RBBP7-Related X-linked Spermatogenic Maturation Arrest

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Inheritance

1

X-linked recessive inheritance HP:0001419

Two affected brothers were hemizygous for an identical RBBP7 frameshift variant with a single Sanger sequencing peak; their unaffected mother was heterozygous with a double peak, consistent with X-linked recessive transmission.

X-linked recessive inheritance

Show evidence (2 references)

PMID:37843278 SUPPORT Human clinical

"Patients II:1 and II:2 had hemizygous mutations of RBBP7 with a single peak."

Both affected brothers carry the variant hemizygously.

PMID:37843278 SUPPORT Human clinical

"Their mother (I:2) had a heterozygous mutation with a double peak (Figure 2A)."

The unaffected mother is a heterozygous carrier, consistent with X-linked recessive inheritance.

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Mechanistic Hypotheses

1

Impaired RBBP7-dependent genome stability links spermatogenic maturation arrest to testicular tumor predisposition through a shared mechanism

rbbp7_shared_dsb_repair_and_tumor_risk EMERGING

Evidence balance 1 support

The founding family shows co-occurrence of early maturation arrest and a benign Leydig cell tumor in the same proband, with RBBP7 and BRCA1 both decreased and gammaH2AX increased in the tumor tissue. The authors propose that RBBP7 loss, via a reported RBBP7-CUL4B-HUWE1-BRCA1 axis, could predispose to both spermatogenic failure and testicular neoplasia through one underlying defect in genome stability, rather than through two unrelated events. This rests on a single kindred; whether it generalizes is an open question (see the linked discussion). Downstream causal edges that belong to this hypothesis opt in via hypothesis_groups: [rbbp7_shared_dsb_repair_and_tumor_risk].

Pathograph links

Reduced BRCA1-Mediated DNA Repair and Genomic Instability -> Testicular Somatic Cell Hyperproliferation INDIRECT UNKNOWN INTERMEDIATES Proposed shared mechanism: the authors speculate that RBBP7 loss, acting through a reported RBBP7-CUL4B-HUWE1-BRCA1 pathway, could link spermatogenic failure to testicular tumor predisposition via the same genomic-instability route, rather than through two independent causes.

Testicular Somatic Cell Hyperproliferation -> Leydig Cell Neoplasm Proposed by analogy to the fly somatic-cell result; Drosophila has no Leydig cell equivalent, so this edge is the hypothesis under test, not a demonstrated model of the human tumor.

Show evidence (1 reference)

PMID:35809576 SUPPORT INDIRECT Other

"we speculate that RBBP7, CUL4B, or HUWE1 may lead to both spermatogenic failure and cancer predisposition."

States the proposed shared-mechanism hypothesis in the authors' own words.

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Discussions and Knowledge Gaps

1

Does RBBP7-related genome instability generally predispose to testicular tumor as well as spermatogenic failure, or was the Leydig cell tumor in the founding proband an independent, coincidental finding?

KNOWLEDGE GAP OPEN rbbp7_tumor_cooccurrence_generalizability

Attached to

pathophysiology#Reduced BRCA1-Mediated DNA Repair and Genomic Instability pathophysiology#Testicular Somatic Cell Hyperproliferation phenotypes#Leydig Cell Neoplasm

The tumor-infertility link rests on one proband in one kindred; his brother, who carries the identical hemizygous variant, was not reported to have a testicular mass. The variant was also absent from 103 additional unrelated men with non-obstructive azoospermia, and the independent 2,354-man cohort that recurrently found RBBP7 variants did not report testicular tumors in those men. Resolving this needs systematic imaging and tumor-marker surveillance across a larger series of RBBP7-variant carriers with non-obstructive azoospermia.

Show evidence (1 reference)

PMID:37843278 SUPPORT Human clinical

"The involvement of RBBP7 in testicular tumors has not been previously reported to our knowledge."

The authors themselves note this is a novel, single-family observation rather than an established association.

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Pathophysiology

6

Hemizygous RBBP7 Loss-of-Function Variant

A hemizygous frameshift variant (c.1200dupA, p.W401Mfs*5) truncates the last beta-propeller blade of the RBBP7 WD40 domain. Independently, a population-level burden of rare pathogenic RBBP7 variants is found across cohorts of men with non-obstructive azoospermia.

RBBP7 hgnc:9890

Genetic context variant_origin: GERMLINE zygosity: HEMIZYGOUS functional_impact_category: LOSS_OF_FUNCTION

The truncating allele removes the C-terminal hydrophilic/charged alpha-helix of the WD40 beta-propeller, with reduced RBBP7 protein detected in patient testicular tissue.

histone binding GO:0042393 ↓ DECREASED

Downstream

Impaired RBBP7 Interaction with Histone H4 and BRCA1 The truncated protein loses the C-terminal structural element required for its normal binding interfaces.

Show evidence (1 reference)

PMID:37843278 SUPPORT Human clinical

"This mutation resulted in premature protein translation termination, affecting the sixth WD40 domain of the RBBP7 and the interaction of the mutated RBBP7 with histone H4."

States the structural consequence of the truncating variant on the RBBP7 WD40 domain.

Impaired RBBP7 Interaction with Histone H4 and BRCA1

Structural modeling shows the truncated RBBP7 loses hydrogen bonds with histone H4 and binds the BRCT domain of BRCA1 with reduced affinity, since both interactions use the same docking surface. In patient testis tissue, RBBP7 immunofluorescence signal is weak and no longer tightly colocalized with condensed histone H4.

histone binding GO:0042393 ↓ DECREASED

Downstream

Reduced BRCA1-Mediated DNA Repair and Genomic Instability Weakened RBBP7-BRCA1 docking is proposed to destabilize BRCA1 at sites of DNA damage.

Show evidence (3 references)

PMID:37843278 SUPPORT Computational

"The loss of the RBBP7 short hydrophilic/charged C-terminal alpha-helix, which sits on top of and extends the RBBP7 N-terminal alpha-helix, affects its interaction with the key residue Arg35 of histone H4"

In silico structural modeling shows the truncation disrupts the histone H4 binding interface.

PMID:37843278 SUPPORT Computational

"The result showed a decrease in the energy (-9.5 kcal/mol) of the BRCT domain of BRCA1 interacting with mutant RBBP7, compared with that with wild-type RBBP7, which shows the energy of -10.9 kcal/mol"

Docking simulation shows reduced binding energy between mutant RBBP7 and the BRCA1 BRCT domain.

PMID:37843278 SUPPORT Human clinical

"However, in the sample of the proband, the signals of RBBP7 remained weak and associated with loosely distributed histone H4 signals (Figure 3J)."

Immunofluorescence in patient testis tissue confirms reduced RBBP7-histone H4 colocalization.

Reduced BRCA1-Mediated DNA Repair and Genomic Instability

BRCA1 protein is decreased and the double-strand-break marker gammaH2AX is increased in the proband's seminiferous tubules and testicular tumor tissue compared with controls, indicating impaired double-strand-break repair and accumulating genomic instability in germ and somatic testicular cells.

Impaired RBBP7-dependent genome stability links spermatogenic maturation arrest to testicular tumor predisposition through a shared mechanism

double-strand break repair GO:0006302 ↓ DECREASED

Downstream

Germ Cell Cycle Arrest and Apoptosis Modeled directly in mouse spermatogonial and spermatocyte-derived cell lines, where rbbp7 knockdown reproduces cell cycle arrest and apoptosis; not directly measured in patient germ cells.

Testicular Somatic Cell Hyperproliferation Proposed shared mechanism: the authors speculate that RBBP7 loss, acting through a reported RBBP7-CUL4B-HUWE1-BRCA1 pathway, could link spermatogenic failure to testicular tumor predisposition via the same genomic-instability route, rather than through two independent causes.

Show evidence (2 references)

PMID:37843278 SUPPORT Human clinical

"We also tested the BRCA1 expression in seminiferous tubules and testicular tumor tissue and found that BRCA1 was obviously decreased in the proband (Figure 3, M and N)."

Direct measurement of decreased BRCA1 in patient testicular tissue.

PMID:37843278 SUPPORT Human clinical

"A higher level of gammaH2AX in the seminiferous tubule of the proband was detected, compared with the control (Figure 3, O and P)."

Increased gammaH2AX marks accumulating DNA double-strand breaks in patient testis tissue.

Germ Cell Cycle Arrest and Apoptosis

In mouse spermatogonial (GC-1) and pachytene spermatocyte-derived (GC-2) cell lines, siRNA knockdown of rbbp7 reduces proliferation, increases apoptosis, and arrests cells at the G2/M transition.

spermatogonium CL:0000020 primary spermatocyte CL:0000656

apoptotic process GO:0006915 ↑ INCREASED G2/M transition of mitotic cell cycle GO:0000086 ↓ DECREASED

Experimental models

rbbp7 siRNA knockdown in mouse GC-1 and GC-2 germ cell lines CELL LINE

Downstream

Germ Cell Depletion and Spermatogenic Maturation Arrest Cellular arrest and apoptosis in germline cells, demonstrated directly in a Drosophila in vivo model, is proposed to deplete the germ cell pool and halt spermatogenesis before meiosis in the human testis.

Show evidence (3 references)

PMID:37843278 SUPPORT In vitro / ex vivo

"the cell proliferation of rbbp7-deprived cells was reduced in both GC-1 and GC-2 cells (Figure 4, E and F)."

Loss of rbbp7 reduces proliferation in two independent mouse germ cell lines.

PMID:37843278 SUPPORT In vitro / ex vivo

"Flow cytometry analysis revealed that a higher apoptosis rate of the rbbp7-deprived cells was also noted, as compared with the siRNA-negative groups (Figure 4, G and H)."

Loss of rbbp7 increases apoptosis in the same cell lines.

PMID:37843278 SUPPORT In vitro / ex vivo

"indicating that silencing rbbp7 led to cell cycle arrest at the G2/M phase."

Flow cytometry shows G2/M cell cycle arrest following rbbp7 knockdown.

Germ Cell Depletion and Spermatogenic Maturation Arrest

Testicular biopsy from the proband shows Sertoli cells present but only a few spermatogonia and no spermatocytes or mature sperm, consistent with early (pre-meiotic) maturation arrest. The same germ-cell-autonomous requirement for RBBP7/Caf1-55 is independently shown in Drosophila germline stem cells.

