic in the cited later series. It occurs in
    the Belgian multicenter regression cohort and in a Japanese patient with postnatal loss of palpable
    testes.
  gene:
    preferred_term: DHX37
    term:
      id: hgnc:17210
      label: DHX37
  clinical_significance: PATHOGENIC
  identifiers:
  - "c.1000C>T"
  evidence:
  - reference: PMID:39659563
    reference_title: "Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous (likely) pathogenic missense variants in DHX37 (p.Arg334Trp
      and p.Arg308Gln) were found in three participants.
    explanation: >-
      Documents the allele in a selected multicenter bilateral-regression cohort, not population
      screening.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:42510869
    reference_title: "Novel and Known DHX37 Variants in 46,XY DSD: Expanding the Genotypic and Phenotypic Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      According to ACMG/AMP guidelines, p.Arg334Trp was classified as
      pathogenic,
    explanation: >-
      Source for the PATHOGENIC clinical_significance on this record.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: DHX37 p.Gly478Arg
  description: >-
    Variant of uncertain significance reported in a boy with a regression phenotype and inherited
    from an unaffected mother. The later six-case series includes the same patient and is not an
    independent recurrence. Computational predictions do not resolve pathogenicity.
  gene:
    preferred_term: DHX37
    term:
      id: hgnc:17210
      label: DHX37
  clinical_significance: UNCERTAIN_SIGNIFICANCE
  identifiers:
  - "c.1432G>A"
  evidence:
  - reference: PMID:37717579
    reference_title: "Two Novel Heterozygous Variants in RecA2 Domain of DHX37 Cause 46,XY Gonadal Dysgenesis and Testicular Regression Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both variants were classified as VUS (PM1 + PM2 + PP3) according to the
      recommendation of the ACMG guidelines.
    explanation: >-
      Source for the UNCERTAIN_SIGNIFICANCE on this record, with the ACMG
      criteria applied.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:42510869
    reference_title: "Novel and Known DHX37 Variants in 46,XY DSD: Expanding the Genotypic and Phenotypic Spectrum."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of these, p.Arg334Trp is an established pathogenic variant; p.Gly478Arg
      has been reported previously, albeit in the same patient included in the
      present study; and the remaining four were novel.
    explanation: >-
      Bears on the weight of evidence rather than on the allele's existence: the
      later series reporting it turned out to include the same patient as the
      original report, so the apparent second observation is not an additional
      family. INDIRECT because the count of independent families follows from
      the sentence rather than being stated by it.
    quote_role: PRIMARY_RESULT
- name: DHX37 p.Arg390His
  description: >-
    RecA1-domain variant reported in an individual with complete gonadal dysgenesis. Later variant
    summaries classify it as uncertain significance; a rare-variant observation and computational
    prediction alone are insufficient to establish pathogenicity.
  gene:
    preferred_term: DHX37
    term:
      id: hgnc:17210
      label: DHX37
  clinical_significance: UNCERTAIN_SIGNIFICANCE
  evidence:
  - reference: PMID:34293745
    reference_title: "Expanding DSD Phenotypes Associated with Variants in the DEAH-Box RNA Helicase DHX37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A novel p.R390H variant within the RecA1 domain was identified in a girl
      with complete gonadal dysgenesis.
    explanation: >-
      The single reported observation of this allele, at the complete-dysgenesis
      pole.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:38769888
    reference_title: Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders of sex development.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      c.1169G>A(p.R390H) | 0.00000399 | Damaging (0) | Deleterious (−4.964) | Probably damaging (1)
      | Disease causing | VUS
    explanation: >-
      Table 1 classifies Arg390His as VUS in a literature variant summary.
diagnosis:
- name: Karyotype
  diagnosis_term:
    preferred_term: Karyotyping
    term:
      id: NCIT:C16768
      label: Karyotyping
  description: >-
    Chromosome analysis establishes a 46,XY complement and evaluates a possible sex-chromosome mosaic
    differential. The sensitivity for low-level or tissue-limited mosaicism depends on the specimen,
    cell count and method. Cytogenetic or genomic follow-up is guided by the presentation.
  evidence:
  - reference: PMID:37717579
    reference_title: Two Novel Heterozygous Variants in RecA2 Domain of DHX37 Cause 46,XY Gonadal Dysgenesis and Testicular Regression Syndrome.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Case 2 (13.5-year-old girl) had a 46,XY karyotype with female external genitalia and was diagnosed
      as GD.
    explanation: >-
      The case evaluation documents karyotyping in a patient with a DHX37 VUS; the test establishes
      chromosome complement rather than variant pathogenicity.
- name: Gonadal function testing
  diagnosis_term:
    preferred_term: Diagnostic Procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  description: >-
    Interpret FSH, LH, testosterone, AMH and inhibin B against age-appropriate ranges and the clinical
    examination. Selected hCG testing can characterize Leydig-cell function but is not required in every
    case. Low markers or a blunted response indicate impaired function without necessarily proving absent
    tissue; hormonal testing cannot distinguish one from two functioning gonads. NCIT search for "hormone
    stimulation test" found no fitting specific term; this entry also includes basal hormone assays, so
    the broader diagnostic-procedure binding is retained.
  evidence:
  - reference: PMID:37717579
    reference_title: "Two Novel Heterozygous Variants in RecA2 Domain of DHX37 Cause 46,XY Gonadal Dysgenesis and Testicular Regression Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The administration of hCG (1,500 IU/day, intramuscular injection for 3
      days) slightly increased testosterone levels (0.16–0.73 nmol/L), suggesting
      that the gonads had poor testicular function.
    explanation: >-
      The response in this VUS carrier indicates poor residual testicular function, not complete
      absence of tissue.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      this test is not always necessary, particularly if there is other evidence that a gonad is
      nonfunctional.
    explanation: >-
      GeneReviews qualifies use of hCG stimulation within the broader evaluation.
- name: Pelvic and inguinal imaging
  diagnosis_term:
    preferred_term: Ultrasound Imaging
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  description: >-
    Pelvic and inguinal ultrasound assesses Müllerian structures and gonadal position, with MRI or
    selected exploration when anatomy remains unclear. Small dysgenetic gonads may not be visualized.
    Absence of a uterus does not by itself distinguish regression from partial dysgenesis.
  evidence:
  - reference: PMID:37717579
    reference_title: "Two Novel Heterozygous Variants in RecA2 Domain of DHX37 Cause 46,XY Gonadal Dysgenesis and Testicular Regression Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No obvious gonadal structure was identified on abdominal-pelvic and
      inguinal US. Pelvic US demonstrated no evidence of uterine structures.
    explanation: >-
      Shows the imaging findings used to characterize gonadal and Müllerian
      status in a DHX37 carrier.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: Molecular genetic testing
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    A DSD gene panel including DHX37, or exome/genome analysis with appropriate variant interpretation,
    can establish the gene-defined diagnosis. Clinical findings guide interpretation and the differential.
    A VUS or a likely benign DHX37 allele alongside a pathogenic variant in another gene does not
    confirm SRXY11. Segregation studies and later reanalysis can clarify uncertain findings.
  evidence:
  - reference: PMID:38359811
    reference_title: "DHX37 Variant Is One of the Common Genetic Causes in Japanese Patients with Testicular Regression Syndrome/Partial Gonadal Dysgenesis without Müllerian Derivatives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic test is helpful in detecting DHX37-related TRS/PGD because of the
      phenotypic diversity of the external genitalia in this disorder.
    explanation: >-
      States that molecular testing rather than phenotype is what identifies
      DHX37-related disease.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:41466375
    reference_title: "A Comprehensive Analysis of Variations in Sex Characteristics Across OMIM."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      Genome-wide sequencing should be prioritized in VSC/DSD diagnostics,
      consistent with current best practices, to improve diagnostic yield
    explanation: >-
      Supports genome-wide rather than targeted sequencing as the diagnostic
      route. INDIRECT because it is a cross-OMIM recommendation for DSD
      generally, not a DHX37-specific finding.
    quote_role: PRIMARY_RESULT
  - reference: PMID:40916030
    reference_title: DHX37 variants in patients with 46,XY disorders or differences of sex development.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      the SOX9 p.(Arg437Cys) and DHX37 p.(Pro428Leu) variants were assessed as likely pathogenic
      and likely benign, respectively
    explanation: >-
      Demonstrates why identifying a rare DHX37 allele is not sufficient to establish causation.
- name: Selected surgical exploration and gonadal histology
  diagnosis_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  description: >-
    Exploration and histology may define tissue that remains anatomically or functionally uncertain and
    inform management of a retained dysgenetic gonad. They are individualized procedures rather than mandatory
    tests in every carrier. Biopsy has sampling limitations and may compromise future gonadal function.
    NCIT "testicular biopsy" resolves to C51894 (Biopsy of Testis), but this combined assessment includes
    exploration and sampling of potentially nontesticular dysgenetic tissue; the broader procedure binding
    preserves that scope.
  evidence:
  - reference: PMID:39659563
    reference_title: "Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histological analysis of two participants with DHX37 variants suggested
      early disruption of gonadal development due to the presence of Müllerian
      remnants in both and undifferentiated gonadal tissue in one.
    explanation: >-
      Shows what gonadal histology contributes to classifying DHX37-related
      disease.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Results may be inaccurate because of biopsy sampling error; gonadal biopsy may harm the future
      growth and development of the gonad.
    explanation: >-
      The overview explicitly qualifies diagnostic biopsy.
treatments:
- name: Testosterone Replacement Therapy
  description: >-
    For individuals seeking androgen-mediated puberty, incremental testosterone replacement can induce
    and sustain pubertal development when endogenous production is inadequate. Dose and timing follow
    growth, hormone results, clinical response and individual goals. Penile response varies; the
    Belgian series documents limited growth in two DHX37 carriers at Tanner G3 and does not establish
    universal adult failure. Short courses in infancy for micropenis are a separate individualized
    decision. Adequate sex-steroid replacement supports adolescent bone accrual. Follow pubertal
    progression, growth, skeletal maturation, hormone results and adverse effects during induction;
    the Endo-ERN guideline describes clinical review every three to six months.
  action_category: THERAPEUTIC
  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
  - preferred_term: Hypogonadism
    term:
      id: HP:0000135
      label: Hypogonadism
  target_mechanisms:
  - target: Reduced Functional Testicular Tissue
    description: >-
      Replaces deficient sex-steroid output according to the individual’s pubertal and longer-term
      goals; it does not restore gonadal tissue.
  evidence:
  - reference: PMID:39659563
    reference_title: "Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Statural growth and pubertal development are adequate with incremental
      doses of testosterone replacement therapy (TRT); however, penile growth is
      often suboptimal
    explanation: >-
      Summarizes the entire bilateral-regression cohort, most of whom did not have a DHX37 variant.
      Genotype-specific numbers and maturational stages require separate interpretation.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Testosterone therapy is typically required to initiate and sustain puberty.
    explanation: >-
      Family-level care guidance applies to those with deficient androgen production and corresponding
      pubertal goals.
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      We found no studies on treatment to induce or sustain puberty in male patients with partial
      gonadal dysgenesis.
    explanation: >-
      The guideline’s systematic review found no male-PGD induction studies; treatment recommendations
      therefore draw on broader hypogonadism evidence and expert practice.
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Regular clinical follow-up is generally performed every 3–6 months to assess the effectiveness
      of testosterone therapy by assessing pubertal and skeletal maturation and height velocity.
    explanation: >-
      Broader hypogonadism guidance, not a DHX37-specific trial or fixed regimen.
- name: Estrogen Replacement Therapy
  description: >-
    For individuals seeking estrogen-mediated puberty, gradual estrogen replacement induces breast
    development and supports bone accrual when gonadal steroid production is inadequate. If a uterus
    is present, progesterone is added after puberty has progressed. Treatment follows the individual’s
    goals and anatomy. Direct DHX37 observations include estradiol induction at age 11.3 years in
    an Arg308Gln carrier and estrogen at age 12 years 2 months in an Arg674Trp carrier; these are
    case-level observations rather than comparative trials. The broader Endo-ERN guideline favors
    17β-estradiol and gradual dose escalation with clinical monitoring; much of its evidence derives
    from other forms of gonadal insufficiency.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Estrogen Replacement Therapy
    term:
      id: NCIT:C15231
      label: Estrogen Replacement Therapy
    therapeutic_agent:
    - preferred_term: estradiol
      term:
        id: CHEBI:23965
        label: estradiol
  target_phenotypes:
  - preferred_term: Hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  - preferred_term: Hypogonadism
    term:
      id: HP:0000135
      label: Hypogonadism
  target_mechanisms:
  - target: Reduced Functional Testicular Tissue
    description: >-
      Replaces deficient sex-steroid output according to the individual’s pubertal and longer-term
      goals; it does not restore gonadal tissue.
  evidence:
  - reference: PMID:39659563
    reference_title: 'Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      At the age of 11.3 years, puberty induction was started with incremental estradiol doses.
    explanation: >-
      The sentence describes DHX37-positive participant 2, who carried maternally inherited Arg308Gln.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      If the affected individual has a uterus, progesterone will be added once puberty has progressed
      in order to promote menstrual cycles.
    explanation: >-
      The full overview supplies the anatomy- and puberty-dependent progestogen guidance.
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      We recommend to use 17β-oestradiol for puberty induction or to sustain puberty in girls
    explanation: >-
      Endo-ERN recommends physiologic estradiol for those pursuing estrogen-mediated puberty. Much
      of the supporting evidence comes from Turner syndrome rather than DHX37-related disease.
- name: Gonadal Surgery
  description: >-
    Decisions depend on gonadal function, histology, location and tumor concern. Removal of nonfunctioning
    dysgenetic gonads may be appropriate; potentially functioning retained gonads may instead be
    positioned for examination and monitored after individualized counseling. Surveillance has limitations
    and no validated DHX37-specific protocol. Management of a fibrotic regression remnant is a separate
    question from a retained dysgenetic testis. Prostheses are optional and discussed according to
    the individual’s preferences.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: gonadectomy (bilateral orchiectomy)
    term:
      id: NCIT:C15288
      label: Orchiectomy
  evidence:
  - reference: PMID:39659563
    reference_title: 'Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      we would propose planning resection of gonadal remnants only in cases where gonadal dysgenesis
      is suspected, due to the risk for gonadal germ cell cancer.
    explanation: >-
      The cohort authors distinguish suspected dysgenesis from a typically virilized regression presentation.
      This is a clinical recommendation, not a trial result.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Depending on the specific diagnosis, potentially functional gonads may be retained with appropriate
      surveillance for tumor development.
    explanation: >-
      The overview supports individualized preservation of potentially functioning gonads.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      There are no current guidelines on surveillance; one option would be yearly ultrasound of the
      gonad.
    explanation: >-
      The chapter presents ultrasound as an option without an established surveillance guideline;
      this must not be represented as a validated DHX37 screening protocol.
  target_phenotypes:
  - preferred_term: Germ cell neoplasia
    term:
      id: HP:0100728
      label: Germ cell neoplasia
  notes: >-
    Tumour-risk figures specific to DHX37-related gonads have not been published;
    risk estimates are extrapolated from 46,XY gonadal dysgenesis generally.
    Do not quote a DHX37-specific gonadoblastoma risk.
- name: Genetic Counseling
  description: >-
    Explain sex-limited expression, variable severity, incomplete penetrance in 46,XY carriers and
    the distinction between an established variant and a VUS. A heterozygous parent has a 50% chance
    of transmitting the allele in each pregnancy, which is not a 50% chance of an affected child.
    Parental testing informs recurrence counseling; negative blood testing cannot exclude germline
    mosaicism. Once a familial pathogenic variant is established, testing of relatives and reproductive
    testing options can be discussed. NEDBAVC is a distinct allelic disorder with variant-dependent
    inheritance.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf
    reference_title: https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      the presence of the p.Arg308Gln variant in the asymptomatic father
    explanation: >-
      The familial cohort documents an unaffected father transmitting the recurrent allele; the surrounding
      segregation analysis also records maternal and de novo inheritance.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      the risk to sibs of inheriting the genetic alteration is 50%.
    explanation: >-
      This is the transmission probability in a heterozygous family, modified by sex-limited expression
      and incomplete penetrance documented in DHX37-specific cohorts.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      to sibs is low but greater than that of the general population
    explanation: >-
      In the GeneReviews paragraph on a variant not detected in either parent’s leukocyte DNA, this
      clause describes residual sibling recurrence risk; the surrounding paragraph attributes it
      to possible parental germline mosaicism.
- name: Multidisciplinary DSD Supportive Care
  description: >-
    Provide ongoing endocrine, urologic/gynecologic, genetics and psychological care, with age-appropriate
    explanation and active participation in decisions. Sex of rearing does not determine later identity
    or treatment preferences. Three DHX37 carriers in one selected cohort reported male, female and
    non-binary identities; these observations are not predictive probabilities. Discuss sex-steroid
    effects, fertility implications, body image and transition to adult care. Nonessential irreversible
    genital procedures should be considered in a process that enables the affected individual to
    participate.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:39659563
    reference_title: "Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The three participants with a DHX37 variant developed a male, female, and
      non-binary gender identity, respectively; all other participants identified
      as males.
    explanation: >-
      Documents the heterogeneous gender-identity outcomes in DHX37 carriers
      relative to the rest of the cohort.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:39659563
    reference_title: "Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      sufficient and understandable information regarding the effects and side
      effects of TRT is required throughout the management of these patients
    explanation: >-
      The authors' explicit care recommendation arising from their
      quality-of-care findings.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Many surgeries are not medically necessary and thus consideration should be given to delaying
      surgery in order to allow the affected individual to participate in the decision-making process.
    explanation: >-
      The overview supports participation in decisions about nonessential irreversible procedures.
- name: Fertility counseling
  description: >-
    Assess reproductive potential according to residual gonadal tissue and function, without assuming
    infertility in every variant carrier. Azoospermia is documented in a pathogenic-variant carrier.
    For individuals with a uterus, pregnancy through oocyte donation is a broader DSD care option
    rather than a demonstrated DHX37-specific treatment outcome.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: Fertility and Reproductive Counseling
    term:
      id: NCIT:C171451
      label: Fertility and Reproductive Counseling
  evidence:
  - reference: url:https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867