Sertoli cell CL:0000216 spermatogonium CL:0000020 primary spermatocyte CL:0000656

male germ-line stem cell population maintenance GO:0036098 ↓ DECREASED

Animal models

Caf1-55 germline- and cyst-cell-specific knockdown Drosophila melanogaster Drosophila recapitulates

Downstream

Non-Obstructive Azoospermia

Decreased Testicular Size

Elevated Follicle-Stimulating Hormone

Male Infertility

Show evidence (2 references)

PMID:37843278 SUPPORT Human clinical

"Results showed that Sertoli cells were obvious, but with only a few spermatogonia and no spermatocytes or sperm present in patient samples (Figure 1E), contrasting with the controls (Figure 1D)."

Histology of the proband's testis shows loss of germ cells beyond the spermatogonial stage, consistent with early maturation arrest.

PMID:35809576 SUPPORT INDIRECT Model organism

"We observed a complete lack of dBigH1- and Vasa-expressing cells at the tip of nos > Caf1-p55RNAi testes, revealing that RBBP7/Caf1-p55 is necessary for GSCs maintenance"

Independent Drosophila knockdown confirms RBBP7/Caf1-p55 is required for germline stem cell maintenance, supporting germ cell depletion as the tissue-level consequence.

Testicular Somatic Cell Hyperproliferation

In Drosophila, somatic cyst-cell-specific (rather than germline) knockdown of RBBP7/Caf1-55 causes hyperproliferative, tumor-like accumulation of cyst cells with elevated DNA double-strand breaks. Drosophila cyst cells are the somatic support-cell analog of mammalian Sertoli cells, not of Leydig cells, so this node records the somatic-hyperproliferation half of the proposed shared mechanism rather than a fly model of the human tumor itself; the human Leydig cell tumor finding is recorded on that phenotype.

Impaired RBBP7-dependent genome stability links spermatogenic maturation arrest to testicular tumor predisposition through a shared mechanism

double-strand break repair GO:0006302 ↓ DECREASED

Animal models

Caf1-55 germline- and cyst-cell-specific knockdown Drosophila melanogaster Drosophila partially recapitulates

Downstream

Leydig Cell Neoplasm Proposed by analogy to the fly somatic-cell result; Drosophila has no Leydig cell equivalent, so this edge is the hypothesis under test, not a demonstrated model of the human tumor.

Show evidence (3 references)

PMID:37843278 SUPPORT Model organism

"In Drosophila, knockdown of RBBP7/Caf1-55 in germ cells resulted in complete absence of germ cells and reduced testis size, whereas knockdown of RBBP7/Caf1-55 in cyst cells resulted in hyperproliferative testicular cells."

Somatic (cyst cell)-specific knockdown, unlike germline knockdown, produces hyperproliferation rather than cell loss.

PMID:37843278 SUPPORT Model organism

"cyst cells accumulated as tumor-like (Figure 6, A and B)."

Immunostaining shows tumor-like cyst cell accumulation following somatic Caf1-55 loss.

PMID:37843278 SUPPORT Model organism

"Knockdown of Caf1-55 in Drosophila somatic cyst cells also resulted in high DSB levels and overproliferated testicular cells."

Ties somatic genomic instability directly to the hyperproliferative phenotype in the fly model.

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Pathograph

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Phenotypes

5

Endocrine 1

Elevated Follicle-Stimulating Hormone Elevated circulating follicle stimulating hormone level HP:0008232

Show evidence (1 reference)

PMID:37843278 SUPPORT Human clinical

"Serum sex hormone tests showed that the levels of FSH were higher than normal, with 45.5 IU/L in the proband (II:1) and 18.76 IU/L in his brother (II:2)."

Reports the elevated FSH levels measured in both affected brothers.

Genitourinary 4

Male Infertility HP:0003251

Show evidence (1 reference)

PMID:37843278 SUPPORT Human clinical

"His wife had not conceived naturally after 3 years of unprotected sexual intercourse."

Documents the proband's infertility presentation.

Non-Obstructive Azoospermia HP:0011961

Show evidence (2 references)

PMID:37843278 SUPPORT Human clinical

"No mature spermatozoa were retrieved after sufficient grinding of the testicular tissue."

Confirms azoospermia on surgical sperm retrieval in the proband.

PMID:35809576 SUPPORT Human clinical

"RBBP7 is the most frequently mutated gene in our four cohorts: nine NOA-affected men carry variants not reported in gnomAD, three of them LoF."

Independent cohort confirms RBBP7 variants recur specifically among men with non-obstructive azoospermia. Cited directly rather than via PMID:37843278's restatement of this finding.

Decreased Testicular Size HP:0008734

Show evidence (1 reference)

PMID:37843278 SUPPORT Human clinical

"the patients' mean testicle size was abnormally small, with 3.6 mL in the proband (II:1) and 4.5 mL in his brother (II:2)."

Reports the measured small testicular volumes in both affected brothers.

Leydig Cell Neoplasm Leydig cell neoplasia HP:0100618

Show evidence (2 references)

PMID:37843278 SUPPORT Human clinical

"These results indicate that this neoplasm is a benign Leydig cell tumor (LCT)."

Establishes the proband's testicular mass as a benign Leydig cell tumor.

PMID:37843278 SUPPORT Human clinical

"RBBP7 signals were hardly detectable in the LCT of the proband, while histone H4 remained abundantly distributed (Figure 3, K and L)."

RBBP7 protein is lost in the patient's own tumor tissue, not only in bulk seminiferous tubule, directly linking the tumor to the same gene loss.

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Genetic Associations

1

RBBP7 (Causative)

Gene: RBBP7 (retinoblastoma-binding protein 7) hgnc:9890 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:37843278 SUPPORT Human clinical

"An identical hemizygous variant (NM_002893.4, c.1201ins1, p.W401M fs*4) was identified in the 2 brothers, occurring on chromosome Xp22.2 and affecting the last 2 exons of RBBP7."

Exome sequencing identifies the causal hemizygous RBBP7 variant shared by both affected brothers.

PMID:35809576 SUPPORT Human clinical

"the burden test showed that pathogenic variants in RBBP7 were significantly more common in infertile men than in gnomAD control individuals (adjusted p value = 5.07E-6)"

Independent cohort-level statistical burden test supports RBBP7 as causally associated with spermatogenic failure.

PMID:35809576 SUPPORT Human clinical

"The most frequently affected prioritized gene, RBBP7, was found mutated in ten men across all cohorts, and our functional studies in Drosophila support its role in germ stem cell maintenance."

RBBP7 is the most recurrently mutated candidate gene across four independent infertility cohorts.

Variants (1)

c.1200dupA (p.W401Mfs*5), hemizygous

A 1-bp insertion causing a frameshift and premature stop codon four amino acids later, truncating the last beta-propeller blade of the C-terminal WD40 domain. Hemizygous in both affected brothers; absent from population databases and from 103 additional unrelated men with non-obstructive azoospermia screened by restriction-fragment-length analysis. The source paper itself names this variant two ways: c.1201ins1/p.W401Mfs*4 in its main narrative and c.1200dupA/p.W401Mfs*5 in its Sanger-sequencing figure legend; the latter (used as this variant's name) matches the stated downstream truncation site.

Show evidence (2 references)

PMID:37843278 SUPPORT Human clinical

"This leads to an earlier translation stop codon 4 amino acids from the insertion position at the last WD40 domain of the RBBP7 protein (p.W401Mfs*5) (Figure 2B)."

Describes the frameshift and truncation produced by the variant.

PMID:37843278 SUPPORT Human clinical

"This RBBP7 mutation was not observed in those 103 unrelated patients with NOA."

The variant is not a common cause of non-obstructive azoospermia in this replication panel, consistent with genetic heterogeneity of the disease.

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Diagnosis

1

Genetic testing for RBBP7 variants in early maturation arrest

Sequencing of RBBP7, alone or as part of a non-obstructive azoospermia gene panel, can be considered in men with early maturation arrest (small testes, elevated FSH, histological absence of meiotic germ cells) once obstructive and chromosomal causes are excluded, both to establish a molecular diagnosis and to inform counseling about the reported association with testicular Leydig cell tumor.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:37843278 SUPPORT Human clinical

"Screening for X-linked RBBP7 variants in azoospermic men could improve genetic counseling for, diagnosis of, and treatment of azoospermia."

The founding study's own recommendation for RBBP7 screening in azoospermic men.

PMID:35809576 SUPPORT Human clinical

"three of them (RBBP7, PASD1, and SCML1) immediately reach the level of moderate evidence and can be added to a diagnostic gene panel"

An independent cohort study concludes RBBP7 is ready for inclusion in a clinical diagnostic gene panel.

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Experimental Models

1

rbbp7 siRNA knockdown in mouse GC-1 and GC-2 germ cell lines CELL_LINE

siRNA-mediated knockdown of rbbp7 in the mouse spermatogonial cell line GC-1 and the pachytene spermatocyte-derived cell line GC-2 reduces proliferation, increases apoptosis, and causes G2/M cell cycle arrest.

Publication

PMID:37843278

Pathograph links

Germ Cell Cycle Arrest and Apoptosis recapitulates fidelity: moderate observes: cellular

Limitations: Immortalized mouse germ-cell-derived lines, not primary human germ cells; they model the cell-autonomous consequence of RBBP7 loss but not tissue-level maturation arrest.

Readouts

Cell proliferation (CCK-8 assay)

Direction: DECREASED

Interpretation: rbbp7 knockdown reduces proliferation in both cell lines.

Show evidence (1 reference)

PMID:37843278 SUPPORT In vitro / ex vivo

"the cell proliferation of rbbp7-deprived cells was reduced in both GC-1 and GC-2 cells (Figure 4, E and F)."

Direct proliferation readout of rbbp7 knockdown in the cell-line model.

Apoptosis rate (Annexin V/PI flow cytometry)

Direction: INCREASED

Interpretation: rbbp7 knockdown increases the apoptotic fraction.

Show evidence (1 reference)

PMID:37843278 SUPPORT In vitro / ex vivo

"Flow cytometry analysis revealed that a higher apoptosis rate of the rbbp7-deprived cells was also noted, as compared with the siRNA-negative groups (Figure 4, G and H)."

Direct apoptosis readout of rbbp7 knockdown in the cell-line model.

Show evidence (1 reference)

PMID:37843278 SUPPORT In vitro / ex vivo

"indicating that silencing rbbp7 led to cell cycle arrest at the G2/M phase."