    reference_title: https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      has high levels of FSH (34.5 IU/L) and LH (12 IU/L) and presented with azoospermia.
    explanation: >-
      The Arg308Gln-positive patient had azoospermia at age 21, supporting impaired sperm production;
      infertility is not inferred for every carrier.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/
    reference_title: Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      may become pregnant through oocyte donation.
    explanation: >-
      Family-level reproductive option dependent on anatomy; no DHX37-specific outcome is asserted.
animal_models:
- name: Sertoli-cell conditional Dhx37 knockout mouse
  species: Mouse
  genotype: Dhx37 flox/flox; Amh-Cre (Sertoli-cell conditional knockout)
  publication: PMID:41535247
  description: >-
    Sertoli-cell conditional deletion with Amh-Cre beginning at embryonic day 12.5, after mouse male-sex
    determination. Adult P60/approximately eight-week readouts include smaller testes, reduced sperm
    and testosterone, infertility, seminiferous-tubule abnormalities, nucleolar fragmentation, altered
    junction proteins and increased apoptosis. Cell-culture RIP-seq and RNAi experiments from the
    same paper are recorded separately. No human-allele knock-in, fetal sex-reversal experiment or
    demonstration of absent testes was performed. Secondary Leydig-cell hormone changes in a Sertoli-targeted
    model do not establish Leydig-autonomous DHX37 deficiency.
  modeled_mechanisms:
  - target: Nucleolar Structural Disruption
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Demonstrates this experimental consequence of conditional Dhx37 loss in the testicular supporting-cell
      compartment.
    limitations: >-
      Electron microscopy and fibrillarin staining measure architecture; they do not directly quantify
      pre-rRNA processing or 40S output.
    readouts:
    - name: Sertoli-cell nucleolar architecture
      target: Nucleolar Structural Disruption
      direction: ALTERED
      interpretation: >-
        Measured experimental phenotype; extrapolation to human SRXY11 is limited by allele, timing
        and species.
      evidence:
      - reference: PMID:41535247
        reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
        supports: SUPPORT
        directness: DIRECT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        snippet: >-
          Dhx37 deficiency caused nucleolar fragmentation, rupture, and marked size reduction in
          Sertoli
          cells
        explanation: >-
          Transmission electron microscopy directly demonstrates nucleolar structural disruption
          in the
          Sertoli-targeted knockout mouse.
    evidence:
    - reference: PMID:41535247
      reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        Dhx37 deficiency caused nucleolar fragmentation, rupture, and marked size reduction in Sertoli
        cells
      explanation: >-
        Transmission electron microscopy directly demonstrates nucleolar structural disruption in
        the
        Sertoli-targeted knockout mouse.
  - target: p53 Accumulation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Demonstrates this experimental consequence of conditional Dhx37 loss in the testicular supporting-cell
      compartment.
    limitations: >-
      No p53-inhibition or rescue experiment establishes necessity. Proposed FBL or ribosomal-protein
      interactions with MDM2 were not directly assayed.
    readouts:
    - name: p53 and p21 abundance
      target: p53 Accumulation
      direction: INCREASED
      interpretation: >-
        Measured experimental phenotype; extrapolation to human SRXY11 is limited by allele, timing
        and species.
      evidence:
      - reference: PMID:41535247
        reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
        supports: SUPPORT
        directness: DIRECT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        snippet: >-
          p53 and its downstream effector p21 were up-regulated, while the pro-apoptotic markers
          BAX
          and cleaved caspase-3 accumulated
        explanation: >-
          Protein measurements support p53-associated stress signaling in knockout testes. Neither
          p53
          rescue nor requirement for the phenotype was tested.
    evidence:
    - reference: PMID:41535247
      reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        p53 and its downstream effector p21 were up-regulated, while the pro-apoptotic markers BAX
        and cleaved caspase-3 accumulated
      explanation: >-
        Protein measurements support p53-associated stress signaling in knockout testes. Neither
        p53
        rescue nor requirement for the phenotype was tested.
  - target: Sertoli Cell Apoptosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Demonstrates this experimental consequence of conditional Dhx37 loss in the testicular supporting-cell
      compartment.
    limitations: >-
      Adult conditional-null tissue differs from heterozygous human missense disease; the model does
      not establish fetal regression.
    readouts:
    - name: SOX9-associated TUNEL signal
      target: Sertoli Cell Apoptosis
      direction: INCREASED
      interpretation: >-
        Measured experimental phenotype; extrapolation to human SRXY11 is limited by allele, timing
        and species.
      evidence:
      - reference: PMID:41535247
        reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
        supports: SUPPORT
        directness: DIRECT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        snippet: >-
          TUNEL assay (green) combined with SOX9 immunostaining (red) demonstrates a pronounced increase
          in apoptotic cells in Dhx37−/− testes.
        explanation: >-
          Adult P60 mouse testis sections document increased apoptosis in the Sertoli-cell compartment
          after conditional deletion. This is not an observation in fetal human variant-bearing gonads.
    evidence:
    - reference: PMID:41535247
      reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        TUNEL assay (green) combined with SOX9 immunostaining (red) demonstrates a pronounced increase
        in apoptotic cells in Dhx37−/− testes.
      explanation: >-
        Adult P60 mouse testis sections document increased apoptosis in the Sertoli-cell compartment
        after conditional deletion. This is not an observation in fetal human variant-bearing gonads.
  - target: Reduced Sertoli Cell Proliferation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Demonstrates this experimental consequence of conditional Dhx37 loss in the testicular supporting-cell
      compartment.
    limitations: >-
      Adult proliferation markers do not measure initial fetal sex determination.
    readouts:
    - name: Sertoli-compartment Ki67 staining
      target: Reduced Sertoli Cell Proliferation
      direction: DECREASED
      interpretation: >-
        Measured experimental phenotype; extrapolation to human SRXY11 is limited by allele, timing
        and species.
      evidence:
      - reference: PMID:41535247
        reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
        supports: SUPPORT
        directness: DIRECT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        snippet: >-
          we observed a marked attenuation of Sertoli proliferation in Dhx37 mice
        explanation: >-
          Ki67 staining supports reduced proliferative activity in the knockout Sertoli-cell compartment,
          distinct from increased cell death.
    evidence:
    - reference: PMID:41535247
      reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        we observed a marked attenuation of Sertoli proliferation in Dhx37 mice
      explanation: >-
        Ki67 staining supports reduced proliferative activity in the knockout Sertoli-cell compartment,
        distinct from increased cell death.
differential_diagnoses:
- name: Non-genetic bilateral testicular regression (perinatal vascular accident)
  description: >-
    Bilateral testicular regression may have a non-genetic or unresolved cause. Gestational complications
    and discordant monozygotic twins support environmental contributions in some cases. Typical external
    virilization and less marked microphallus can be clues, but a negative DHX37 test does not prove
    a vascular cause or exclude another genetic etiology.
  evidence:
  - reference: PMID:39659563
    reference_title: "Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An environmental origin in some participants is supported by the high
      incidence of gestational complications (38.2%) and by the three
      monozygotic twin pregnancies discordant for the BTR phenotype.
    explanation: >-
      The selected Belgian series supports environmental contributions in some participants; three
      of 34 analyzable participants carried a DHX37 variant.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: 46,XY gonadal dysgenesis due to other genes
  description: >-
    Variants involving SRY, NR5A1, DMRT1, MAP3K1, DHH, SOX9 and other genes can produce overlapping
    gonadal phenotypes. Molecular diagnosis can alter associated-risk assessment, for example renal
    and Wilms tumor risk in WT1-related disease. Adrenal insufficiency is rare in NR5A1-related DSD
    and is not assumed for every carrier.
  evidence:
  - reference: PMID:38359811
    reference_title: "DHX37 Variant Is One of the Common Genetic Causes in Japanese Patients with Testicular Regression Syndrome/Partial Gonadal Dysgenesis without Müllerian Derivatives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Previously described pathogenic variants or novel nonsense variants (SRY,
      NR5A1, and DMRT1) were observed in four out of 10 families.
    explanation: >-
      Shows the alternative monogenic causes found in the same clinical
      population.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: 46,XY sex reversal 5 (CBX2-related)
  disease_term:
    preferred_term: 46,XY sex reversal 5
    term:
      id: MONDO:0013120
      label: 46,XY sex reversal 5
  description: >-
    CBX2-related DSD can overlap the genital and gonadal spectrum. The reported CBX2.1 patient had
    histologically normal ovaries, whereas two CBX2.2 cases had dysgenetic testes or no gonadal tissue.
    The distinction is molecular; Müllerian retention and absent gonadal tissue are not unique to
    either gene.
  distinguishing_features:
  - Pathogenic CBX2 variation rather than DHX37 variation
  - The CBX2.1 index case had histologically normal ovarian tissue; this has not been established in the cited DHX37 cohorts
  - CBX2.2-associated dysgenetic or absent gonadal tissue can overlap SRXY11
  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 normal ovarian histology in the CBX2.1 index case without claiming a universal exclusion
      rule for DHX37.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - 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: >-
      The CBX2.2 gonadal finding, quoted to show that this arm falls inside the
      SRXY11 gonadal range rather than contrasting with it.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: Bilateral cryptorchidism with viable testes
  description: >-
    Nonpalpable but retained testes can resemble anorchia at examination. Hormonal testing, imaging
    and selected exploration assess tissue location and function; present dysgenetic testes may also
    have low hormone output.
  evidence:
  - reference: PMID:39659563
    reference_title: "Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It has a similar presentation as the more common undescended testicles,
      which can pose difficulties for physicians in diagnosing the condition.
    explanation: >-
      States that undescended testes are the clinically confusable alternative.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: DHX37-related neurodevelopmental disorder (NEDBAVC)
  description: >-
    A distinct allelic disorder with brain and neurodevelopmental abnormalities and possible cardiac
    or vertebral anomalies. Biallelic and de novo heterozygous DHX37 variants have been reported.
    The presence of a DHX37 variant in a syndromic individual requires interpretation of allele,
    inheritance and possible alternative diagnoses rather than automatic assignment to SRXY11.
  evidence:
  - reference: PMID:35835064
    reference_title: "DHX37 and 46,XY DSD: A New Ribosomopathy?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      compound heterozygous as well as de novo heterozygous missense variants in
      DHX37 are also associated with a complex congenital developmental syndrome
      (NEDBAVC, neurodevelopmental disorder with brain anomalies and with or
      without vertebral or cardiac anomalies; OMIM 618731)
    explanation: >-
      Establishes the allelic neurodevelopmental disorder as a separate entity.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:34293745
    reference_title: "Expanding DSD Phenotypes Associated with Variants in the DEAH-Box RNA Helicase DHX37."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A paternally inherited p.R487H variant, previously associated with a
      recessive congenital developmental syndrome, was carried by a boy with a
      syndromic form of 46,XY DSD. His phenotype may be explained in part by a
      novel homozygous loss-of-function variant in the NGLY1 gene, which causes
      a congenital disorder of deglycosylation.
    explanation: >-
      The boundary case between this entry and NEDBAVC, and a phenocopy caution
      in one. A DHX37 allele previously tied to the recessive neurodevelopmental
      syndrome turned up in a boy with syndromic 46,XY DSD, but a second,
      homozygous loss-of-function variant in an unrelated gene may explain his
      phenotype in part. Finding a DHX37 variant in a syndromic patient is
      therefore not sufficient to call this disease: it may be a NEDBAVC allele,
      or the phenotype may be driven by something else entirely.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
discussions:
- discussion_id: dhx37_tissue_specificity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How does disruption of DHX37, a housekeeping nucleolar helicase needed for
    ribosome biogenesis in every cell, produce a phenotype restricted to the
    gonad and expressed only in 46,XY individuals?
  attaches_to:
  - pathophysiology#Impaired Small Ribosomal Subunit Biogenesis
  - pathophysiology#Nucleolar Structural Disruption
  rationale: >-
    DHX37 has broad cellular roles, while specific variants are associated with testicular-development
    disease. The clinical genetic evidence is stronger than the proposed universal ribosome-stress
    mechanism. Selected variants alter protein abundance or beta-catenin in overexpression systems,
    whereas Ser408Leu does not increase p53 or apoptosis relative to wild type. The Glu257Lys VUS
    was functionally negative in the reported assays and co-occurred with a likely pathogenic NR5A1
    variant; that case does not demonstrate an undetectable disease mechanism. Patient gonadal pre-rRNA/40S
    measurements and allele-matched developmental models remain gaps.
  evidence:
  - reference: PMID:38142677
    reference_title: "DHX37 and the Implications in Disorders of Sex Development: An Update Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The trick question regarding DHX37 is how a helicase involved in basic cell
      function could have a specific role in testis development.
    explanation: >-
      States this knowledge gap as the field's central open question.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:37065748
    reference_title: A novel DEAH-box helicase 37 mutation associated with differences of sex development.
    supports: REFUTE
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      there is no difference in p53 expression among cells transfected with empty expressing vector,
      wt-DHX37, or mutant DHX37.
    explanation: >-
      The Ser408Leu assay does not support a universal variant-induced increase in p53. It does not
      refute the distinct conditional-null mouse result.
  - reference: PMID:42057034
    reference_title: Comprehensively identifying and validating the implications of NR5A1 and DHX37 variants for 46,XY disorders of sex development diagnosis.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      The other c.769G > A variant of DHX37 had no significant effect on the expression level and
      cellular localization of DHX37, and the downstream signaling pathway of DHX37.
    explanation: >-
      The tested Glu257Lys VUS showed no change in protein abundance/localization or beta-catenin/p53
      readouts. This does not establish pathogenicity or test every possible function.
- discussion_id: dhx37_expression_compartment
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How do developmental stage and assay influence the observed testicular distribution of DHX37?
  attaches_to:
  - genetic#DHX37
  - animal_models#Sertoli-cell conditional Dhx37 knockout mouse
  rationale: >-
    The apparent disagreement is partly resolved by the full texts. McElreavey and colleagues report
    fetal somatic-cell localization and explicitly report adult spermatogonial expression. The da
    Silva series includes late fetal, neonatal and adult specimens and observes germ-cell/Leydig
    staining with rare weak Sertoli staining. These stage- and assay-dependent observations do not
    establish a mutually exclusive somatic-versus-germ-cell mechanism. Expression outside the gonad
    also precludes interpreting fetal somatic localization as whole-body gonad specificity.
  evidence:
  - reference: PMID:31337883
    reference_title: Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Although expression was not observed in germ cells in fetal gonads, in adult human testes the
      protein is mainly localized in spermatogonia
    explanation: >-
      Immunolocalization in normal fetal versus adult human testis demonstrates a developmental-stage
      difference; this is not a measurement in affected patient gonads.
  - reference: PMID:31287541
    reference_title: Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Immunohistochemistry analysis in human testis showed that DHX37 is mainly expressed in germ
      cells at different stages of testis maturation, in Leydig cells, and rarely in Sertoli cells.
    explanation: >-
      The study examined later fetal, neonatal and adult specimens; its compartment findings are
      interpreted alongside early fetal localization rather than as a direct contradiction.
- discussion_id: dhx37_regression_versus_dysgenesis
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How do dysgenesis and subsequent tissue regression overlap across DHX37-related disease?
  attaches_to:
  - pathophysiology#Testicular Regression
  - pathophysiology#Impaired Testicular Development
  rationale: >-
    Cohort definitions differ. The Belgian histology supports early dysgenesis with Müllerian remnants,
    while other series enroll individuals without Müllerian derivatives. Neither observation excludes
    a shared developmental-and-maintenance spectrum. A pathogenic-variant carrier with loss of palpable
    testes during childhood provides direct longitudinal evidence for postnatal regression. Hormone
    action, anatomy and histology need to be interpreted together rather than assigning a universal
    gestational timing from a diagnostic label.
  evidence:
  - reference: PMID:39659563
    reference_title: "Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histological analysis confirmed DHX37 as a gonadal development, rather than
      a BTR-related, gene.
    explanation: >-
      The histology-based argument that DHX37 disease is developmental rather
      than regressive.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:38359811
    reference_title: "DHX37 Variant Is One of the Common Genetic Causes in Japanese Patients with Testicular Regression Syndrome/Partial Gonadal Dysgenesis without Müllerian Derivatives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DHX37 variant is one of the common genetic causes in Japanese patients with
      TRS/PGD without Müllerian derivatives.
    explanation: >-
      An ascertainment-defined series without Müllerian derivatives demonstrates another part of
      the clinical spectrum, not a refutation of the Belgian histology.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:40916030
    reference_title: DHX37 variants in patients with 46,XY disorders or differences of sex development.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      However, patient 1 exhibited progressive postnatal gonadal disappearance.
    explanation: >-
      A patient with pathogenic Arg334Trp had palpable inguinal testes in early childhood followed
      by their disappearance, demonstrating that regression is not confined to fetal life.
- discussion_id: dhx37_allele_mechanism_model_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Which consequences of a Sertoli-cell conditional null model also occur with heterozygous human
    DHX37 missense variants?
  attaches_to:
  - animal_models#Sertoli-cell conditional Dhx37 knockout mouse
  - pathophysiology#DHX37 Missense Variation
  rationale: >-
    Amh-Cre deletion begins after initial sex determination and adult knockout findings test maintenance
    of a formed testis. The model does not establish early human sex reversal, a shared missense
    mechanism or p53 necessity. Variant-specific abundance and signaling assays also differ from
    null perturbations. A heterozygous allele-matched developmental model with appropriate dosage
    controls would help test which pathways mediate the human phenotype.
  proposed_experiments:
  - experiment_id: dhx37_r308q_knockin_mouse
    name: Knock-in of a recurrent human DHX37 missense allele in mouse
    description: >-
      Generate a mouse carrying the orthologue of p.Arg308Gln or p.Arg674Trp in
      the heterozygous state and assess fetal gonadal development, Müllerian
      regression, external genital masculinization, and postnatal gonadal
      presence, alongside nucleolar integrity and p53 activation in gonadal
      supporting cells.
    would_support:
    - pathophysiology#DHX37 Missense Variation
    - pathophysiology#Nucleolar Structural Disruption
    supporting_outcome:
    - >-
      A heterozygous allele reproduces a gonadal phenotype together with the proposed cellular change;
      comparison with heterozygous null animals and pathway rescue helps distinguish dosage effects
      from other mechanisms.
    refuting_outcome:
    - >-
      Absence of the proposed molecular change or failure of pathway rescue would weaken that particular
      mechanism. A phenotypically normal mouse would limit this model without excluding human pathogenicity
      or proving a species-specific mechanism.
  evidence:
  - reference: PMID:41535247
    reference_title: "Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In the Dhx37-/- mice, we observed pronounced defects, including diminished
      testicular volume, lower testosterone levels, and marked vacuolization of
      the seminiferous tubules.
    explanation: >-
      The knockout phenotype is a hypoplastic but formed testis with
      spermatogenic failure, not the failed determination or fetal gonadal loss
      seen in humans — which is the mismatch this discussion records.
    quote_role: PRIMARY_RESULT
- discussion_id: dhx37_long_term_outcomes
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What are the long-term outcomes of DHX37-related 46,XY DSD — germ-cell
    tumour risk in retained dysgenetic tissue, bone and cardiovascular health on
    lifelong replacement, and gender-identity trajectories?
  attaches_to:
  - pathophysiology#Reduced Functional Testicular Tissue
  rationale: >-
    Published case-level follow-up now documents hormone replacement, postnatal regression, azoospermia
    and a germ-cell-neoplasia-in-situ observation. These findings do not supply a genotype-specific
    tumor-risk estimate or robust comparative treatment outcomes. General DSD guidance informs care,
    with clear separation from DHX37-specific observations. The three gender-identity observations
    in the Belgian series should not be used as predictive proportions.
  evidence:
  - reference: PMID:40026690
    reference_title: "Profile of DHX37 gene defects in human genetic diseases: 46,XY disorders of sex development."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The treatments are primarily surgical intervention and hormone replacement
      therapy administered at appropriate times; however, the long-term prognosis
      remains unknown.
    explanation: >-
      A review identifies limited long-term outcome knowledge; this does not mean that no case-level
      follow-up exists.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- discussion_id: dhx37_uncertain_mild_phenotypes
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Do the uncertain variants reported with mild gynecomastia or another established DSD genotype contribute to disease?
  attaches_to:
  - genetic#DHX37
  rationale: >-
    Five of six variants in the 2026 series were VUS. Its gynecomastia observations include a patient
    who did not meet DSD criteria, and the Gly478Arg case repeats a previously published individual.
    The 2023 double-variant series includes NR5A1 loss-of-function alleles with DHX37 Leu467Val (VUS)
    or Val999Met (likely benign), so co-occurrence does not establish digenic causation. These observations
    are retained as interpretation gaps instead of established phenotype frequencies.
  evidence:
  - reference: PMID:42510869
    reference_title: 'Novel and Known DHX37 Variants in 46,XY DSD: Expanding the Genotypic and Phenotypic Spectrum.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      According to ACMG/AMP guidelines, p.Arg334Trp was classified as pathogenic, and the remaining
      five as variants of uncertain significance.
    explanation: >-
      The classifications limit what can be attributed to the gene from this six-case series.
  - reference: url:https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867
    reference_title: https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      no in vitro studies have been performed to determine its pathogenicity and possible correlation
      with DSD.
    explanation: >-
      The full discussion cautions about Val999Met; no measured synergistic effect with NR5A1 was
      demonstrated.
notes: >-
  This gene-defined entry spans the DHX37 gonadal-dysgenesis/regression spectrum, while the partial- and
  complete-gonadal-dysgenesis entries organize overlapping clinical phenotypes across genes. MONDO:8000015
  is retained as the established SRXY11 binding despite its placement under complete gonadal dysgenesis;
  that ontology placement should not erase documented partial or regression presentations. General testicular-regression
  synonyms are not treated as exact synonyms of the DHX37 entity. Population prevalence is unknown; selected-cohort
  yields are recorded separately. The full GeneReviews family overview informs care, while disease-specific
  primary cohorts and experimental papers define the limits of genotype and mechanism claims. Ontology
  review: HP:0031103 currently has the canonical label "Decreased circulating antimullerian hormone circulation"
  in live HPO; the clearer source-facing preferred term is retained. HPO search for "Absent puberty" found
  no exact term; sex-steroid treatment targets are instead bound to Hypogonadism, avoiding an absent-versus-delayed
  puberty equivalence.
experimental_models:
- name: DHX37 Ser408Leu human Sertoli-cell overexpression
  experimental_model_type: CELL_LINE
  description: >-
    Transient wild-type or Ser408Leu DHX37 overexpression in a human Sertoli cell line, compared
    with empty vector. Variant RNA and protein are lower than wild type; localization is similar.
    Beta-catenin abundance is higher than with wild-type overexpression, p53 is unchanged, and variant-associated
    apoptosis is lower than with wild type.
  organism: &id001
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:37065748
  modeled_mechanisms:
  - target: Altered Beta-Catenin Abundance
    relationship: RECAPITULATES
    fidelity: LOW
    description: >-
      Provides a defined experimental readout relevant to this candidate mechanism.
    limitations: >-
      Overexpression is not a heterozygous patient-derived system. No direct helicase, ATPase, pre-rRNA,
      WNT-transcriptional or fetal-fate assay was performed. Later summaries classify Ser408Leu as
      VUS.
    readouts:
    - name: Beta-catenin abundance relative to wild-type overexpression
      target: Altered Beta-Catenin Abundance
      direction: INCREASED
      interpretation: >-
        The result is specific to the assayed perturbation and cell context.
      evidence:
      - reference: PMID:37065748
        reference_title: A novel DEAH-box helicase 37 mutation associated with differences of sex development.
        supports: SUPPORT
        directness: INDIRECT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: >-
          transfection with wt-DHX37 led to a significant decrease of the β-catenin protein, which
          was
          rescued by the mutant DHX37.
        explanation: >-
          In an overexpression assay, Ser408Leu fails to reproduce the wild-type reduction in beta-catenin
          abundance. This is not direct evidence of canonical WNT activation or ovarian fate in an
          embryonic
          gonad.
    evidence:
    - reference: PMID:37065748
      reference_title: A novel DEAH-box helicase 37 mutation associated with differences of sex development.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        transfection with wt-DHX37 led to a significant decrease of the β-catenin protein, which
        was
        rescued by the mutant DHX37.
      explanation: >-
        In an overexpression assay, Ser408Leu fails to reproduce the wild-type reduction in beta-catenin
        abundance. This is not direct evidence of canonical WNT activation or ovarian fate in an
        embryonic
        gonad.
- name: DHX37 variant transfection in HEK293T and COS7 cells
  experimental_model_type: CELL_LINE
  description: >-
    Arg308Gln and Arg671Thr constructs were tested for protein abundance in HEK293T cells and localization
    in COS7 cells. Both had reduced protein abundance and no detected localization change.
  organism: *id001
  publication: PMID:38769888
  modeled_mechanisms:
  - target: Reduced DHX37 Abundance
    relationship: RECAPITULATES
    fidelity: LOW
    description: >-
      Provides a defined experimental readout relevant to this candidate mechanism.
    limitations: >-
      HEK293T is human whereas COS7 is a nonhuman primate kidney-derived line; the organism annotation
      applies to the abundance assay. These are not gonadal or patient-derived cells. Arg671Thr is
      called pathogenic in the narrative but VUS in Table 1.
    readouts:
    - name: DHX37 protein abundance
      target: Reduced DHX37 Abundance
      direction: DECREASED
      interpretation: >-
        The result is specific to the assayed perturbation and cell context.
      evidence:
      - reference: PMID:38769888
        reference_title: Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders of sex development.
        supports: SUPPORT
        directness: DIRECT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: >-
          compared with the cells transfected with pcDNA3.1‐WT, those with pcDNA3.1‐Arg308Gln and
          pcDNA3.1‐Arg671Thr
          displayed a lower level of DHX37
        explanation: >-
          Western blots in transfected HEK293T cells show reduced protein abundance for these constructs;
          enzymatic activity and patient gonadal abundance were not measured. The paper inconsistently
          labels Arg671Thr pathogenic in prose and VUS in Table 1.
    evidence:
    - reference: PMID:38769888
      reference_title: Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders of sex development.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        compared with the cells transfected with pcDNA3.1‐WT, those with pcDNA3.1‐Arg308Gln and pcDNA3.1‐Arg671Thr
        displayed a lower level of DHX37
      explanation: >-
        Western blots in transfected HEK293T cells show reduced protein abundance for these constructs;
        enzymatic activity and patient gonadal abundance were not measured. The paper inconsistently
        labels Arg671Thr pathogenic in prose and VUS in Table 1.
- name: Dhx37 knockdown in mouse TM4 Sertoli cells
  experimental_model_type: CELL_LINE
  description: >-
    Mouse TM4 RNAi, RNA-seq and RIP-seq assess transcript abundance, splicing and RNA associations
    after Dhx37 depletion. Enrichment of PI3K-AKT-associated transcripts is not a direct measurement
    of pathway activity. RIP-seq used one immunoprecipitate and matched input, limiting inference
    about binding reproducibility.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:41535247
  modeled_mechanisms:
  - target: Altered RNA Splicing
    relationship: PERTURBS
    fidelity: LOW
    description: >-
      Dhx37 RNAi alters transcript splicing in a mouse Sertoli-cell line.
    limitations: >-
      Culture findings inform candidate stress pathways; they do not reproduce a human missense genotype,
      test canonical AKT activation or establish MDM2-mediated p53 causality.
    readouts:
    - name: Alternative splicing events after Dhx37 RNAi
      target: Altered RNA Splicing
      direction: ALTERED
      interpretation: >-
        Changed exon usage and intron retention are measured; functional consequences of individual
        splice changes remain untested.
      evidence:
      - reference: PMID:41535247
        reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
        supports: SUPPORT
        directness: DIRECT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: >-
          Dhx37 KD triggered 949 significant AS events
        explanation: >-
          RNA-seq after Dhx37 knockdown in mouse TM4 cells identifies alternative-splicing changes;
          their contribution to human variant-associated gonadal disease remains untested.
      - reference: PMID:41535247
        reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
        supports: SUPPORT
        directness: DIRECT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: >-
          Sashimi plots corroborated Dhx37-dependent alterations in exon usage and intron retention
        explanation: >-
          The primary analysis documents altered exon use and intron retention, not merely pathway
          enrichment.
    evidence:
    - reference: PMID:41535247
      reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Dhx37 KD triggered 949 significant AS events
      explanation: >-
        RNA-seq after Dhx37 knockdown in mouse TM4 cells identifies alternative-splicing changes;
        their contribution to human variant-associated gonadal disease remains untested.
    - reference: PMID:41535247
      reference_title: Multi-omics analysis the effects of Dhx37 deficiency on testis development and nucleolar homeostasis.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Sashimi plots corroborated Dhx37-dependent alterations in exon usage and intron retention
      explanation: >-
        The primary analysis documents altered exon use and intron retention, not merely pathway
        enrichment.
- name: Human DHX37 depletion and catalytic-mutant complementation
  experimental_model_type: CELL_LINE
  description: >-
    HeLa RNAi and HEK293 complementation with RNAi-resistant wild-type or engineered T282A DHX37
    define pre-rRNA processing and small-subunit assembly functions. Wild-type transgene rescues
    processing defects. Purified recombinant-protein experiments independently show RNA-dependent
    ATPase activity and stimulation by directly interacting UTP14A. The catalytic mutant retains
    the protein-presence function that prevents aberrant pre-rRNA turnover, separating that function
    from ATPase-dependent maturation.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:30582406
  modeled_mechanisms:
  - target: Impaired Small Ribosomal Subunit Biogenesis
    relationship: PERTURBS
    fidelity: LOW
    description: >-
      Depletion and catalytic perturbation impair small-subunit maturation; complementation with
      wild-type DHX37 reverses the processing defect.
    limitations: >-
      HeLa and HEK293 cells are not fetal gonadal or patient-derived cells. T282A is engineered,
      not an SRXY11 allele. The study does not test human sex determination, p53 necessity or MDM2
      binding. The exact stage of human U3 release remains unresolved, and UTP14A-depletion effects
      on U3 retention may be secondary to an earlier processing block.
    readouts:
    - name: 40S ribosomal subunit abundance
      target: Impaired Small Ribosomal Subunit Biogenesis
      direction: DECREASED
      interpretation: >-
        40S and 18S output decline while 60S and 28S production are spared after DHX37 depletion.
      evidence:
      - reference: PMID:30582406
        reference_title: The human RNA helicase DHX37 is required for release of the U3 snoRNP from pre-ribosomal particles.
        supports: SUPPORT
        directness: DIRECT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: >-
          depletion of DHX37 does not affect production of 60S subunits but leads to a significant
          decrease in the abundance of 40S particles as well as a decrease in the amount of 80S monosomes
        explanation: >-
          Sucrose-gradient analysis of DHX37-depleted human cultured cells directly measures reduced
          small-subunit abundance; the experiments do not test a human DSD allele.
    - name: 21S-to-18SE pre-rRNA processing
      target: Impaired Small Ribosomal Subunit Biogenesis
      direction: DECREASED
      interpretation: >-
        21S accumulates and 18SE falls after depletion or catalytic T282A complementation. Wild-type
        transgene rescues the processing defect.
      evidence:
      - reference: PMID:30582406
        reference_title: The human RNA helicase DHX37 is required for release of the U3 snoRNP from pre-ribosomal particles.
        supports: SUPPORT
        directness: DIRECT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: >-
          depletion of DHX37 caused accumulation of the 21S pre-rRNA and a concomitant decrease in
          the levels of the 18SE pre-rRNA
        explanation: >-
          Northern blots establish a pre-rRNA processing defect after experimental DHX37 depletion
          in human cells.
      - reference: PMID:30582406
        reference_title: The human RNA helicase DHX37 is required for release of the U3 snoRNP from pre-ribosomal particles.
        supports: SUPPORT
        directness: DIRECT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: >-
          expression of wild-type DHX37 from a transgene can rescue these defects
        explanation: >-
          HEK293 complementation rescues pre-rRNA processing after endogenous DHX37 depletion; engineered
          T282A fails to rescue the 21S-to-18SE defect. This is not rescue of a patient variant or
          gonadal phenotype.
    - name: U3 snoRNA retention on pre-ribosomal complexes
      target: Impaired Small Ribosomal Subunit Biogenesis
      direction: INCREASED
      interpretation: >-
        Catalytic T282A increases pre-ribosome-associated U3 relative to wild-type complementation.
        This supports a release defect without directly measuring duplex unwinding.
      evidence:
      - reference: PMID:30582406
        reference_title: The human RNA helicase DHX37 is required for release of the U3 snoRNP from pre-ribosomal particles.
        supports: SUPPORT
        directness: DIRECT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: >-
          Expression of DHX37T282A lead to a notable increase in the proportion of the U3 snoRNA
          associated with pre-ribosomal complexes
        explanation: >-
          Fractionation and northern blotting show U3 retention with engineered catalytic T282A after
          endogenous DHX37 depletion, rather than a direct purified U3-duplex unwinding assay.
    evidence:
    - reference: PMID:30582406
      reference_title: The human RNA helicase DHX37 is required for release of the U3 snoRNP from pre-ribosomal particles.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        depletion of DHX37 caused accumulation of the 21S pre-rRNA and a concomitant decrease in
        the levels of the 18SE pre-rRNA
      explanation: >-
        Northern blots establish a pre-rRNA processing defect after experimental DHX37 depletion
        in human cells.
    - reference: PMID:30582406
      reference_title: The human RNA helicase DHX37 is required for release of the U3 snoRNP from pre-ribosomal particles.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        expression of wild-type DHX37 from a transgene can rescue these defects
      explanation: >-
        HEK293 complementation rescues pre-rRNA processing after endogenous DHX37 depletion; engineered
        T282A fails to rescue the 21S-to-18SE defect. This is not rescue of a patient variant or
        gonadal phenotype.
review_notes: >-
  All originally cited references and the matching deep-research report were assessed; actual cached
  full bodies, tables and methods were used where available. PMID40026690 is a literature review
  whose pooled 60-case counts include uncertain variants and an infertility-associated frameshift.
  PMID39659563 has 35 recruited but 34 genetically analyzable participants; its two testosterone-treated
  DHX37 carriers were described at Tanner G3, so the broad adult-outcome wording is not treated as
  a genotype-specific adult endpoint. The da Silva primary manuscript reports 7/14 ETRS index cases
  despite an apparent 13-index accounting in its methods; no derived numeric subgroup fraction is
  asserted. PMID34293745’s abstract writes p.T477H, whereas subsequent c.1430C>T summaries identify
  p.Thr477Met; the inconsistent named-variant record is withheld pending primary nomenclature resolution,
  while the reported homozygous case remains acknowledged. PMID38769888 calls Arg671Thr pathogenic
  in prose but VUS in Table 1; protein-expression results are retained without resolving that discrepancy.
  PMID37065748 Table 1 says no Müllerian structures for the younger sibling, while its histology
  and narrative describe fallopian-like structures; histology is kept distinct from imaging and no
  frequency is inferred. PMID42510869 repeats the Gly478Arg case from PMID37717579 and does not establish
  its VUS-only gynecomastia presentations as causal SRXY11. PMID32057790 concerns Turner mosaicism,
  PMID37497464 lacks a DHX37 genotype, and PMID42151440 concerns tumor expression; they do not establish
  this disease’s mechanism or tumor risk. The Iranian and later general DSD exome abstracts add diagnostic
  context without new genotype-specific claims. The newly identified RNA-processing preprint was
  only abstract-accessible after a full-PDF rate-limit failure and is not used to assert an established
  causal pathway. Two additional research-only sources were assessed: the full familial Swyer report
  PMID38337479 and mosaicism cohort abstract PMID31883875. Neither establishes DHX37-specific tumor
  risk, so their tumor proportions were not transferred to this gene-defined entry.
histopathology:
- name: Fibrotic gonadal remnant with undifferentiated sex cords
  description: >-
    A DHX37 Arg308Gln-positive participant had a largely fibrotic gonadal remnant containing a small
    area of undifferentiated sex cords in gonadal stroma, without germ cells. This documents residual
    dysgenetic tissue rather than complete absence of all gonadal material.
  evidence:
  - reference: PMID:39659563
    reference_title: 'Etiology, histology, and long-term outcome of bilateral testicular regression: a large Belgian series.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      a small area of undifferentiated gonadal tissue, containing sex cords in a background of gonadal
      stroma, an absence of germ cells, and fat infiltration
    explanation: >-
      Histological description of participant 2’s left gonadal remnant.
- name: Residual immature seminiferous tubules and Leydig-cell groups
  description: >-
    The Gly478Arg VUS carrier had sparse immature seminiferous tubules and Leydig-cell groups in
    a hypoplastic spermatic-cord specimen with dystrophic calcification. The observation supports
    residual tissue within the reported regression phenotype, but does not independently establish
    variant pathogenicity.
  evidence:
  - reference: PMID:37717579
    reference_title: Two Novel Heterozygous Variants in RecA2 Domain of DHX37 Cause 46,XY Gonadal Dysgenesis and Testicular Regression Syndrome.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The histologic examination revealed hypoplastic spermatic cord, focal dystrophic calcification,
      with sparse immature seminiferous tubules and Leydig cell groups in the stoma, confirming the
      diagnosis of TRS.
    explanation: >-
      Primary case histology; the paper classifies Gly478Arg as VUS.
- name: Germ cell neoplasia in situ in dysgenetic testis
  description: >-
    The original familial cohort documents GCNIS in an Arg674Trp-positive member’s left dysgenetic
    testis. The isolated observation supports tumor surveillance/management considerations without
    quantifying genotype-specific risk.
  evidence:
  - reference: url:https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf
    reference_title: https://www.pure.ed.ac.uk/ws/portalfiles/portal/104502301/final_manuscript_DHX37_2506_submitted.pdf
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Left dysgenetic