Supports treating this cell-line model as informative for the germ cell cycle arrest node.

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Animal Models

1

Caf1-55 germline- and cyst-cell-specific knockdown Drosophila melanogaster

Caf1-55 is the Drosophila ortholog of RBBP7, 96% identical at the amino acid level. Germline-specific knockdown (nos-GAL4) depletes germ cells and severely shrinks the testis, whereas somatic cyst-cell-specific knockdown (tj-GAL4) causes hyperproliferative, tumor-like cyst cells instead. Ectopic wild-type human RBBP7 rescues the male infertility caused by Caf1-55 deficiency; mutant human RBBP7 does not.

Species

Drosophila

Genotype

nos-GAL4 or tj-GAL4 driven Caf1-55 RNAi (Caf1-55 IR1, Caf1-55 IR2); Caf1-55 null (Caf1-55-/-)

Publication

PMID:37843278

Pathograph links

Germ Cell Depletion and Spermatogenic Maturation Arrest recapitulates fidelity: moderate observes: tissue

Limitations: Drosophila testis architecture and spermatogenesis differ substantially from mammalian testis; the germline-specific knockdown models cell-autonomous germ cell loss but not the human histological pattern of residual Sertoli cells with scattered spermatogonia.

Readouts

Germ cell presence (Vasa/dBigH1 immunostaining) and testis size

Direction: DECREASED

Interpretation: Germline knockdown of Caf1-55 depletes germ cells and reduces testis size.

Show evidence (1 reference)

PMID:37843278 SUPPORT Model organism

"In Drosophila, knockdown of RBBP7/Caf1-55 in germ cells resulted in complete absence of germ cells and reduced testis size, whereas knockdown of RBBP7/Caf1-55 in cyst cells resulted in hyperproliferative testicular cells."

Germline-specific knockdown reproduces germ cell loss and testis size reduction.

Show evidence (1 reference)

PMID:37843278 SUPPORT INDIRECT Model organism

"Interestingly, male infertility caused by Caf1-55 deficiency was rescued by ectopic expression of wild-type human RBBP7 but not mutant variants, suggesting the importance of RBBP7 in spermatogenesis."

Genetic rescue with wild-type but not mutant human RBBP7 supports the model's relevance to the human variant's loss-of-function effect.

Testicular Somatic Cell Hyperproliferation partially recapitulates fidelity: low observes: tissue

Limitations: No fly equivalent of a discrete, hormonally active Leydig cell tumor exists; the model demonstrates somatic hyperproliferation from genomic instability, which is the proposed shared mechanism, not a Leydig cell tumor itself.

Divergences from the human mechanism

species mismatch qualifying

Fly cyst cells support germ cells somatically and are not homologous to mammalian Leydig cells, which are steroidogenic rather than supportive; the model shows that somatic loss of Caf1-55 causes hyperproliferation, not that the resulting cells are a true Leydig cell tumor analog.

Readouts

Cyst cell accumulation and testis DSB marker staining

Direction: INCREASED

Interpretation: Somatic (cyst-cell) knockdown of Caf1-55 causes hyperproliferation with elevated DNA damage markers.

Show evidence (1 reference)

PMID:37843278 SUPPORT Model organism

"cyst cells accumulated as tumor-like (Figure 6, A and B)."

Direct readout of somatic cyst cell hyperproliferation following Caf1-55 loss.

Show evidence (1 reference)

PMID:37843278 SUPPORT INDIRECT Model organism

"Knockdown of Caf1-55 in Drosophila somatic cyst cells also resulted in high DSB levels and overproliferated testicular cells."

Links somatic genomic instability to hyperproliferation in the fly model, the basis for the proposed shared mechanism with the human Leydig cell tumor.

{ }

Source YAML

click to show

name: RBBP7-Related X-linked Spermatogenic Maturation Arrest
creation_date: "2026-10-30T03:30:00Z"
category: Mendelian
disease_term:
  preferred_term: spermatogenic failure, X-linked, 9
  term:
    id: MONDO:0976123
    label: spermatogenic failure, X-linked, 9
synonyms:
- spermatogenic failure, X-linked, 9
- SPGFX9
- RBBP7-related maturation arrest
description: >-
  RBBP7-related X-linked spermatogenic maturation arrest (spermatogenic
  failure, X-linked, 9; OMIM:301137) is a form of early maturation arrest, a
  histopathological subtype of non-obstructive azoospermia, caused by a
  hemizygous loss-of-function variant in X-linked RBBP7 (retinoblastoma-binding
  protein 7). RBBP7 is a WD40-repeat histone chaperone and core subunit of
  chromatin-modifier complexes such as CAF-1, binding histone H4 and the BRCT
  domain of BRCA1. A truncating RBBP7 variant identified in two brothers with
  early maturation arrest disrupted these interactions, was associated with
  reduced BRCA1 and increased DNA double-strand-break marker (gammaH2AX)
  staining in the testis, and co-occurred with a benign testicular Leydig cell
  tumor in the proband. Independently, a large X-chromosome exome screen of
  2,354 infertile men found RBBP7 to be the most frequently and significantly
  affected gene, and functional knockdown of the Drosophila ortholog Caf1-55
  showed that the gene is required for germline stem cell maintenance,
  supporting a causal role in human spermatogenic failure.
parents:
- hereditary disease
- male reproductive system disease
notes: >-
  No GeneReviews chapter covers this disorder; a PubMed search for "RBBP7"
  combined with "spermatogenic failure", "azoospermia", or "maturation arrest"
  (all fields, 2026-10-30) returned only the two primary sources cited here, no
  GeneReviews or StatPearls chapter. The causal RBBP7 truncating variant
  (c.1200dupA, p.W401Mfs*5) found in the founding family was absent from 103
  additional unrelated men with non-obstructive azoospermia screened by the
  same group and is distinct from the variants recurrently found in the
  independent 2,354-man cohort, so the allelic spectrum and overall prevalence
  of RBBP7-related disease remain unresolved. No external gene-disease validity
  classification (e.g., ClinGen) has been published for RBBP7 and male
  infertility as of this entry's creation. A deep-research pass
  (research/Spermatogenic_Failure_X-linked_9-deep-research-claude_code.md)
  surfaced Balboula et al. 2014 (PMID:24317350), which shows Rbbp7 knockdown in
  mouse oocytes causes chromosome missegregation and spindle-assembly-checkpoint
  failure via a histone-deacetylation route; it is not cited as pathophysiology
  evidence here because it is female-germline (oocyte meiosis) data and this
  entry's mechanism is specific to male germ cells.
references:
- reference: PMID:37843278
  title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
- reference: PMID:35809576
  title: "Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure."
inheritance:
- name: X-linked recessive inheritance
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    Two affected brothers were hemizygous for an identical RBBP7 frameshift
    variant with a single Sanger sequencing peak; their unaffected mother was
    heterozygous with a double peak, consistent with X-linked recessive
    transmission.
  evidence:
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients II:1 and II:2 had hemizygous mutations of RBBP7 with a single
      peak.
    explanation: Both affected brothers carry the variant hemizygously.
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Their mother (I:2) had a heterozygous mutation with a double peak
      (Figure 2A).
    explanation: The unaffected mother is a heterozygous carrier, consistent with X-linked recessive inheritance.
genetic:
- name: RBBP7
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: RBBP7 (retinoblastoma-binding protein 7)
    term:
      id: hgnc:9890
      label: RBBP7
  notes: >-
    Identified by whole-exome sequencing of a two-brother family with early
    maturation arrest; independently and more recently confirmed as the most
    recurrently affected gene in a 2,354-man X-chromosome exome screen, with a
    significant case-control burden of pathogenic variants. No ClinGen or
    other external gene-disease validity classification has been published;
    this is a research-level, not yet externally adjudicated, gene-disease
    association.
  evidence:
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An identical hemizygous variant (NM_002893.4, c.1201ins1, p.W401M fs*4)
      was identified in the 2 brothers, occurring on chromosome Xp22.2 and
      affecting the last 2 exons of RBBP7.
    explanation: Exome sequencing identifies the causal hemizygous RBBP7 variant shared by both affected brothers.
  - reference: PMID:35809576
    reference_title: "Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the burden test showed that pathogenic variants in RBBP7 were
      significantly more common in infertile men than in gnomAD control
      individuals (adjusted p value = 5.07E-6)
    explanation: Independent cohort-level statistical burden test supports RBBP7 as causally associated with spermatogenic failure.
  - reference: PMID:35809576
    reference_title: "Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most frequently affected prioritized gene, RBBP7, was found mutated
      in ten men across all cohorts, and our functional studies in Drosophila
      support its role in germ stem cell maintenance.
    explanation: RBBP7 is the most recurrently mutated candidate gene across four independent infertility cohorts.
  variants:
  - name: c.1200dupA (p.W401Mfs*5), hemizygous
    description: >-
      A 1-bp insertion causing a frameshift and premature stop codon four
      amino acids later, truncating the last beta-propeller blade of the
      C-terminal WD40 domain. Hemizygous in both affected brothers; absent
      from population databases and from 103 additional unrelated men with
      non-obstructive azoospermia screened by restriction-fragment-length
      analysis. The source paper itself names this variant two ways:
      c.1201ins1/p.W401Mfs*4 in its main narrative and c.1200dupA/p.W401Mfs*5
      in its Sanger-sequencing figure legend; the latter (used as this
      variant's name) matches the stated downstream truncation site.
    evidence:
    - reference: PMID:37843278
      reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This leads to an earlier translation stop codon 4 amino acids from
        the insertion position at the last WD40 domain of the RBBP7 protein
        (p.W401Mfs*5) (Figure 2B).
      explanation: Describes the frameshift and truncation produced by the variant.
    - reference: PMID:37843278
      reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This RBBP7 mutation was not observed in those 103 unrelated patients with NOA."
      explanation: The variant is not a common cause of non-obstructive azoospermia in this replication panel, consistent with genetic heterogeneity of the disease.
pathophysiology:
- name: Hemizygous RBBP7 Loss-of-Function Variant
  role: TRIGGER
  biological_scale: MOLECULAR
  description: >-
    A hemizygous frameshift variant (c.1200dupA, p.W401Mfs*5) truncates the
    last beta-propeller blade of the RBBP7 WD40 domain. Independently, a
    population-level burden of rare pathogenic RBBP7 variants is found across
    cohorts of men with non-obstructive azoospermia.
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    zygosity: HEMIZYGOUS
    description: >-
      The truncating allele removes the C-terminal hydrophilic/charged
      alpha-helix of the WD40 beta-propeller, with reduced RBBP7 protein
      detected in patient testicular tissue.
  genes:
  - preferred_term: RBBP7
    term:
      id: hgnc:9890
      label: RBBP7
  molecular_functions:
  - preferred_term: histone binding
    term:
      id: GO:0042393
      label: histone binding
    modifier: DECREASED
  evidence:
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This mutation resulted in premature protein translation termination,
      affecting the sixth WD40 domain of the RBBP7 and the interaction of the
      mutated RBBP7 with histone H4.
    explanation: States the structural consequence of the truncating variant on the RBBP7 WD40 domain.
  downstream:
  - target: Impaired RBBP7 Interaction with Histone H4 and BRCA1
    causal_link_type: DIRECT
    description: >-
      The truncated protein loses the C-terminal structural element required
      for its normal binding interfaces.
- name: Impaired RBBP7 Interaction with Histone H4 and BRCA1
  biological_scale: MOLECULAR
  description: >-
    Structural modeling shows the truncated RBBP7 loses hydrogen bonds with
    histone H4 and binds the BRCT domain of BRCA1 with reduced affinity, since
    both interactions use the same docking surface. In patient testis tissue,
    RBBP7 immunofluorescence signal is weak and no longer tightly colocalized
    with condensed histone H4.
  molecular_functions:
  - preferred_term: histone binding
    term:
      id: GO:0042393
      label: histone binding
    modifier: DECREASED
  evidence:
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The loss of the RBBP7 short hydrophilic/charged C-terminal alpha-helix,
      which sits on top of and extends the RBBP7 N-terminal alpha-helix,
      affects its interaction with the key residue Arg35 of histone H4
    explanation: In silico structural modeling shows the truncation disrupts the histone H4 binding interface.
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The result showed a decrease in the energy (-9.5 kcal/mol) of the BRCT
      domain of BRCA1 interacting with mutant RBBP7, compared with that with
      wild-type RBBP7, which shows the energy of -10.9 kcal/mol
    explanation: Docking simulation shows reduced binding energy between mutant RBBP7 and the BRCA1 BRCT domain.
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, in the sample of the proband, the signals of RBBP7 remained
      weak and associated with loosely distributed histone H4 signals
      (Figure 3J).
    explanation: Immunofluorescence in patient testis tissue confirms reduced RBBP7-histone H4 colocalization.
  downstream:
  - target: Reduced BRCA1-Mediated DNA Repair and Genomic Instability
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Weakened RBBP7-BRCA1 docking is proposed to destabilize BRCA1 at sites
      of DNA damage.
- name: Reduced BRCA1-Mediated DNA Repair and Genomic Instability
  biological_scale: CELLULAR
  description: >-
    BRCA1 protein is decreased and the double-strand-break marker gammaH2AX is
    increased in the proband's seminiferous tubules and testicular tumor
    tissue compared with controls, indicating impaired double-strand-break
    repair and accumulating genomic instability in germ and somatic
    testicular cells.
  biological_processes:
  - preferred_term: double-strand break repair
    term:
      id: GO:0006302
      label: double-strand break repair
    modifier: DECREASED
  evidence:
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also tested the BRCA1 expression in seminiferous tubules and
      testicular tumor tissue and found that BRCA1 was obviously decreased in
      the proband (Figure 3, M and N).
    explanation: Direct measurement of decreased BRCA1 in patient testicular tissue.
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A higher level of gammaH2AX in the seminiferous tubule of the proband
      was detected, compared with the control (Figure 3, O and P).
    explanation: Increased gammaH2AX marks accumulating DNA double-strand breaks in patient testis tissue.
  downstream:
  - target: Germ Cell Cycle Arrest and Apoptosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Modeled directly in mouse spermatogonial and spermatocyte-derived cell
      lines, where rbbp7 knockdown reproduces cell cycle arrest and apoptosis;
      not directly measured in patient germ cells.
  - target: Testicular Somatic Cell Hyperproliferation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - rbbp7_shared_dsb_repair_and_tumor_risk
    description: >-
      Proposed shared mechanism: the authors speculate that RBBP7 loss, acting
      through a reported RBBP7-CUL4B-HUWE1-BRCA1 pathway, could link
      spermatogenic failure to testicular tumor predisposition via the same
      genomic-instability route, rather than through two independent causes.
    evidence:
    - reference: PMID:35809576
      reference_title: "Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        we speculate that RBBP7, CUL4B, or HUWE1 may lead to both
        spermatogenic failure and cancer predisposition.
      explanation: The authors' own interpretive hypothesis linking the RBBP7/CUL4B/HUWE1/BRCA1 axis to both infertility and cancer risk, not a directly demonstrated causal link.
    - reference: PMID:35809576
      reference_title: "Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: BACKGROUND
      evidence_source: IN_VITRO
      snippet: >-
        knockdown of RBBP7 through siRNA in cell culture leads to a shortened
        BRCA1 half-life as a result of the lack of HUWE1 inhibition
      explanation: >-
        PMID:35809576 cites this siRNA/HUWE1 finding (its own reference 58) to
        motivate the CRL4B-RBBP7-HUWE1-BRCA1 route it then speculates about;
        it is not this paper's own experiment. Names a specific candidate
        molecular route (RBBP7-CUL4B complex normally degrades HUWE1, and
        HUWE1 in turn degrades BRCA1) for how RBBP7 loss could reduce BRCA1,
        distinct from the direct H4/BRCA1 binding-disruption route above;
        still a proposed, not demonstrated, mechanism.
    - reference: PMID:37843278
      reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        Thus, the concurrent presence of male infertility and LCT may be
        linked to RBBP7 mutations affecting key genome stability factors,
        such as histone H4 and BRCA1.
      explanation: The founding family's own authors frame the tumor-infertility co-occurrence as a proposed, not established, shared mechanism.
- name: Germ Cell Cycle Arrest and Apoptosis
  biological_scale: CELLULAR
  description: >-
    In mouse spermatogonial (GC-1) and pachytene spermatocyte-derived (GC-2)
    cell lines, siRNA knockdown of rbbp7 reduces proliferation, increases
    apoptosis, and arrests cells at the G2/M transition.
  cell_types:
  - preferred_term: spermatogonium
    term:
      id: CL:0000020
      label: spermatogonium
  - preferred_term: primary spermatocyte
    term:
      id: CL:0000656
      label: primary spermatocyte
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  - preferred_term: G2/M transition of mitotic cell cycle
    term:
      id: GO:0000086
      label: G2/M transition of mitotic cell cycle
    modifier: DECREASED
  evidence:
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the cell proliferation of rbbp7-deprived cells was reduced in both GC-1
      and GC-2 cells (Figure 4, E and F).
    explanation: Loss of rbbp7 reduces proliferation in two independent mouse germ cell lines.
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Flow cytometry analysis revealed that a higher apoptosis rate of the
      rbbp7-deprived cells was also noted, as compared with the
      siRNA-negative groups (Figure 4, G and H).
    explanation: Loss of rbbp7 increases apoptosis in the same cell lines.
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "indicating that silencing rbbp7 led to cell cycle arrest at the G2/M phase."
    explanation: Flow cytometry shows G2/M cell cycle arrest following rbbp7 knockdown.
  downstream:
  - target: Germ Cell Depletion and Spermatogenic Maturation Arrest
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Cellular arrest and apoptosis in germline cells, demonstrated directly
      in a Drosophila in vivo model, is proposed to deplete the germ cell pool
      and halt spermatogenesis before meiosis in the human testis.
    evidence:
    - reference: PMID:37843278
      reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In Drosophila, knockdown of RBBP7/Caf1-55 in germ cells resulted in
        complete absence of germ cells and reduced testis size, whereas
        knockdown of RBBP7/Caf1-55 in cyst cells resulted in hyperproliferative
        testicular cells.
      explanation: Germline-specific knockdown of the fly ortholog shows that cell-autonomous loss of RBBP7/Caf1-55 depletes germ cells, bridging the cellular arrest/apoptosis node to tissue-level germ cell loss.
- name: Germ Cell Depletion and Spermatogenic Maturation Arrest
  biological_scale: TISSUE
  description: >-
    Testicular biopsy from the proband shows Sertoli cells present but only a
    few spermatogonia and no spermatocytes or mature sperm, consistent with
    early (pre-meiotic) maturation arrest. The same germ-cell-autonomous
    requirement for RBBP7/Caf1-55 is independently shown in Drosophila
    germline stem cells.
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  - preferred_term: spermatogonium
    term:
      id: CL:0000020
      label: spermatogonium
  - preferred_term: primary spermatocyte
    term:
      id: CL:0000656
      label: primary spermatocyte
  biological_processes:
  - preferred_term: male germ-line stem cell population maintenance
    term:
      id: GO:0036098