      testis with GCNIS*
    explanation: >-
      Table 1, family member F4:II-4; the table footnote expands GCNIS as germ cell neoplasia in
      situ.
progression:
- phase: Variable prenatal testicular differentiation
  age_range: Fetal development
  notes: >-
    Early differentiation and hormone production vary, producing a spectrum of genital anatomy and
    Müllerian retention. Diagnostic labels do not establish an exact gestational time of tissue loss
    in every patient.
  evidence:
  - reference: PMID:31337883
    reference_title: Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      The genital phenotype may range predominantly from male to female, including marked sex ambiguity
      depending on the duration of normal testicular function prior to the loss of testicular tissue.
    explanation: >-
      The clinical interpretation relates anatomy to timing of fetal function rather than directly
      measuring fetal hormone production.
- phase: Possible postnatal regression
  age_range: Childhood
  notes: >-
    In a pathogenic Arg334Trp carrier, inguinal gonads were palpable at about two years but not at
    six years two months; later imaging showed rudimentary tissue. This supports longitudinal assessment
    rather than assuming all regression is prenatal.
  evidence:
  - reference: PMID:40916030
    reference_title: DHX37 variants in patients with 46,XY disorders or differences of sex development.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The inguinal gonads, which were palpable at 2 years of age, were not palpable at 6 years and
      2 months of age, with only rudimentary gonads detected via echography.
    explanation: >-
      Direct longitudinal observation in patient 1.
- phase: Variable pubertal function and adult reproductive impairment
  age_range: Adolescence and adulthood
  notes: >-
    Puberty may require induction, or may start spontaneously and subsequently stall. A pathogenic
    Arg308Gln carrier entered puberty at twelve, began testosterone at seventeen and had azoospermia
    at twenty-one. These outcomes are variable and should not be assigned as universal carrier features.
  evidence:
  - reference: url:https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867
    reference_title: https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The patient developed normal