      label: male germ-line stem cell population maintenance
    modifier: DECREASED
  evidence:
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Results showed that Sertoli cells were obvious, but with only a few
      spermatogonia and no spermatocytes or sperm present in patient samples
      (Figure 1E), contrasting with the controls (Figure 1D).
    explanation: Histology of the proband's testis shows loss of germ cells beyond the spermatogonial stage, consistent with early maturation arrest.
  - reference: PMID:35809576
    reference_title: "Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We observed a complete lack of dBigH1- and Vasa-expressing cells at the
      tip of nos > Caf1-p55RNAi testes, revealing that RBBP7/Caf1-p55 is
      necessary for GSCs maintenance
    explanation: Independent Drosophila knockdown confirms RBBP7/Caf1-p55 is required for germline stem cell maintenance, supporting germ cell depletion as the tissue-level consequence.
  downstream:
  - target: Non-Obstructive Azoospermia
  - target: Decreased Testicular Size
  - target: Elevated Follicle-Stimulating Hormone
  - target: Male Infertility
- name: Testicular Somatic Cell Hyperproliferation
  biological_scale: TISSUE
  description: >-
    In Drosophila, somatic cyst-cell-specific (rather than germline) knockdown
    of RBBP7/Caf1-55 causes hyperproliferative, tumor-like accumulation of
    cyst cells with elevated DNA double-strand breaks. Drosophila cyst cells
    are the somatic support-cell analog of mammalian Sertoli cells, not of
    Leydig cells, so this node records the somatic-hyperproliferation half of
    the proposed shared mechanism rather than a fly model of the human tumor
    itself; the human Leydig cell tumor finding is recorded on that phenotype.
  biological_processes:
  - preferred_term: double-strand break repair
    term:
      id: GO:0006302
      label: double-strand break repair
    modifier: DECREASED
  evidence:
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In Drosophila, knockdown of RBBP7/Caf1-55 in germ cells resulted in
      complete absence of germ cells and reduced testis size, whereas
      knockdown of RBBP7/Caf1-55 in cyst cells resulted in hyperproliferative
      testicular cells.
    explanation: Somatic (cyst cell)-specific knockdown, unlike germline knockdown, produces hyperproliferation rather than cell loss.
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "cyst cells accumulated as tumor-like (Figure 6, A and B)."
    explanation: Immunostaining shows tumor-like cyst cell accumulation following somatic Caf1-55 loss.
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Knockdown of Caf1-55 in Drosophila somatic cyst cells also resulted in high DSB levels and overproliferated testicular cells."
    explanation: Ties somatic genomic instability directly to the hyperproliferative phenotype in the fly model.
  downstream:
  - target: Leydig Cell Neoplasm
    hypothesis_groups:
    - rbbp7_shared_dsb_repair_and_tumor_risk
    description: >-
      Proposed by analogy to the fly somatic-cell result; Drosophila has no
      Leydig cell equivalent, so this edge is the hypothesis under test, not a
      demonstrated model of the human tumor.
phenotypes:
- name: Male Infertility
  category: Reproductive
  description: >-
    Both brothers were unable to conceive naturally with their partners after
    years of unprotected intercourse.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His wife had not conceived naturally after 3 years of unprotected
      sexual intercourse.
    explanation: Documents the proband's infertility presentation.
- name: Non-Obstructive Azoospermia
  category: Reproductive
  description: >-
    No mature spermatozoa were retrieved from either brother by
    microdissection testicular sperm extraction, with normal karyotype and no
    Y-chromosome azoospermia factor microdeletion, consistent with
    non-obstructive azoospermia from early (pre-meiotic) maturation arrest.
  phenotype_term:
    preferred_term: Non-obstructive azoospermia
    term:
      id: HP:0011961
      label: Non-obstructive azoospermia
  evidence:
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No mature spermatozoa were retrieved after sufficient grinding of the testicular tissue."
    explanation: Confirms azoospermia on surgical sperm retrieval in the proband.
  - reference: PMID:35809576
    reference_title: "Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RBBP7 is the most frequently mutated gene in our four cohorts: nine
      NOA-affected men carry variants not reported in gnomAD, three of them
      LoF.
    explanation: Independent cohort confirms RBBP7 variants recur specifically among men with non-obstructive azoospermia. Cited directly rather than via PMID:37843278's restatement of this finding.
- name: Decreased Testicular Size
  category: Reproductive
  description: >-
    Both brothers had abnormally small testes on ultrasound examination.
  phenotype_term:
    preferred_term: Decreased testicular size
    term:
      id: HP:0008734
      label: Decreased testicular size
  evidence:
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the patients' mean testicle size was abnormally small, with 3.6 mL in
      the proband (II:1) and 4.5 mL in his brother (II:2).
    explanation: Reports the measured small testicular volumes in both affected brothers.
- name: Elevated Follicle-Stimulating Hormone
  category: Endocrine
  description: >-
    Serum FSH levels were above normal in both brothers, consistent with
    primary (early) spermatogenic failure.
  phenotype_term:
    preferred_term: Elevated circulating follicle stimulating hormone level
    term:
      id: HP:0008232
      label: Elevated circulating follicle stimulating hormone level
  evidence:
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serum sex hormone tests showed that the levels of FSH were higher than
      normal, with 45.5 IU/L in the proband (II:1) and 18.76 IU/L in his
      brother (II:2).
    explanation: Reports the elevated FSH levels measured in both affected brothers.
- name: Leydig Cell Neoplasm
  category: Neoplasm
  description: >-
    The proband developed a benign, well-circumscribed Leydig cell tumor in
    one testis, diagnosed by ultrasound and confirmed by histopathology and
    immunostaining (inhibin-positive, Wilms' tumor 1-negative). RBBP7 protein
    was undetectable and BRCA1 was decreased in the tumor tissue itself,
    consistent with the same genomic-instability mechanism proposed for the
    germline phenotype operating in the tumor.
  phenotype_term:
    preferred_term: Leydig cell tumor
    term:
      id: HP:0100618
      label: Leydig cell neoplasia
  evidence:
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results indicate that this neoplasm is a benign Leydig cell tumor (LCT)."
    explanation: Establishes the proband's testicular mass as a benign Leydig cell tumor.
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RBBP7 signals were hardly detectable in the LCT of the proband, while
      histone H4 remained abundantly distributed (Figure 3, K and L).
    explanation: RBBP7 protein is lost in the patient's own tumor tissue, not only in bulk seminiferous tubule, directly linking the tumor to the same gene loss.
diagnosis:
- name: Genetic testing for RBBP7 variants in early maturation arrest
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Sequencing of RBBP7, alone or as part of a non-obstructive azoospermia
    gene panel, can be considered in men with early maturation arrest
    (small testes, elevated FSH, histological absence of meiotic germ cells)
    once obstructive and chromosomal causes are excluded, both to establish a
    molecular diagnosis and to inform counseling about the reported
    association with testicular Leydig cell tumor.
  evidence:
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Screening for X-linked RBBP7 variants in azoospermic men could improve
      genetic counseling for, diagnosis of, and treatment of azoospermia.
    explanation: The founding study's own recommendation for RBBP7 screening in azoospermic men.
  - reference: PMID:35809576
    reference_title: "Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      three of them (RBBP7, PASD1, and SCML1) immediately reach the level of
      moderate evidence and can be added to a diagnostic gene panel
    explanation: An independent cohort study concludes RBBP7 is ready for inclusion in a clinical diagnostic gene panel.
experimental_models:
- name: rbbp7 siRNA knockdown in mouse GC-1 and GC-2 germ cell lines
  experimental_model_type: CELL_LINE
  description: >-
    siRNA-mediated knockdown of rbbp7 in the mouse spermatogonial cell line
    GC-1 and the pachytene spermatocyte-derived cell line GC-2 reduces
    proliferation, increases apoptosis, and causes G2/M cell cycle arrest.
  publication: PMID:37843278
  modeled_mechanisms:
  - target: Germ Cell Cycle Arrest and Apoptosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    limitations: >-
      Immortalized mouse germ-cell-derived lines, not primary human germ
      cells; they model the cell-autonomous consequence of RBBP7 loss but not
      tissue-level maturation arrest.
    readouts:
    - name: Cell proliferation (CCK-8 assay)
      target: Germ Cell Cycle Arrest and Apoptosis
      direction: DECREASED
      interpretation: rbbp7 knockdown reduces proliferation in both cell lines.
      evidence:
      - reference: PMID:37843278
        reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          the cell proliferation of rbbp7-deprived cells was reduced in both
          GC-1 and GC-2 cells (Figure 4, E and F).
        explanation: Direct proliferation readout of rbbp7 knockdown in the cell-line model.
    - name: Apoptosis rate (Annexin V/PI flow cytometry)
      target: Germ Cell Cycle Arrest and Apoptosis
      direction: INCREASED
      interpretation: rbbp7 knockdown increases the apoptotic fraction.
      evidence:
      - reference: PMID:37843278
        reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Flow cytometry analysis revealed that a higher apoptosis rate of
          the rbbp7-deprived cells was also noted, as compared with the
          siRNA-negative groups (Figure 4, G and H).
        explanation: Direct apoptosis readout of rbbp7 knockdown in the cell-line model.
    evidence:
    - reference: PMID:37843278
      reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "indicating that silencing rbbp7 led to cell cycle arrest at the G2/M phase."
      explanation: Supports treating this cell-line model as informative for the germ cell cycle arrest node.
animal_models:
- name: Caf1-55 germline- and cyst-cell-specific knockdown Drosophila melanogaster
  species: Drosophila
  genotype: "nos-GAL4 or tj-GAL4 driven Caf1-55 RNAi (Caf1-55 IR1, Caf1-55 IR2); Caf1-55 null (Caf1-55-/-)"
  publication: PMID:37843278
  description: >-
    Caf1-55 is the Drosophila ortholog of RBBP7, 96% identical at the amino
    acid level. Germline-specific knockdown (nos-GAL4) depletes germ cells and
    severely shrinks the testis, whereas somatic cyst-cell-specific knockdown
    (tj-GAL4) causes hyperproliferative, tumor-like cyst cells instead.
    Ectopic wild-type human RBBP7 rescues the male infertility caused by
    Caf1-55 deficiency; mutant human RBBP7 does not.
  modeled_mechanisms:
  - target: Germ Cell Depletion and Spermatogenic Maturation Arrest
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    limitations: >-
      Drosophila testis architecture and spermatogenesis differ substantially
      from mammalian testis; the germline-specific knockdown models
      cell-autonomous germ cell loss but not the human histological pattern of
      residual Sertoli cells with scattered spermatogonia.
    readouts:
    - name: Germ cell presence (Vasa/dBigH1 immunostaining) and testis size
      target: Germ Cell Depletion and Spermatogenic Maturation Arrest
      direction: DECREASED
      interpretation: Germline knockdown of Caf1-55 depletes germ cells and reduces testis size.
      evidence:
      - reference: PMID:37843278
        reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In Drosophila, knockdown of RBBP7/Caf1-55 in germ cells resulted in
          complete absence of germ cells and reduced testis size, whereas
          knockdown of RBBP7/Caf1-55 in cyst cells resulted in
          hyperproliferative testicular cells.
        explanation: Germline-specific knockdown reproduces germ cell loss and testis size reduction.
    evidence:
    - reference: PMID:37843278
      reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Interestingly, male infertility caused by Caf1-55 deficiency was
        rescued by ectopic expression of wild-type human RBBP7 but not mutant
        variants, suggesting the importance of RBBP7 in spermatogenesis.
      explanation: Genetic rescue with wild-type but not mutant human RBBP7 supports the model's relevance to the human variant's loss-of-function effect.
  - target: Testicular Somatic Cell Hyperproliferation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Fly cyst cells support germ cells somatically and are not
        homologous to mammalian Leydig cells, which are steroidogenic rather
        than supportive; the model shows that somatic loss of Caf1-55 causes
        hyperproliferation, not that the resulting cells are a true Leydig
        cell tumor analog.
    limitations: >-
      No fly equivalent of a discrete, hormonally active Leydig cell tumor
      exists; the model demonstrates somatic hyperproliferation from genomic
      instability, which is the proposed shared mechanism, not a Leydig cell
      tumor itself.
    readouts:
    - name: Cyst cell accumulation and testis DSB marker staining
      target: Testicular Somatic Cell Hyperproliferation
      direction: INCREASED
      interpretation: Somatic (cyst-cell) knockdown of Caf1-55 causes hyperproliferation with elevated DNA damage markers.
      evidence:
      - reference: PMID:37843278
        reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "cyst cells accumulated as tumor-like (Figure 6, A and B)."
        explanation: Direct readout of somatic cyst cell hyperproliferation following Caf1-55 loss.
    evidence:
    - reference: PMID:37843278
      reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Knockdown of Caf1-55 in Drosophila somatic cyst cells also resulted in high DSB levels and overproliferated testicular cells."
      explanation: Links somatic genomic instability to hyperproliferation in the fly model, the basis for the proposed shared mechanism with the human Leydig cell tumor.
mechanistic_hypotheses:
- hypothesis_group_id: rbbp7_shared_dsb_repair_and_tumor_risk
  hypothesis_label: >-
    Impaired RBBP7-dependent genome stability links spermatogenic maturation
    arrest to testicular tumor predisposition through a shared mechanism
  status: EMERGING
  description: >-
    The founding family shows co-occurrence of early maturation arrest and a
    benign Leydig cell tumor in the same proband, with RBBP7 and BRCA1 both
    decreased and gammaH2AX increased in the tumor tissue. The authors
    propose that RBBP7 loss, via a reported RBBP7-CUL4B-HUWE1-BRCA1 axis,
    could predispose to both spermatogenic failure and testicular neoplasia
    through one underlying defect in genome stability, rather than through two
    unrelated events. This rests on a single kindred; whether it generalizes
    is an open question (see the linked discussion). Downstream causal edges
    that belong to this hypothesis opt in via
    hypothesis_groups: [rbbp7_shared_dsb_repair_and_tumor_risk].
  evidence:
  - reference: PMID:35809576
    reference_title: "Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      we speculate that RBBP7, CUL4B, or HUWE1 may lead to both spermatogenic
      failure and cancer predisposition.
    explanation: States the proposed shared-mechanism hypothesis in the authors' own words.
discussions:
- discussion_id: rbbp7_tumor_cooccurrence_generalizability
  prompt: >-
    Does RBBP7-related genome instability generally predispose to testicular
    tumor as well as spermatogenic failure, or was the Leydig cell tumor in
    the founding proband an independent, coincidental finding?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced BRCA1-Mediated DNA Repair and Genomic Instability
  - pathophysiology#Testicular Somatic Cell Hyperproliferation
  - phenotypes#Leydig Cell Neoplasm
  rationale: >-
    The tumor-infertility link rests on one proband in one kindred; his
    brother, who carries the identical hemizygous variant, was not reported to
    have a testicular mass. The variant was also absent from 103 additional
    unrelated men with non-obstructive azoospermia, and the independent
    2,354-man cohort that recurrently found RBBP7 variants did not report
    testicular tumors in those men. Resolving this needs systematic imaging
    and tumor-marker surveillance across a larger series of RBBP7-variant
    carriers with non-obstructive azoospermia.
  evidence:
  - reference: PMID:37843278
    reference_title: X-linked RBBP7 mutation causes maturation arrest and testicular tumors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The involvement of RBBP7 in testicular tumors has not been previously
      reported to our knowledge.
    explanation: The authors themselves note this is a novel, single-family observation rather than an established association.