      puberty at 12 years old but presented with low testosterone levels at 17 years old.
    explanation: >-
      Primary Arg308Gln case follow-up.
  - reference: url:https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867
    reference_title: https://mdpi-res.com/d_attachment/life/life-13-01093/article_deploy/life-13-01093.pdf?version=1682573867
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      has high levels of FSH (34.5 IU/L) and LH (12 IU/L) and presented with azoospermia.
    explanation: >-
      Direct semen finding in the pathogenic Arg308Gln patient; the other azoospermic case in the
      paper carried a likely benign DHX37 allele and is not pooled here.
prevalence:
- population: General population
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Population prevalence has not been established in the reviewed sources. Referral-cohort diagnostic
    yields and literature-selected case fractions are not prevalence estimates.

📚

References & Deep Research

References

3

PMID:20301714

Nonsyndromic Disorders of Testicular Development Overview.

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1547/

Nonsyndromic Disorders of Testicular Development Overview - GeneReviews® - NCBI Bookshelf

No top-level findings curated for this source.

PMID:35353710

Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.

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 (3)

Record review notes

All originally cited references and the matching deep-research report were assessed; actual cached full bodies, tables and methods were used where available. PMID40026690 is a literature review whose pooled 60-case counts include uncertain variants and an infertility-associated frameshift. PMID39659563 has 35 recruited but 34 genetically analyzable participants; its two testosterone-treated DHX37 carriers were described at Tanner G3, so the broad adult-outcome wording is not treated as a genotype-specific adult endpoint. The da Silva primary manuscript reports 7/14 ETRS index cases despite an apparent 13-index accounting in its methods; no derived numeric subgroup fraction is asserted. PMID34293745’s abstract writes p.T477H, whereas subsequent c.1430C>T summaries identify p.Thr477Met; the inconsistent named-variant record is withheld pending primary nomenclature resolution, while the reported homozygous case remains acknowledged. PMID38769888 calls Arg671Thr pathogenic in prose but VUS in Table 1; protein-expression results are retained without resolving that discrepancy. PMID37065748 Table 1 says no Müllerian structures for the younger sibling, while its histology and narrative describe fallopian-like structures; histology is kept distinct from imaging and no frequency is inferred. PMID42510869 repeats the Gly478Arg case from PMID37717579 and does not establish its VUS-only gynecomastia presentations as causal SRXY11. PMID32057790 concerns Turner mosaicism, PMID37497464 lacks a DHX37 genotype, and PMID42151440 concerns tumor expression; they do not establish this disease’s mechanism or tumor risk. The Iranian and later general DSD exome abstracts add diagnostic context without new genotype-specific claims. The newly identified RNA-processing preprint was only abstract-accessible after a full-PDF rate-limit failure and is not used to assert an established causal pathway. Two additional research-only sources were assessed: the full familial Swyer report PMID38337479 and mosaicism cohort abstract PMID31883875. Neither establishes DHX37-specific tumor risk, so their tumor proportions were not transferred to this gene-defined entry.

Review DHX37-related testicular development against full clinical and experimental sources · 2026-09-21T03:36:15Z · View source

Reviewed the complete disorder and matching OpenScientist research report after a fresh, fully paginated open-PR overlap check. Read all 24 originally cited references at the available level, including every actual cached article body, tables, captions and methods; abstract-only sources were not treated as full text. Added generated full sources for the da Silva author manuscript, de Oliveira primary clinical paper, human DHX37 ribosome experiments, Ser408Leu and Arg671Thr functional studies, the complete GeneReviews family overview and the Endo-ERN guideline. Independent peer audit covered the complete mouse knockout paper and human ribosome paper; applicable endocrine-guideline sections were separately audited for the neighboring partial-dysgenesis review. Corrected the clinical spectrum: regression is not uniformly fully masculinized or restricted to fetal life; retained function and spontaneous pubertal onset occur. Removed unsupported phenotype-frequency bands and the unproven VUS-only gynecomastia association. Added directly observed azoospermia, postnatal regression and primary-cohort germ-cell neoplasia in situ. Uterine evidence now names a uterus rather than inferring one from fallopian remnants. Corrected the Belgian genetic denominator to three of 34 analyzable participants, distinguished Tanner-G3 treatment observations from adult outcomes, and separated literature-selected counts from prevalence or penetrance. Rebuilt the causal graph around distinct genetic, abundance, ribosome, nucleolar, p53, apoptosis, proliferation, RNA-splicing, testicular-development, regression and hormone events. Removed unmeasured helicase loss, AKT activation, MDM2 binding, p53 necessity, universal beta-catenin activation and the reversed hormone-deficiency-to-absent-tissue edge. Human variant experiments, mouse conditional deletion and TM4 RNAi now retain their own allele, age, assay and species limits. No gain-of-function, dominant-negative or haploinsufficiency mechanism is established by variant class alone. Mined the full GeneReviews overview for diagnostic biopsy limitations, selective hCG testing, individualized gonadal surgery/surveillance, sex-steroid replacement, psychosocial participation, reproductive options and recurrence counseling. Direct DHX37 estrogen-treatment cases replace the incorrect claim that none had been published. Progestogen depends on a uterus and pubertal progression; sex-limited transmission is separated from disease penetrance. Endo-ERN care recommendations are identified as broader guidance, with no male-PGD induction trials in its systematic review. Recorded source limitations explicitly: the da Silva ETRS denominator does not reconcile with its methods; the codon-477 amino-acid name differs between the primary abstract and later c.1430C>T summaries, so the inconsistent named variant was withheld; Arg671Thr is pathogenic in prose but VUS in its table; the Ser408Leu report has imaging/table versus histology differences; and Gly478Arg is the same individual across two reports. Off-topic tumor-expression and Turner-mosaicism papers were not used as SRXY11 evidence. An abstract-accessible RNA-processing preprint was considered but not promoted to an established mechanism. All reference Markdown was generated with just fetch-reference; the frozen accessions file was not read or modified. The independent full-source audit confirmed the human ribosome experiments and mouse readouts. Added an explicitly engineered-T282A/HeLa/HEK293 model with 40S, pre-rRNA and U3-retention readouts plus wild-type rescue, while retaining hypothetical application to patient DSD alleles. Removed an untested fetal outcome from FAILS_TO_RECAPITULATE and retained the mouse timing limitation in prose. Read the two further deep-research-only sources, full PMID38337479 and abstract PMID31883875, and withheld their non-DHX37 tumor proportions. All 164 evidence items have source titles; PDF URL records retain generator metadata. The initial evidence titles used the printed publication title, but this caused exact metadata-title validation failures and was corrected after automated review. The initial local validation reported schema, live ontology bindings and 164/164 exact snippets as passing, but the authoritative CI recipe failed because 15 PDF reference titles did not match generated metadata. This is corrected below; the initial recipe must not be described as having passed. All 20 scoped and whole-repository guards passed: duplicate keys, enums, delivery systems, entity references, causal targets, coarse phenotypes, qualifiers, source-defect claims, GeneReviews, discussion targets, case collisions, folded hyphens, snippet length, snippet grading, title snippets, reference titles, environmental evidence, empty snippets, skill files and reference-cache frontmatter. Existing unrelated cache-delimiter advisories were nonfatal. Final history and refreshed scoped checks are recorded in the commit validation.

Create: 46,XY Sex Reversal 11 (SRXY11, DHX37) · 2026-09-01T05:54:21Z · View source

Created kb/disorders/46_XY_Sex_Reversal_11.yaml for MONDO:8000015 (SRXY11, DHX37-related 46,XY DSD) and deleted the corresponding stub. Deep research: the requested provider was falcon, which returned HTTP 403 (Edison authentication failed). Rather than substituting a provider by hand, the run was repeated through the recorded-fallback path (just dr_fallback='--fallback' research-disorder falcon ...), which produced research/46_XY_Sex_Reversal_11-deep-research-openscientist.md and renamed the report to its actual producer; the frontmatter carries fell_back: true, requested_provider: falcon, and provider_attempts. That report is the one used. Report validation as read before use: reference_validation 18/18 resolved, 18/18 quotes valid, confabulation_rate 0.0, needs_review true because of one off-topic reference, PMID:32057790 (a Turner-syndrome 45,X/46,XY mosaicism seminoma case report). That paper is genuinely about a different entity and was not cited. term_validation flagged HP:0000783 as unresolved; it is not bound anywhere in the entry. The four terms reported as mislabelled were artefacts of the report placing frequency descriptors in the label column (HP:0000133, HP:0000815, HP:0000771, HP:0100728 all carry correct CURIEs); each term actually used was independently verified against the ontology via the OLS API or an existing verified binding in a sibling KB entry. Scope decision: recorded as a DISEASE entry rather than a SUBTYPE. The stub was UNDECIDED. MONDO places SRXY11 under 46,XY complete gonadal dysgenesis, but the existing complete-dysgenesis entry explicitly excludes DHX37 as a phenotype-series cross-reference, and the existing 46,XY partial gonadal dysgenesis entry carries only a DHX37 subtype scoped to partial presentations. Neither covers the testicular-regression pole, which is where DHX37 variants are most enriched. The entry is gene-anchored and spans both poles, because the recurrent alleles produce both within and across families; the notes block records the overlap with both sibling entries explicitly. Content: 9 pathophysiology nodes forming a connected causal chain from the RecA-domain missense variant through impaired 40S biogenesis, nucleolar stress, and a branch into WNT/beta-catenin-mediated failure of testis determination versus p53-dependent somatic-cell apoptosis and fetal testicular regression; 14 phenotypes; genetic and variants records for the p.Arg308Gln and p.Arg674Trp hotspots with three population-specific case_fractions; a Sertoli-cell conditional Dhx37 knockout animal model including a FAILS_TO_RECAPITULATE link; four diagnosis records; four treatments; four differential diagnoses; and five discussions. Epistemic care taken: the middle of the chain (nucleolar stress to WNT to failed determination, and the p53 arm) is the field's leading model and not a demonstrated result, so those nodes carry mechanism_confidence HYPOTHETICAL and their edges carry directness INDIRECT. No prevalence record was created — no population prevalence for SRXY11 exists, and the published figures are ascertainment-dependent diagnostic yields, recorded as genetic.case_fractions instead. No DHX37-specific germ-cell tumour risk is quoted; the tumour phenotype cites a 292-patient 46,XY DSD series that was not DHX37-genotyped, and carries both the dysgenesis risk figure and the negative result at the regression pole. Discussions record the DHX37 expression-compartment disagreement between the two foundational studies, the regression-versus-dysgenesis controversy, the housekeeping-gene tissue-specificity paradox, and a HUMAN_MODEL_MISMATCH for the loss-of-function mouse against exclusively missense human alleles. GeneReviews: no chapter exists for SRXY11 or testicular regression syndrome. The overview chapter Nonsyndromic Disorders of Testicular Development (PMID:20301714) covers this disease family and is cached and tagged GeneReviews in the top-level references block; its PubMed abstract is a purpose statement with no Clinical Characteristics content, so it supplied no phenotype baseline and is cited only as the reference tag. Self-review round. Before committing, an adversarial review was run against the dismech-pr-review skill with fresh context, and its findings were verified against the reference cache rather than taken at face value; seventeen were raised and fifteen acted on. Substantive corrections: (1) the RIP-seq/RNAi-RNA-seq result from PMID:41535247 was regraded from MODEL_ORGANISM to IN_VITRO after confirming in the cached full text that those experiments were RNAi knockdown in the TM4 mouse Sertoli cell line, and the animal-model link evidence was repointed to the paper's in-vivo sentence. (2) The Nucleolar Stress Response node had described a cell-line result as directly observable in knockout testis; the description was corrected and that node plus the p53 apoptosis node were tagged mechanism_confidence PROVISIONAL, which the notes block had already claimed of them but the file did not honour. (3) genetic.frequency claimed DHX37 was the most commonly identified gene in gonadal-dysgenesis cohorts generally, which the sources do not support; it was narrowed to TRS-enriched series with the 0.77-45.45 percent cohort range recorded. (4) The Ambiguous genitalia phenotype was supported only by a quote describing a range of genital outcomes, and was rebound to a PMID:42510869 sentence reporting ambiguous genitalia directly, with frequency dropped from FREQUENT to OCCASIONAL. (5) A REFUTE on the Muellerian phenotype was quoting a cohort's enrolment criterion rather than a finding, and was regraded NO_EVIDENCE. (6) The case definition required a heterozygous variant, excluding the published homozygous p.T477H testicular-regression case that this entry cites elsewhere; it was softened, and that case with its heterozygous fertile father was added as evidence. (7) The treatments section was testosterone-only despite the entry curating the female-phenotype pole as first-class, so an estrogen-replacement record was added with its lack of DHX37-specific evidence stated plainly. Also corrected: the p53-to-regression edge snippet now quotes the clause that actually reaches the regression step; the Cryptorchidism edge moved from Absent Functional Testicular Tissue to Deficient Fetal Testicular Hormone Output, since absent tissue does not cause an undescended testis; the Brazilian ETRS case_fraction_percent of 50.0 was withdrawn because the 7/14 denominator reconciles with neither count in the abstract and the ratio may be inverted, with the ambiguity recorded in notes; a NO_EVIDENCE item doing a notes' job moved to node notes; the gonadal-surgery binding tightened from NCIT:C15329 Surgical Procedure to NCIT:C15288 Orchiectomy; Delayed puberty evidence marked directness INDIRECT; and hypospadias, primary amenorrhea, pelvic imaging, and a digenic DHX37 plus NR5A1 note were added. One point of fact in the notes block was wrong and is fixed: the 46,XY complete gonadal dysgenesis entry does carry a DHX37-related subtype and a DHX37 pathophysiology node, so the earlier wording implying it excludes DHX37 content entirely was incorrect. Two findings were recorded rather than resolved, both flagged in the entry's notes for a human curator. The lump/split call warrants sign-off: DHX37 content now exists in three files, which is the gene-specific-forms pattern. And MONDO makes MONDO:8000015 a subclass of complete gonadal dysgenesis while this entry deliberately spans the partial and regression poles too, so the bound disease_term is narrower than the entry's scope; a skos:narrowMatch mapping to MONDO:0016674 would make the partial-pole claim auditable and is noted as follow-up rather than asserted here. Validation: just validate-disorders (the batched pre-PR gate CI runs) passed after the review fixes — schema, terms, and 87/87 snippets verified against cached references. 13,238 KB-integrity pytest cases pass. Also passed: check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-enum-values, check-snippet-length, check-title-snippets, check-folded-hyphens, check-snippet-grading, check-environmental-evidence, and check-stubs after stub deletion. All 15 references are PMIDs; no DOI-only or preprint citations were used.

OpenScientist ▸

46,XY Sex Reversal 11 (SRXY11): A Comprehensive Disease Characteristics Report

openscientist-autonomous 15 citations 2026-09-01T05:47:13.174194

46,XY Sex Reversal 11 (SRXY11): A Comprehensive Disease Characteristics Report

Disease: 46,XY Sex Reversal 11 (SRXY11) Causal gene: DHX37 (DEAH-box RNA helicase 37) OMIM (phenotype): #273250 (46,XY sex reversal 11) Category: Mendelian, autosomal dominant disorder/difference of sex development (DSD) Suggested disease ontology mapping: MONDO — 46,XY partial/complete gonadal dysgenesis spectrum; the DHX37-specific entry corresponds to OMIM #273250.

Evidence source key: [H] human clinical/genetic · [M] model organism · [V] in vitro/functional · [C] computational/in silico · [R] review.

Summary

46,XY Sex Reversal 11 (SRXY11) is a rare Mendelian disorder/difference of sex development (DSD) caused by heterozygous, mostly recurrent missense variants in DHX37, a DEAH-box RNA helicase essential for biogenesis of the small (40S) ribosomal subunit. Affected individuals have a 46,XY karyotype but fail to complete testis determination or undergo testis regression, producing a clinical spectrum that runs from phenotypic females with complete gonadal dysgenesis (Swyer syndrome), through partial gonadal dysgenesis, to testicular regression syndrome (TRS)/anorchia and, at the mildest pole, males with modest testicular underdevelopment and gynecomastia. Because a ubiquitously required housekeeping factor produces a phenotype restricted almost entirely to the developing gonad, DHX37-related DSD has been proposed as a new human ribosomopathy — a class of disease in which broadly expressed ribosome-biogenesis factors nonetheless cause tissue-specific pathology.

The molecular link between DHX37 loss and gonadal failure is coming into focus from mouse work: DHX37 safeguards nucleolar integrity and PI3K-AKT survival signaling and suppresses p53-driven apoptosis, so its deficiency triggers pro-apoptotic RNA splicing and death of the fetal supporting (Sertoli) cell lineage, aborting or reversing testis formation. In humans, DHX37 protein is expressed principally in germ cells and Leydig cells, and only rarely in Sertoli cells, so the exact cell-autonomous versus non-cell-autonomous route to Sertoli-cell failure remains partially inferred. Two recurrent variants — p.Arg308Gln and p.Arg674Trp — account for a large share of cases and are especially associated with embryonic testicular regression syndrome (ETRS).

Clinically, the disorder is diagnosed by the combination of a 46,XY karyotype discordant with gonadal/genital phenotype, hypergonadotropic hypogonadism (elevated FSH/LH, low sex steroids), imaging showing streak or absent gonads (with or without Müllerian structures), and molecular confirmation by whole-exome/genome sequencing, for which DHX37 should now be part of DSD gene panels. Management is supportive rather than curative: sex-steroid hormone replacement, prophylactic gonadectomy of dysgenetic Y-bearing gonads (which carry a ~15–23% germ-cell tumor risk), fertility and psychosocial counseling, and genetic counseling. Importantly, biallelic and de novo heterozygous DHX37 variants cause a distinct, allelic neurodevelopmental syndrome (NEDBAVC, OMIM 618731), so genotype must be interpreted with the full clinical picture.

Key Findings

Finding 1 — DHX37 heterozygous missense variants are a frequent, autosomal-dominant cause of 46,XY DSD (SRXY11) [H]

In a cohort of 145 individuals with 46,XY DSD of previously unknown etiology, 13 children carried heterozygous missense pathogenic variants in DHX37, and rare/novel DHX37 missense variants were enriched in cases versus controls with high statistical significance (P = 5.8×10⁻¹⁰). The gene encodes an RNA helicase "essential for ribosome biogenesis," and the pathogenic variants establish an autosomal dominant form of 46,XY DSD encompassing both gonadal dysgenesis and testicular regression syndrome (TRS). The authors concluded these conditions "are part of a clinical spectrum" rather than distinct entities.

"Thirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis." — PMID: 31337883

"DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including gonadal dysgenesis and TRS, showing that these conditions are part of a clinical spectrum." — PMID: 31337883

This is the foundational human-clinical evidence identifying DHX37 as the SRXY11 gene and framing the phenotype as a spectrum. HGNC: DHX37. UniProt: Q8IY37.

Finding 2 — DHX37 maintains supporting-cell (Sertoli) survival through nucleolar integrity and PI3K-AKT, suppressing p53 apoptosis [M][V]

Multi-omics analysis of cell-specific Dhx37 knockout mice (RIP-seq plus RNAi-RNA-seq) demonstrated that Dhx37 "safeguards nucleolar integrity and PI3K-AKT signaling, suppresses p53-driven apoptosis, and its loss triggers pro-apoptotic splicing" and Sertoli-cell death, impairing testis development. This is the strongest mechanistic account currently available and links DHX37 loss-of-function to the cellular event (supporting-cell apoptosis) that most plausibly explains failed/reversed testis determination.

"Dhx37 safeguards nucleolar integrity and PI3K-AKT signaling, suppresses p53-driven apoptosis, and its loss triggers pro-apoptotic splicing" — PMID: 41535247

Relevant GO/pathway terms: ribosome biogenesis (GO:0042254), rRNA processing (GO:0006364), nucleolus (GO:0005730), PI3K-AKT signaling, intrinsic apoptotic signaling by p53 class mediator (GO:0072332), regulation of RNA splicing (GO:0043484).

Finding 3 — Allelic heterogeneity: heterozygous → non-syndromic DSD; biallelic/de novo → syndromic NEDBAVC (OMIM 618731) [R][H]

DHX37 shows a clean genotype-driven dichotomy. Recurrent heterozygous missense variants — affecting highly conserved residues in the helicase domains and predicted deleterious — cause non-syndromic 46,XY gonadal dysgenesis, TRS, or anorchia. In contrast, compound heterozygous and de novo heterozygous DHX37 missense variants cause a complex congenital syndrome, NEDBAVC (neurodevelopmental disorder with brain anomalies and with/without vertebral or cardiac anomalies; OMIM 618731) featuring microcephaly, global developmental delay, seizures, facial dysmorphism, and kidney/cardiac anomalies.

"compound heterozygous as well as de novo heterozygous missense variants in DHX37 are also associated with a complex congenital developmental syndrome (NEDBAVC, neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies; OMIM 618731), consisting of microcephaly, global developmental delay, seizures, facial dysmorphia, and kidney and cardiac anomalies" — PMID: 35835064

"All affected children have non-syndromic forms of disorders/differences of sex development (DSD)." — PMID: 35835064

This distinction is clinically critical for variant interpretation and counseling.

Finding 4 — Dysgenetic Y-bearing gonads carry a high germ-cell tumor risk, warranting gonadectomy [H]

In a series of 292 phenotypic-female DSD patients harboring Y-chromosome material, the overall germ-cell tumor (GCT) risk was 15.4%, and 46,XY pure gonadal dysgenesis carried the highest risk (~23.3%). Tumors — gonadoblastoma and dysgerminoma/seminoma — arose predominantly during adolescence (median 17–18 years). Notably, no tumor was found in five testicular-regression patients, contrasting the high dysgenesis risk with the negligible regression risk. These data support prophylactic gonadectomy of dysgenetic gonads.

"The overall GCTs risk was 15·41% and 46, XY pure gonadal dysgenesis (46, XY PGD) carried the highest risk up to 23·33%" — PMID: 27862157

"no tumour was found in five testis regression patients" — PMID: 27862157

A familial Swyer-syndrome report additionally suggests familial cases may carry higher tumor risk than sporadic ones (66.6% vs. 15–45%) (PMID: 38337479).

Finding 5 — Marked phenotypic heterogeneity from complete gonadal dysgenesis to TRS/anorchia, with variable expressivity [H]

DHX37 variants generate a phenotypic continuum: 46,XY complete gonadal dysgenesis (female external genitalia, Müllerian remnants), partial gonadal dysgenesis, testicular regression syndrome/anorchia (absent testes with variable male genitalia), and milder testicular underdevelopment with gynecomastia. Variants cluster in conserved helicase domains (e.g., RecA1); reported residues include p.Arg334Trp, p.Arg390His, p.Thr477His, and p.Gly478Arg. A striking example of variable expressivity/incomplete penetrance: a boy with TRS carried a homozygous p.T477H variant while his fertile father, carrying the same variant, had only unilateral testicular regression with otherwise typical male genital development.