📚

References & Deep Research

References

2

PMID:37843278

X-linked RBBP7 mutation causes maturation arrest and testicular tumors.

No top-level findings curated for this source.

PMID:35809576

Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (2)

Record notes

No GeneReviews chapter covers this disorder; a PubMed search for "RBBP7" combined with "spermatogenic failure", "azoospermia", or "maturation arrest" (all fields, 2026-10-30) returned only the two primary sources cited here, no GeneReviews or StatPearls chapter. The causal RBBP7 truncating variant (c.1200dupA, p.W401Mfs*5) found in the founding family was absent from 103 additional unrelated men with non-obstructive azoospermia screened by the same group and is distinct from the variants recurrently found in the independent 2,354-man cohort, so the allelic spectrum and overall prevalence of RBBP7-related disease remain unresolved. No external gene-disease validity classification (e.g., ClinGen) has been published for RBBP7 and male infertility as of this entry's creation. A deep-research pass (research/Spermatogenic_Failure_X-linked_9-deep-research-claude_code.md) surfaced Balboula et al. 2014 (PMID:24317350), which shows Rbbp7 knockdown in mouse oocytes causes chromosome missegregation and spindle-assembly-checkpoint failure via a histone-deacetylation route; it is not cited as pathophysiology evidence here because it is female-germline (oocyte meiosis) data and this entry's mechanism is specific to male germ cells.

Address review round 1: debundle Leydig tumor node, add deep-research artifact · 2026-10-30T04:31:17Z · View source

Addressed the automated reviewer's findings on PR #15977. Ran the required deep-research step (just research-disorder claude_code), producing research/Spermatogenic_Failure_X-linked_9-deep-research-claude_code.md (and .citations.md): 8/8 references verified, 0 confabulation. The report surfaced and I fetched one additional reference, PMID:24317350 (Balboula et al. 2014, mouse oocyte Rbbp7 knockdown), but did not cite it as pathophysiology evidence since it is female-germline (oocyte meiosis) data outside this entry's male-specific mechanism; noted in top-level notes instead. Debundled the pathophysiology node 'Testicular Somatic Cell Hyperproliferation and Leydig Cell Tumor', which mixed the Drosophila cyst-cell result with the human tumor finding and duplicated its own phenotype target: split into a fly-only 'Testicular Somatic Cell Hyperproliferation' node (downstream to the Leydig Cell Neoplasm phenotype, keeping the EMERGING hypothesis_groups tag) and moved the human RBBP7/BRCA1-loss-in-tumor-tissue evidence onto the Leydig Cell Neoplasm phenotype itself; updated the animal_models modeled_mechanisms targets/readouts and the discussions attaches_to reference accordingly, and removed the CL:0000178 Leydig cell binding from the fly-only node (Drosophila cyst cells are the Sertoli-cell analog, not a Leydig cell analog). Added a second mechanistic-hypothesis edge citing PMID:35809576's CRL4B-RBBP7-HUWE1-BRCA1 degradation route (marked quote_role: BACKGROUND, since that paper is citing its own reference 58's siRNA finding rather than reporting new data). Replaced a Non-Obstructive Azoospermia evidence item that quoted PMID:37843278's restatement of Riera-Escamilla's cohort finding with a direct quote from PMID:35809576 itself. Added CL:0000656 primary spermatocyte to the Germ Cell Cycle Arrest and Apoptosis node (GC-2 is spermatocyte-derived) and GO:0036098 (male germ-line stem cell population maintenance, DECREASED) plus a downstream edge to the Male Infertility phenotype on the Germ Cell Depletion node, which closed the one disconnected-phenotype gap the reviewer flagged (list-disconnected-phenotypes now reports 5/5 connected). Added a sentence to the causal variant's description noting the source paper names it two ways (c.1201ins1/p.W401Mfs*4 in its main text, c.1200dupA/p.W401Mfs*5 in its Sanger figure legend). Re-ran just validate, just validate-disorders, just count-verified-snippets (43/43), just validate-terms, just check-entity-refs, just check-causal-targets, just check-gene-activity-grounding, just check-logical-rules, just check-coarse-phenotypes, just check-duplicate-keys, just check-enum-values, just check-snippet-grading, just model-scale-audit --strict, and just list-disconnected-phenotypes; all pass.

Claude Code ▸

1. Disease Information

claude-haiku-5-5, claude-opus-5-5 10 citations 2026-10-30T04:16:45.669996

1. Disease Information

Overview. SPGFX9 is a monogenic form of male infertility caused by hemizygous loss-of-function variants in the X-linked gene RBBP7 (retinoblastoma-binding protein 7, also called RbAp46). It presents as non-obstructive azoospermia (NOA). On histology it is early maturation arrest: Sertoli cells are present, spermatogonia are few, and there are no spermatocytes or sperm. In the founding family the proband also had a benign Leydig cell tumor.

Li et al. 2023 (PMID:37843278, J Clin Invest): "we identified a deleterious hemizygous variant of X-linked retinoblastoma-binding protein 7 (RBBP7) as a potential key cause of MA, which was also found to be associated with the development of Leydig cell tumors."
Riera-Escamilla et al. 2022 (PMID:35809576, Am J Hum Genet): "The most frequently affected prioritized gene, RBBP7, was found mutated in ten men across all cohorts, and our functional studies in Drosophila support its role in germ stem cell maintenance."

Identifiers

System	ID
MONDO	MONDO:0976123 (spermatogenic failure, X-linked, 9)
OMIM	301137 (phenotype); 300825 (RBBP7 gene)
DOID	DOID:0061177 (Disease Ontology)
Orphanet	No disorder-specific ORPHA code found. It falls under the general NOA/male infertility groupings.
ICD-10 / ICD-11	No specific code. Nearest: N46.01 (azoospermia, organic) / GB04.0 (male infertility due to azoospermia).
MeSH	Azoospermia (D053713); Infertility, Male (D007248)

Synonyms: spermatogenic failure, X-linked, 9; SPGFX9; RBBP7-related maturation arrest; X-linked RBBP7 maturation arrest.

Data provenance: all of the evidence comes from individual patients: one family, plus 10 men from aggregated sequencing cohorts. No registry or EHR-derived data exist.

2. Etiology

Cause: germline, hemizygous, X-linked loss-of-function variants in RBBP7.
Genetic risk factors:
Family variant: c.1200dupA, p.W401Mfs5 (NM_002893.4; the paper also writes it as c.1201ins1, p.W401Mfs4). It was found in two brothers.
Cohort variants: 10 men in a 2,354-man X-chromosome exome screen carried RBBP7 variants, three of them loss-of-function. Burden versus gnomAD gave an adjusted p = 5.07E−6 (PMID:35809576).
Environmental risk factors: none described. The founding family had no mumps orchitis, trauma, toxins, radiation, STIs, anabolic steroids or chemotherapy (PMID:37843278).
Protective factors and gene–environment interactions: none reported.
Possible modifiers (speculative): Riera-Escamilla et al. suggest RBBP7 forms a CRL4B^RBBP7 complex with CUL4B, which degrades HUWE1. They note that both CUL4B and HUWE1 carried variants in infertile men. This is a hypothesis about a possible pathway interaction, not an established modifier effect: "we speculate that RBBP7, CUL4B, or HUWE1 may lead to both spermatogenic failure and cancer predisposition."

3. Phenotypes

Phenotype	Suggested HPO	Type	Onset	Frequency / evidence
Male infertility	HP:0003251 Male infertility	Clinical sign	Recognized in adulthood (2–3 years of failure to conceive)	2/2 brothers; 10/10 cohort carriers
Non-obstructive azoospermia	HP:0011961 Non-obstructive azoospermia	Laboratory / clinical	Adult presentation; congenital in nature	2/2 (family); cohort = NOA/cryptozoospermia
Early maturation arrest (spermatogonial/meiotic)	No precise HPO term. Consider HP:0011961 plus a free-text descriptor; check HPO for a "spermatogenic maturation arrest" term.	Histopathology	—	2/2 brothers (mTESE histology)
Decreased testicular size	HP:0008734 Decreased testicular size	Physical sign	Adult	2/2 (3.6 mL and 4.5 mL)
Elevated FSH	HP:0008232 Elevated circulating follicle stimulating hormone level	Laboratory	Adult	2/2 (45.5 and 18.76 IU/L)
Leydig cell tumor (benign)	HP:0100618 Leydig cell neoplasia	Neoplasm	Adult (27 y)	1/2 (proband only)
Variable LH and testosterone	(HP:0040085 Abnormal circulating testosterone — [verify])	Laboratory	Adult	Discordant between the brothers
Failed sperm retrieval at mTESE	—	Procedure outcome	—	2/2

Supporting quotes (PMID:37843278): - "Sertoli cells were obvious, but with only a few spermatogonia and no spermatocytes or sperm present in patient samples" - "the levels of FSH were higher than normal, with 45.5 IU/L in the proband (II:1) and 18.76 IU/L in his brother (II:2)" - "the patients' mean testicle size was abnormally small, with 3.6 mL in the proband (II:1) and 4.5 mL in his brother (II:2)" - "these results indicate that this neoplasm is a benign Leydig cell tumor (LCT)."

Severity and course: spermatogenic failure is complete in the reported patients, and the condition appears stable rather than progressive. The disease is non-syndromic: general health was normal and erectile and ejaculatory function were preserved.

Quality of life: no disease-specific data. The general NOA literature describes the psychosocial burden of infertility. The Leydig cell tumor needed surgery (testis-sparing enucleation).

4. Genetic / Molecular Information

Causal gene: RBBP7, hgnc:9890, Xp22.2. It encodes a 425-aa WD40-repeat histone chaperone, a 7-bladed β-propeller with an N-terminal α-helix and a short C-terminal α-helix. It is a core subunit of CAF-1, NuRD, Sin3-HDAC and PRC2-type chromatin complexes, and is ubiquitously expressed.

Variants

Variant	Type	Origin	Classification	Population frequency	Source
NM_002893.4: c.1200dupA, p.(Trp401Metfs*5)	Frameshift (1-bp insertion in the last 2 exons, sixth/last WD40 blade)	Germline; maternally inherited (heterozygous mother)	Predicted pathogenic (FATHMM-indel, CRAVAT, SIFT_indels2). No ClinVar classification was found.	Absent from 1000G, ESP6500, ExAC and gnomAD; absent from 103 further Chinese NOA men	PMID:37843278
10 rare variants in 10 men (3 LoF, others missense)	LoF + missense	Germline, hemizygous	Prioritized as a "strong candidate" (score ≥5)	Not in gnomAD	PMID:35809576 (variant details are in its Fig. 2 / Table S4)

Supporting quotes: - "An identical hemizygous variant (NM_002893.4, c.1201ins1, p.W401M fs4) was identified in the 2 brothers, occurring on chromosome Xp22.2 and affecting the last 2 exons of RBBP7." (PMID:37843278) - "RBBP7 is the most frequently mutated gene in our four cohorts: nine NOA-affected men carry variants not reported in gnomAD, three of them LoF." (PMID:35809576) - "the burden test showed that pathogenic variants in RBBP7 were significantly more common in infertile men than in gnomAD control individuals (adjusted p value = 5.07E−6)"* (PMID:35809576)

Functional consequence: loss of function. The truncated protein loses its C-terminal hydrophilic α-helix (in silico modelling: 23 hydrogen bonds fall to 8). Modelling also predicts weaker binding to histone H4 Arg35 and to the BRCA1 BRCT domain, and RBBP7 protein is reduced in patient testis. In the fly rescue experiment, the mutant human RBBP7 failed to rescue while the wild-type protein did. That points to a null or hypomorphic allele, not a dominant-negative one.

Gene-disease validity: no ClinGen or GenCC classification was found. The evidence is research-level: one family plus a cohort burden test.

Modifier genes, epigenetics, chromosomal abnormalities: - No modifier genes have been established. - RBBP7 is itself an epigenetic regulator (it chaperones histones and is part of HDAC complexes), but no patient methylome or histone-mark data exist. - Patients had normal karyotypes and no AZF microdeletions, which is a prerequisite for this diagnosis.

5. Environmental Information

Not applicable. There are no known environmental, lifestyle or infectious contributors. In the founding family, the documented absence of acquired causes (varicocele, torsion, orchitis, gonadotoxins) is part of the diagnostic work-up.

6. Mechanism / Pathophysiology

Ordered causal chain

Hemizygous germline RBBP7 LoF variant, e.g. p.W401Mfs5 in the sixth WD40 blade. There is no second X allele to compensate. (Demonstrated genetically.)*
→ results in a truncated protein that has lost its C-terminal α-helix and has reduced testicular RBBP7 protein. (The protein reduction was shown by immunostaining and western blot of patient tissue; the structural effect is in silico.)
→ leads to impaired binding of RBBP7 to histone H4 and to the BRCA1 BRCT domain. (Binding to both was predicted by modelling. In patient tubules, weak RBBP7 signal with loosely distributed H4 was observed; the BRCA1 effect was inferred from docking energies of −9.5 vs −10.9 kcal/mol.)
→ results in reduced BRCA1 and defective double-strand-break repair, with increased γH2AX in the seminiferous tubules. (Observed in the proband only. The causal direction from step 3 is inferred. A proposed alternative route runs through CRL4B^RBBP7 → HUWE1 → BRCA1 degradation; this is speculative.)
→ leads to G2/M cell-cycle arrest and apoptosis of spermatogonia and spermatocytes. (Shown in mouse GC-1 and GC-2 cell lines after siRNA knockdown, in vitro.)
Parallel branch 5′: loss of germline stem cell maintenance. In Drosophila, knocking down the ortholog Caf1-55 in germ cells (nos-GAL4) removed all GSCs and germ cells (model organism).
→ results in germ cell depletion with early (spermatogonial/meiotic) maturation arrest: few spermatogonia, no spermatocytes or spermatids. (Human histology.)
→ leads to non-obstructive azoospermia, small testes and raised FSH (loss of inhibin-B feedback is inferred), and therefore male infertility.
Branch B (somatic): RBBP7 loss in somatic testicular cells, together with a DSB-repair defect, may lead to somatic hyperproliferation and a Leydig cell tumor. (The human evidence is one tumor with hardly detectable RBBP7 and low BRCA1. In Drosophila, cyst-cell knockdown with tj-GAL4 caused tumor-like cyst-cell accumulation. The causal link is hypothesized.)

Key quotes (PMID:37843278): - "This mutation resulted in premature protein translation termination, affecting the sixth WD40 domain of the RBBP7 and the interaction of the mutated RBBP7 with histone H4. Decreased BRCA1 and increased γH2AX were observed in the proband. In mouse spermatogonial and pachytene spermatocyte-derived cells, deprivation of rbbp7 led to cell cycle arrest and apoptosis." - "knockdown of RBBP7/Caf1-55 in germ cells resulted in complete absence of germ cells and reduced testis size, whereas knockdown of RBBP7/Caf1-55 in cyst cells resulted in hyperproliferative testicular cells."

Quote from PMID:35809576: - "We observed a complete lack of dBigH1- and Vasa-expressing cells at the tip of nos > Caf1-p55RNAi testes, revealing that RBBP7/Caf1-p55 is necessary for GSCs maintenance"

Checklist detail

Pathways: chromatin assembly (CAF-1 / histone H3-H4 deposition); HDAC complexes (NuRD, Sin3); PRC2; the BRCA1 DSB-repair / homologous recombination pathway; the CRL4B ubiquitin ligase and HUWE1 axis (hypothesized).
Cellular processes: germline stem cell maintenance; mitotic G2/M transition; apoptosis; meiotic entry/progression (inferred). Mouse oocyte knockdown evidence also links Rbbp7 to histone deacetylation and to chromosome segregation during meiosis: Balboula et al., Cell Cycle 2014, PMID:24317350 [verify].
Protein dysfunction: C-terminal truncation of the WD40 β-propeller, giving loss of function.
Metabolic and immune involvement: none reported.
Molecular profiling: human testis scRNA-seq shows RBBP7 is highest in spermatogonia and spermatocytes and lower in spermatids. The protein is also present in Sertoli and Leydig cells (PMID:37843278). No disease-specific transcriptomic, proteomic or GEO datasets were found.