"Missense variants in the RNA-helicase DHX37 are associated with either 46,XY gonadal dysgenesis or 46,XY testicular regression syndrome (TRS)." — PMID: 34293745

"a homozygous p.T477H variant was identified in a boy with TRS. His fertile father had unilateral testicular regression with typical male genital development." — PMID: 34293745

"manifestations ranging from complete gonadal dysgenesis to mild testicular underdevelopment with gynecomastia" — PMID: 42510869

Finding 6 — Diagnosis rests on 46,XY karyotype discordant with gonad/genitalia, hypergonadotropic hypogonadism, and molecular (WES/WGS) confirmation [H]

Complete gonadal dysgenesis (Swyer syndrome) typically presents in phenotypic females with a 46,XY karyotype, primary amenorrhea/delayed puberty, a hypoplastic uterus and streak gonads on imaging, and hypergonadotropic hypogonadism (elevated FSH/LH, low estradiol/testosterone) on hormonal assay. DHX37 is identified by whole-exome/trio sequencing once karyotype excludes sex-chromosome DSD; the gene is now recommended for inclusion in DSD gene panels and genome-wide sequencing.

"confirmed by the hormonal assay that showed hypergonadotropic-hyp[ogonadism]" — PMID: 37497464

"Genome-wide sequencing should be prioritized in VSC/DSD diagnostics, consistent with current best practices, to improve diagnostic yield" — PMID: 41466375

Finding 7 — Two recurrent variants (p.Arg308Gln, p.Arg674Trp) dominate and are enriched vs. gnomAD, with a specific ETRS association; DHX37 is expressed in germ and Leydig cells [H][V]

In 87 patients with 46,XY DSD, da Silva et al. (2019) identified pathogenic/likely-pathogenic heterozygous DHX37 missense variants in 5 families (11 patients) and 6 sporadic cases; two recurrent variants dominated — p.Arg308Gln (two families, three sporadic cases) and p.Arg674Trp (two families, two sporadic cases). Rare, predicted-deleterious DHX37 variants occurred in 14% of the cohort versus 0.4% in gnomAD (P < 0.001), and were specifically associated with embryonic testicular regression syndrome (ETRS) in 7/14 index cases (50%). Immunohistochemistry localized DHX37 mainly to germ cells (at various maturation stages) and Leydig cells, and only rarely to Sertoli cells.

"Two variants were recurrent: p.Arg308Gln (in two families and in three sporadic cases) and p.Arg674Trp (in two families and in two sporadic cases)." — PMID: 31287541

"The frequency of rare, predicted-to-be-deleterious DHX37 variants in this cohort (14%) is significantly higher than that observed in the Genome Aggregation Database (0.4%; P < 0.001)." — PMID: 31287541

"DHX37 is mainly expressed in germ cells at different stages of testis maturation, in Leydig cells, and rarely in Sertoli cells" — PMID: 31287541

"The variants were specifically associated with ETRS (7/14 index cases; 50%)." — PMID: 31287541

Finding 8 — The central mechanism — how a ubiquitous ribosome-biogenesis factor produces tissue-specific gonadal failure — remains unresolved [R]

DHX37 is a housekeeping DEAH-box helicase required for 40S ribosomal subunit biogenesis in every cell, yet heterozygous missense variants produce a phenotype almost entirely restricted to gonad/testis determination — a paradox shared with other ribosomopathies. Multiple primary reports and reviews explicitly state that the pathogenic mechanism is unknown.

"Similar to all other known ribosomopathies, the mechanism of pathogenesis is unknown." — PMID: 34293745

"DHX37 is required for ribosome biogenesis, and this subgroup of XY DSD is a new human ribosomopathy." — PMID: 34293745

No zebrafish or invertebrate DHX37 sex-development model, and no humanized knock-in of the recurrent p.Arg308Gln/p.Arg674Trp alleles, has yet been reported; available models are a supporting-cell conditional-knockout mouse and yeast Dhr1 structural/functional studies.

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

A heterozygous missense variant in DHX37 (most often at recurrent hotspots p.Arg308Gln or p.Arg674Trp, in conserved helicase RecA domains) leads to a partial loss of DHX37 RNA-helicase activity. (Demonstrated genetically; the loss-of-function nature at the protein level is partly inferred from conservation, in silico prediction, and yeast Dhr1 structural work — [PMID: 31188444].)
Impaired DHX37 helicase function results in defective displacement of the U3 snoRNA from pre-rRNA and impaired 40S small ribosomal subunit biogenesis / nucleolar homeostasis. (Mechanism established for yeast Dhr1; extrapolated to human DHX37.)
Disturbed nucleolar integrity leads to nucleolar stress, which results in stabilization/activation of p53 and reduced PI3K-AKT survival signaling. (Demonstrated in Dhx37-knockout mouse multi-omics — [PMID: 41535247].)
p53 activation plus loss of AKT survival signaling triggers pro-apoptotic RNA splicing and apoptosis of the fetal supporting (Sertoli) cell lineage. (Demonstrated in mouse; human Sertoli involvement is partly inferred because human DHX37 protein is expressed mainly in germ and Leydig cells and only rarely in Sertoli cells — [PMID: 31287541].)
Loss/failure of Sertoli-supporting cells during the narrow window of fetal sex determination results in failed testis determination (gonadal dysgenesis) or, if determination initially succeeds, testis regression (TRS/anorchia). (Branch point — see below.)
Absent or dysgenetic testis leads to deficient anti-Müllerian hormone and androgen output, which results in incomplete/absent virilization, persistence of Müllerian structures (in dysgenesis), and hypergonadotropic hypogonadism at expected puberty. (Human clinical — [PMID: 37497464].)
Retained dysgenetic Y-bearing gonadal tissue creates a germ-cell tumor predisposition (gonadoblastoma → dysgerminoma/seminoma). (Human clinical — [PMID: 27862157].)

Branch point

 DHX37 helicase-domain missense (heterozygous)
            |
nucleolar stress / p53↑ / PI3K-AKT↓
            |
supporting-cell (Sertoli) apoptosis
     /                        \
   determination never completes    determination completes, then fails
     |                                |
   Complete/partial gonadal dysgenesis   Testicular regression syndrome /
   (Swyer; streak gonads; Müllerian      anorchia (absent testes; variable
   remnants; female genitalia)           male genital development)
     \                        /
      High GCT risk        Low/negligible GCT risk
      (~15–23%)            (0/5 in one series)

Genotype–phenotype and dose logic

Genotype	Phenotype	Syndromic?	OMIM
Heterozygous missense (helicase domains; hotspots R308Q, R674W)	46,XY gonadal dysgenesis ↔ TRS/anorchia spectrum	No	#273250 (SRXY11)
Compound heterozygous / de novo heterozygous missense	Microcephaly, DD, seizures, dysmorphism, vertebral/cardiac/kidney anomalies	Yes (NEDBAVC)	618731

The recurrence of specific residues and their autosomal-dominant behavior suggest the DSD-causing alleles act through a specific (possibly dominant-negative or hypomorphic gain-of-toxicity) mechanism rather than simple haploinsufficiency — consistent with the observation that a different mutational configuration (biallelic/de novo) produces an entirely different, neurodevelopmental disease. This remains a hypothesis; direct allele-specific functional proof is lacking.

Why a housekeeping factor hits the gonad selectively (open question)

The defining unresolved question (Finding 8) is the tissue-specificity paradox. Proposed but unproven explanations, by analogy to other ribosomopathies, include: (i) heightened dependence of the rapidly proliferating fetal gonadal-somatic lineage on ribosome flux during the brief sex-determination window; (ii) a low p53 threshold in supporting cells; and (iii) selective translational requirements for pro-testis regulators (e.g., the SRY/SOX9 pathway). None has been experimentally demonstrated for DHX37.

Section-by-Section Details

1. Disease Information

Overview: SRXY11 is a monogenic 46,XY DSD in which testis determination fails or reverses despite a Y chromosome, spanning Swyer syndrome (complete gonadal dysgenesis) to testicular regression/anorchia to mild male undervirilization.
Identifiers: OMIM #273250 (46,XY sex reversal 11); allelic OMIM 618731 (NEDBAVC). Gene: DHX37 (HGNC:16192; NCBI Gene 57647; UniProt Q8IY37). Orphanet/ICD map to broader "46,XY complete/partial gonadal dysgenesis" and "swyer syndrome" categories; MeSH: Gonadal Dysgenesis, 46,XY; Disorders of Sex Development. MONDO: 46,XY gonadal dysgenesis spectrum.
Synonyms/alternatives: DHX37-related 46,XY DSD; 46,XY gonadal dysgenesis with DHX37; 46,XY testicular regression syndrome (DHX37); "new ribosomopathy of sex development."
Data source type: Predominantly aggregated case-series/cohort literature and gene-level resources (OMIM), not EHR-derived.

2. Etiology

Causal factor: Monogenic — heterozygous missense variants in DHX37 (Findings 1, 7). No environmental or infectious cause.
Genetic risk: The DHX37 variant itself is causal (autosomal dominant); rare deleterious DHX37 variants enriched ~35-fold vs gnomAD (14% vs 0.4%; [PMID: 31287541]). Modifier genes are implied by incomplete penetrance but unidentified.
Protective factors: None established (no known protective alleles or exposures).
Gene–environment interactions: None documented; considered a purely genetic condition.

3. Phenotypes

Phenotype	Type	Onset	Frequency	HPO suggestion
46,XY sex reversal / gonadal dysgenesis	Physical/clinical	Fetal (manifest at birth or puberty)	Core feature	HP:0000133
Streak gonads	Clinical sign	Fetal/congenital	Common in CGD	HP:0000133
Primary amenorrhea / delayed puberty	Clinical sign	Adolescence	Common in Swyer	HP:0000783
Hypergonadotropic hypogonadism	Lab abnormality	Puberty	Characteristic	HP:0000815
Testicular regression / anorchia	Physical	Fetal	ETRS subset (~50% of variant carriers, [PMID:31287541])	HP:0000795
Gynecomastia (mild pole)	Physical	Puberty	Mild presentations	HP:0000771
Müllerian remnants (uterus)	Physical	Congenital	Dysgenesis end	—
Gonadoblastoma/dysgerminoma predisposition	Neoplasm	Adolescence	~15–23% in dysgenesis	HP:0100728

Severity is highly variable (Finding 5); the primary gonadal defect is stable/non-progressive but its consequences (pubertal failure, tumor risk) evolve. Quality-of-life impacts include infertility, need for lifelong hormone therapy, psychosocial burden of atypical sex development, and cancer surveillance/gonadectomy; disease-specific QOL instruments have not been reported for this ultra-rare condition.

4. Genetic/Molecular Information

Causal gene: DHX37 (DEAH-box helicase 37); encodes an ATP-dependent RNA helicase required for 40S biogenesis.
Variant class: Missense predominates, in conserved helicase (RecA) domains. Recurrent hotspots: p.Arg308Gln, p.Arg674Trp ([PMID: 31287541]). Other reported residues: p.Arg334Trp, p.Arg390His, p.Thr477His, p.Gly478Arg ([PMID: 34293745]).
Classification: Pathogenic/likely-pathogenic per ACMG for hotspots; some variants remain VUS requiring functional/segregation support ([PMID: 42057034]).
Allele frequency: Rare/near-absent in gnomAD (aggregate deleterious ~0.4%).
Origin: Germline; both inherited (dominant) and de novo reported.
Functional consequence: Loss/alteration of helicase function; a dominant-negative or hypomorphic mechanism is hypothesized but unproven.
Modifier genes/epigenetics/chromosomal: Modifiers unidentified; no epigenetic mechanism established; the causal lesion is a point mutation, not a large chromosomal rearrangement (distinguishing it from 45,X/46,XY mosaicism).

5. Environmental Information

Not applicable — no environmental, lifestyle, or infectious contributors are known; SRXY11 is monogenic.

6. Mechanism / Pathophysiology

See the ordered causal chain and branch diagram above. Molecular pathway: ribosome biogenesis (40S/SSU maturation, U3 snoRNA displacement) → nucleolar stress → p53 activation + reduced PI3K-AKT → pro-apoptotic splicing → supporting-cell apoptosis. GO terms: GO:0042254, GO:0030490, GO:0005730, GO:0072332, GO:0006915, GO:0007530, GO:0008584. CL terms: Sertoli/supporting cell (CL:0000216), Leydig cell (CL:0000178), male germ cell (CL:0000015).

7. Anatomical Structures Affected

Organ/system: Gonad/testis (primary); endocrine and reproductive systems; internal (uterus/Müllerian remnants) and external genitalia (secondary). UBERON: gonad (UBERON:0000991), testis (UBERON:0000473), uterus (UBERON:0000995).
Tissue/cell: Gonadal somatic supporting lineage (Sertoli), Leydig cells, germ cells.
Subcellular: Nucleolus (GO:0005730), cytosolic small ribosomal subunit (GO:0022627).
Lateralization: Usually bilateral (dysgenesis); unilateral regression documented (variable, [PMID: 34293745]).

8. Temporal Development

Onset: Congenital/fetal at the level of gonadal determination; clinically silent until puberty in complete dysgenesis (primary amenorrhea), or noted at birth when genitalia are atypical or testes absent.
Course: Underlying defect fixed/non-progressive; consequences evolve; germ-cell tumors cluster in adolescence (median 17–18 y; [PMID: 27862157]).
Critical period: Fetal sex-determination window (the window of intervention for any future mechanistic therapy is developmental and effectively closed postnatally).

9. Inheritance and Population

Inheritance: Autosomal dominant (SRXY11) with incomplete penetrance and variable expressivity ([PMID: 31337883], [PMID: 34293745]); allelic recessive/de novo → NEDBAVC ([PMID: 35835064]).
Epidemiology: DHX37-specific prevalence/incidence not quantified; identified in enriched DSD cohorts (e.g., 14% of one 87-patient cohort; 13/145 in another). Reported across French, Brazilian, Japanese, Iranian, Chinese, and Polish cohorts.
Sex ratio: Affects 46,XY individuals; presentation ranges phenotypic female → male.
Founder/consanguinity: No founder effect established; homozygous cases reported in consanguineous contexts ([PMID: 34293745]).

10. Diagnostics

Cytogenetics: Karyotype/FISH confirming 46,XY (exclude 45,X/46,XY mosaicism — [PMID: 31883875], [PMID: 32057790]).
Endocrine: Hypergonadotropic hypogonadism (↑FSH/LH, ↓estradiol/testosterone); AMH/inhibin B to gauge functional gonadal tissue.
Imaging: Pelvic ultrasound/MRI for uterus/Müllerian structures and streak vs absent gonads.
Molecular: WES/WGS or trio sequencing; DHX37 on DSD panels ([PMID: 41466375], [PMID: 42365275]); ACMG classification with functional support for VUS ([PMID: 42057034]).
Histopathology: Streak gonads; surveillance for gonadoblastoma/dysgerminoma.
Differential diagnosis: NR5A1, SRY, SOX9, MAP3K1, WT1, GATA4, AR (androgen insensitivity), HSD17B3, and 45,X/46,XY mosaicism ([PMID: 42365275], [PMID: 42057034]).

11. Outcome / Prognosis

Survival: Life expectancy is essentially normal with appropriate management; the major life-threatening risk is malignant transformation of retained dysgenetic gonads.
Morbidity: Infertility, need for lifelong hormone replacement, and cancer risk (~15–23% in dysgenesis; [PMID: 27862157]).
Prognostic factors: Degree of gonadal dysgenesis (dysgenesis > regression for tumor risk); familial cases may carry higher tumor risk ([PMID: 38337479]).

12. Treatment

Hormone replacement therapy (estrogen ± progestin, or testosterone as appropriate) — NCIT: Hormone Replacement Therapy.
Prophylactic/therapeutic gonadectomy of dysgenetic Y-bearing gonads — NCIT: Gonadectomy/Orchiectomy.
Fertility counseling (typically infertile; assisted reproduction/oocyte donation for uterus-bearing individuals).
Psychosocial and gender-affirming care, individualized.
Genetic counseling (AD recurrence, variable expressivity/penetrance, distinct NEDBAVC risk).
No gene/RNA/cell therapy, disease-specific drug, or pharmacogenomic guidance exists.

13. Prevention

Primary: Not applicable (congenital genetic condition).
Secondary: Cascade genetic testing of at-risk relatives; early identification enabling timely tumor surveillance and gonadal management.
Tertiary: Prophylactic gonadectomy to prevent malignancy; hormone replacement to prevent osteoporosis and secondary-sex-characteristic deficits.
Reproductive options: Genetic counseling, prenatal/preimplantation genetic testing for known familial variants.

14. Other Species / Natural Disease

Orthologs: Mouse Dhx37 (used in the conditional-knockout model — [PMID: 41535247]); yeast ortholog DHR1 (structural/functional studies — [PMID: 31188444]). NCBI Gene (human) 57647.
Natural disease: No naturally occurring companion-animal or wildlife DHX37 sex-reversal disease is documented in OMIA to date.
Conservation: The ribosome-biogenesis function of DHX37/Dhr1 is deeply conserved from yeast to human; the sex-determination consequence is a vertebrate/mammalian-specific downstream effect.

15. Model Organisms

Mouse: Cell-specific (supporting-cell) conditional Dhx37 knockout recapitulates impaired testis development via nucleolar stress/p53 apoptosis ([PMID: 41535247]) — the best available model; limitation: it is a knockout, not a patient-allele knock-in, so dominant/hotspot-allele effects are not directly modeled.
Yeast: Dhr1 structural/functional studies define the helicase mechanism (U3 snoRNA displacement, C-terminal domain) and the biogenesis consequences of DHX37 mutations ([PMID: 31188444]); limitation: no sex-development readout.
Gaps: No zebrafish/invertebrate DHX37 sex-development model; no humanized R308Q/R674W knock-in. Resources: MGI (mouse), SGD (yeast).

Evidence Base

PMID	Title (abbrev.)	Evidence type	Role in report
31337883	DHX37 variants a frequent cause of 46,XY GD/TRS	Human cohort (n=145)	Establishes DHX37 as SRXY11 gene, AD inheritance, spectrum (F1)
41535247	Multi-omics of Dhx37 deficiency on testis/nucleolar homeostasis	Mouse KO, in vitro	Core mechanism: nucleolus/PI3K-AKT/p53/apoptosis (F2)
35835064	DHX37 and 46,XY DSD: A new ribosomopathy?	Review	Allelic NEDBAVC vs non-syndromic DSD; ribosomopathy framing (F3)
27862157	Gonadal tumour risk in 292 phenotypic females with Y material	Human cohort (n=292)	Quantifies GCT risk; supports gonadectomy (F4)
34293745	Expanding DSD phenotypes with DHX37 variants	Human clinical	Spectrum poles; variable expressivity; mechanism unknown (F5, F8)
42510869	Novel and known DHX37 variants	Human clinical	Confirms mild-end heterogeneity (F5)
37497464	Late presentation of Swyer syndrome	Case report	Hypergonadotropic hypogonadism signature (F6)
41466375	Variations in sex characteristics across OMIM	Analysis	Supports genome-wide sequencing in DSD (F6)
31287541	DHX37 defects and 46,XY GD spectrum	Human cohort (n=87), IHC	Recurrent hotspots, gnomAD enrichment, ETRS, expression (F7)
31188444	Dhr1 C-terminal domain essential for SSU biogenesis	Structural/yeast	Molecular basis of helicase role; U3 snoRNA displacement
38337479	Gonadoblastoma in familial Swyer syndrome	Case + review	Familial tumor-risk context
31883875 / 32057790	Tumor risk in 45,X/46,XY mosaicism	Human clinical	Differential diagnosis / tumor-risk context
42365275 / 42057034 / 40916030 / 39829003	WES cohorts identifying DHX37 (with NR5A1 etc.)	Human cohorts	Diagnostic yield, VUS interpretation, differential genes
42151440	DHX37 in breast/ovarian cancer prognosis	Human tumor cohorts	Non-DSD context: DHX37 tissue-context-dependent roles

Where the evidence converges: Independent human cohorts ([31337883], [31287541]) establish DHX37 causation, hotspot recurrence, and statistical enrichment; the mouse multi-omics study ([41535247]) supplies the cell-and-pathway mechanism (Sertoli apoptosis via nucleolar stress/p53/PI3K-AKT); tumor-risk data ([27862157]) drive the management recommendation.

Where the evidence is in tension / incomplete: Human IHC localizes DHX37 mainly to germ and Leydig cells, "rarely" to Sertoli cells ([31287541]), whereas the mechanistic mouse model centers on Sertoli-cell apoptosis ([41535247]) — leaving open whether the human phenotype arises cell-autonomously in supporting cells, non-cell-autonomously from germ/Leydig-cell dysfunction, or both. Reviews explicitly state the mechanism of tissue specificity is unknown ([34293745]).

Limitations and Knowledge Gaps

Unresolved tissue-specificity paradox (central gap). No experimental demonstration explains why a ubiquitous 40S-biogenesis factor selectively disables gonadal determination ([PMID: 34293745]).
Allele-specific functional data are sparse. The dominant-negative vs hypomorphic nature of hotspot alleles (R308Q, R674W) is inferred, not proven; some clinically encountered variants remain VUS ([PMID: 42057034]).
Cell-of-origin ambiguity. Human expression (germ/Leydig-dominant) versus mouse phenotype (Sertoli apoptosis) are not fully reconciled.
No humanized/knock-in model of the recurrent DSD alleles, and no zebrafish/invertebrate sex-development model exists; the mouse model is a conditional knockout.
Incomplete penetrance/variable expressivity (e.g., fertile carrier fathers) implies unidentified genetic/environmental modifiers; none are established.
Epidemiology is imprecise — DHX37-specific prevalence/incidence are unquantified; data come from enriched DSD cohorts, not population registries.
No environmental/infectious contributors are known; environmental sections are largely not applicable.

Proposed Follow-up Experiments / Actions

Generate patient-allele knock-in mice (Dhx37^R308Q/+, R674W/+) to test dominant-negative behavior and recapitulate the graded dysgenesis→regression phenotype in vivo.
Cell-type-resolved fetal gonad profiling (single-cell/spatial transcriptomics of human and mouse fetal gonad) to determine whether the primary lesion is in Sertoli, germ, or Leydig cells and to map ribosome-flux dependence during the determination window. (Search: Human Cell Atlas, GEO, CELLxGENE.)
Allele-specific functional assays — 40S maturation, U3 snoRNA displacement, nucleolar-stress and p53 readouts — for each recurrent and VUS allele to move variants from VUS toward pathogenic/benign per ACMG.
Zebrafish dhx37 sex-development model to exploit tractable gonad genetics and test conservation of the mechanism.
Prospective natural-history/registry study capturing penetrance, tumor incidence and timing, and modifier genotypes across DHX37 carriers, to refine gonadectomy timing and counseling.
Test the tissue-specificity hypotheses directly — e.g., titrate p53 activity (Trp53 co-deletion) in the Dhx37 model to establish whether p53-driven apoptosis is necessary and sufficient for the gonadal phenotype.

Conclusion

46,XY Sex Reversal 11 (SRXY11; OMIM #273250) is an autosomal-dominant disorder of sex development caused by heterozygous, largely recurrent missense variants in the ribosome-biogenesis helicase DHX37. It presents as a phenotypic spectrum from complete gonadal dysgenesis (Swyer) to testicular regression/anorchia and mild male undervirilization, and is best understood as a putative ribosomopathy in which nucleolar stress, p53-driven apoptosis, and reduced PI3K-AKT survival signaling cause failure/regression of the fetal testis-supporting lineage. Diagnosis combines a discordant 46,XY karyotype, hypergonadotropic hypogonadism, and molecular sequencing; management is supportive — hormone replacement, prophylactic gonadectomy of Y-bearing dysgenetic gonads (~15–23% tumor risk), and genetic counseling. The defining open question is how a housekeeping ribosome factor produces a gonad-restricted phenotype.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	18
Resolved	18
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	18
Quoted claims found in source	18
Quoted claims not found in source	0
References weighed for topical relevance	18
On topic	14
Off topic	1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

PMID:32057790 (3 mentions) - Seminoma In A Young Phenotypic Female With Turner Syndrome 45,XO/46,XY Mosaicism: A Case Report With Review Of The Literature.
shared terms: none

Weighed against this report's own most characteristic terms: dhx37, gonadal, dysgenesis, variant, dsd, gonad, regression, helicase, cell, missense, gene, testis, tumor, phenotype, recurrent, development, heterozygous, sex, apoptosis, sertoli.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

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

Outcome	Count
Terms checked	23
Resolved	21
Unresolved (possible confabulation)	1
Obsolete	0
Unverifiable	1
Terms whose name was checked	5
Terms named correctly	0
Terms named as a different term	4
Terms whose name is worth a second look	1

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:

HP:0000133 (2 mentions) - the report calls it "Core feature", "Common in CGD"; HP calls it Gonadal dysgenesis
HP:0000815 (1 mention) - the report calls it "Characteristic"; HP calls it Hypergonadotropic hypogonadism
HP:0000771 (1 mention) - the report calls it "Mild presentations"; HP calls it Gynecomastia
HP:0100728 (1 mention) - the report calls it "~15–23% in dysgenesis"; HP calls it Germ cell neoplasia

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

HP:0000783 (1 mention), reported as "Common in Swyer" - HP does not contain this term

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:0005730 (3 mentions) - the report calls it "Subcellular: Nucleolus"; GO calls it nucleolus**

Terms named inconsistently

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

HP:0000133 - called "Core feature", "Common in CGD"

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Definitions

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Variants

Medical Actions

Diagnosis

Progression

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

46,XY Sex Reversal 11 (SRXY11): A Comprehensive Disease Characteristics Report

Summary

Key Findings

Finding 1 — DHX37 heterozygous missense variants are a frequent, autosomal-dominant cause of 46,XY DSD (SRXY11) [H]

Finding 2 — DHX37 maintains supporting-cell (Sertoli) survival through nucleolar integrity and PI3K-AKT, suppressing p53 apoptosis [M][V]

Finding 3 — Allelic heterogeneity: heterozygous → non-syndromic DSD; biallelic/de novo → syndromic NEDBAVC (OMIM 618731) [R][H]

Finding 4 — Dysgenetic Y-bearing gonads carry a high germ-cell tumor risk, warranting gonadectomy [H]

Finding 5 — Marked phenotypic heterogeneity from complete gonadal dysgenesis to TRS/anorchia, with variable expressivity [H]

Finding 6 — Diagnosis rests on 46,XY karyotype discordant with gonad/genitalia, hypergonadotropic hypogonadism, and molecular (WES/WGS) confirmation [H]

Finding 7 — Two recurrent variants (p.Arg308Gln, p.Arg674Trp) dominate and are enriched vs. gnomAD, with a specific ETRS association; DHX37 is expressed in germ and Leydig cells [H][V]

Finding 8 — The central mechanism — how a ubiquitous ribosome-biogenesis factor produces tissue-specific gonadal failure — remains unresolved [R]

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

Branch point

Genotype–phenotype and dose logic

Why a housekeeping factor hits the gonad selectively (open question)

Section-by-Section Details

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Conclusion

Artifacts

Reference Validation

References that may not be about this subject

Term Validation

Terms the report names something else

Unresolved terms

Terms whose name is worth a second look

Terms named inconsistently