Suggested GO terms (the first four are already bound and validated in the KB entry):

Term	Label
GO:0042393	histone binding (DECREASED)
GO:0006302	double-strand break repair
GO:0000086	G2/M transition of mitotic cell cycle
GO:0006915	apoptotic process
GO:0036098	male germ-line stem cell population maintenance [verify]
GO:0007283	spermatogenesis [verify]
GO:0006335	DNA replication-dependent chromatin assembly [verify]

Suggested CL terms:

Term	Label
CL:0000020	spermatogonium
CL:0000656	primary spermatocyte
CL:0000216	Sertoli cell
CL:0000178	Leydig cell
CL:0000014	germ line stem cell [verify]

7. Anatomical Structures Affected

Organ: testis (UBERON:0000473 [verify]). The disease is restricted to the male reproductive system, with no reported extragonadal involvement.
Tissue: seminiferous tubule epithelium (UBERON:0001343 seminiferous tubule of testis [verify]); the testicular interstitium is the site of the Leydig cell tumor.
Cells: spermatogonia (depleted), spermatocytes (absent), Sertoli cells (preserved), Leydig cells (tumor in the proband).
Subcellular: nucleus / chromatin (GO:0005634 nucleus; GO:0000785 chromatin [verify]).
Lateralization: testicular hypotrophy was bilateral; the Leydig tumor was unilateral (right upper pole, 0.6 × 0.5 cm).

8. Temporal Development

Onset: the defect is presumed congenital or prepubertal (a germ-cell maintenance failure), but it is clinically recognized in adulthood (ages 26–27) through infertility.
Course: stable and lifelong. There is no evidence of progression; post-pubertal germ-cell loss is plausible but unproven.
Remission: none is expected.
Critical periods: fertility preservation before germ-cell depletion is theoretical only, since the timing of germ-cell loss in humans is unknown. The Leydig tumor did not recur after one year of follow-up.

9. Inheritance and Population

Inheritance: X-linked recessive (HP:0001419). Affected males are hemizygous and the carrier mother is unaffected: "Their mother (I:2) had a heterozygous mutation with a double peak" (PMID:37843278). Because affected men are infertile, transmission runs through carrier females.
Penetrance: apparently complete in hemizygous males among reported cases (12/12), but ascertainment was through infertility. No unaffected hemizygous males have been reported.
Expressivity: variable for the Leydig tumor (1/2 brothers) and for hormone profiles. Spermatogenic failure was consistent.
Anticipation, mosaicism, founder effects: none reported.
Frequency: RBBP7 variants were found in 10/2,354 men with idiopathic azoospermia or cryptozoospermia, about 0.42%. Li et al. noted this figure explicitly: "Riera-Escamilla et al. identified RBBP7 mutations in 10 out of 2,354 men (0.42%)." The family variant was absent from 103 Chinese NOA men.
Population prevalence: not established; this is ultra-rare. Prevalence class: NOT_YET_DOCUMENTED, or CASES_IN_LITERATURE with about 12 cases.
Demographics: males only. Cases come from a Chinese family and from European, US and Australian cohorts (the Barcelona, MERGE/Münster and GEMINI cohorts).

10. Diagnostics

Semen analysis: azoospermia on repeated centrifuged samples.
Hormones: raised FSH; variable LH and testosterone. Tumor markers (LDH, AFP, hCG) were normal in the proband.
Imaging: scrotal ultrasound shows small testes and may show a hypoechoic, vascularized lesion (Leydig tumor). CT was used for staging.
Histology (mTESE or biopsy): early maturation arrest. Immunohistochemistry: WT1 marks Sertoli cells; the tumor was inhibin+++, vimentin+, calretinin+, WT1−, with Ki67 <5%.
Genetic work-up: first karyotype and Y-chromosome AZF microdeletion testing, both normal by definition here. Then whole-exome sequencing or an NOA gene panel that includes RBBP7. Sanger segregation testing (carrier mother) confirms the result. Li et al. suggest "a panel of RBBP7 combined with other azoospermia-associated gene variants." NCIT: C15709 Genetic Testing (in the entry).
Differential diagnosis:
other X-linked NOA genes: TEX11, AR, USP26, GCNA, HUWE1, CUL4B, FANCB;
autosomal meiotic-arrest genes, e.g. SYCP3, TEX14, MEIOB;
Klinefelter syndrome (excluded by karyotype);
AZFa/b/c deletions;
acquired NOA (orchitis, chemotherapy, cryptorchidism);
Leydig cell hyperplasia (diffuse) as opposed to Leydig cell tumor (a solitary, well-defined nodule).
Screening: none established. After an index case, cascade carrier testing of female relatives is reasonable.

11. Outcome / Prognosis

Survival: normal life expectancy is expected; the disease is non-syndromic.
Fertility: in both reported mTESEs, sperm retrieval failed ("No mature spermatozoa were retrieved"). The prognosis for biological paternity is therefore poor.
Complications: Leydig cell tumor (benign; surgical enucleation; no recurrence at one year). After the tumor was removed, the proband's testosterone fell, and long-term hypogonadism is possible. Both Li and Riera-Escamilla raise a possible wider cancer predisposition through BRCA1 / DNA-repair biology; this is unproven.
Prognostic markers: the early-arrest histology and genotype predict a poor mTESE outcome (inferred from two cases).

12. Treatment

No disease-specific therapy exists. Management:

Intervention	NCIT suggestion	Notes
Microdissection TESE ± ICSI	NCIT:C15329 Surgical Procedure (bind and verify any more specific term)	Failed in both reported cases
Testis-sparing tumor enucleation	NCIT:C15329 Surgical Procedure	Used for the Leydig cell tumor
Genetic counseling	NCIT:C15240 Genetic Counseling	X-linked recessive; carrier mother
Testosterone replacement for hypogonadism	NCIT:C15986 Pharmacotherapy + CHEBI:17347 testosterone [verify]	Only if symptomatic hypogonadism; suppresses spermatogenesis
Donor sperm / adoption	—	Family-building alternatives

Pharmacogenomics, gene therapy, cell therapy, RNA therapies: none.
Clinical trials: no RBBP7-specific trials were found.
Other: hormonal stimulation (FSH, hCG, clomiphene) has no evidence base in this genotype.

13. Prevention

Primary prevention: none.
Genetic counseling for carrier females: each son has a 50% risk of being affected. Options include preimplantation genetic testing or prenatal diagnosis once the familial variant is known.
Cascade testing: testing female relatives clarifies carrier status. Testing brothers of an index case allows early counseling and sperm-banking discussion, although sperm is unlikely to be present.
Tertiary prevention: ultrasound surveillance for testicular tumors is suggested by the authors ("special attention should be paid toward screening for possible RBBP7 mutation–related testicular tumors"). This is expert opinion and has not been validated.

14. Other Species / Natural Disease

No naturally occurring RBBP7-associated infertility has been reported in animals (no OMIA entry found).
Orthologs: mouse Rbbp7 (X-linked; 99% similarity to human), zebrafish rbbp7, Drosophila Caf1-55 (96% similarity per Li et al.; 94% per Riera-Escamilla et al.). This is a highly conserved WD40 histone chaperone.
Zoonotic potential: not applicable.

15. Model Organisms

Model	Manipulation	Recapitulation	Limitations	Source
D. melanogaster (NCBITaxon:7227), germline knockdown nos>Caf1-55 RNAi	Germline RNAi	Testes very underdeveloped in 94% (n=36), about 74% smaller testes, loss of GSCs and Vasa+ germ cells, sterility. Recapitulates germ-cell depletion well.	Invertebrate testis architecture; Drosophila has no Leydig cells	PMID:35809576; PMID:37843278
D. melanogaster, cyst-cell knockdown tj>Caf1-55 RNAi	Somatic RNAi	Cyst-cell (Sertoli analog) hyperproliferation, germ-cell overproliferation and accumulation of undifferentiated cells, reduced fertility. Partially models somatic tumorigenesis.	Cyst cells ≠ Leydig cells	PMID:37843278
Drosophila Caf1-55 null	Null mutant	Small larval testis, γH2Av (DSB) elevation, tumor-like cyst cells	Lethal at L2	PMID:37843278
Drosophila rescue	Human WT vs mutant RBBP7 transgene	WT human RBBP7 rescues fertility; p.W401Mfs mutant does not	Supports pathogenicity of the specific allele	PMID:37843278
Mouse GC-1 (spermatogonia) / GC-2 (spermatocyte) lines	siRNA knockdown	↓ proliferation, ↑ apoptosis, G2/M arrest (S phase 43.9→31.2% in GC-1)	Immortalized lines; in vitro	PMID:37843278
Mouse oocytes	siRNA/morpholino	Chromosome misalignment, spindle assembly checkpoint (SAC) failure, HDAC defects in female meiosis	Female germline only	PMID:24317350 [verify]
Mouse Rbbp7 conditional knockout	—	No published male germline knockout phenotype was found. A floxed line is commercially available (Cyagen S-CKO-08695).	Knowledge gap	—

Main knowledge gap: no mammalian in vivo model exists. A germ-cell-specific Rbbp7 knockout (Stra8-Cre or Ddx4-Cre) would test the mechanism, and a Leydig-specific deletion would test the tumor link. These are good candidates for a HUMAN_MODEL_MISMATCH or KNOWLEDGE_GAP discussion in the KB entry.

Evidence Summary and Caveats

The evidence base is thin. It consists of one family (two brothers) and one cohort study (10 carriers plus a burden test). Nothing new on RBBP7 and male infertility turned up in searches for 2024–2026 work.
The Leydig cell tumor association rests on a single patient. Treat it as a hypothesis, not an established phenotype frequency.
The BRCA1 and histone H4 mechanism is supported by in silico modelling and immunostaining of one proband. It has not been shown biochemically with the mutant protein.
No ClinGen classification exists. gene_disease_validity should stay absent.
The variant nomenclature is inconsistent within the source: the paper uses both c.1200dupA p.W401Mfs5 and c.1201ins1 p.W401Mfs4. The HGVS-correct form appears to be c.1200dupA p.(Trp401Metfs*5).

Sources

Primary (cached in references_cache/): - Li J et al. X-linked RBBP7 mutation causes maturation arrest and testicular tumors. J Clin Invest 2023. PMID:37843278. doi:10.1172/JCI171541. PMC10575721 - Riera-Escamilla A et al. Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure. Am J Hum Genet 2022. PMID:35809576. doi:10.1016/j.ajhg.2022.06.007

Not cached; verify before use: - Balboula AZ et al. Mouse oocyte Rbbp7 knockdown, Cell Cycle 2014. PMID:24317350 (Taylor & Francis)

Web resources consulted: - MalaCards: SPGFX9 - Disease Ontology DOID:0061177 - GeneCards: RBBP7 - LabMedica: X chromosome genes linked to male infertility - Münster CRIS record for PMID:35809576 - MGI expression assay MGI:7266366 - Cyagen Rbbp7 cKO line - PMC8411525 (BRD7, a different gene; excluded as a name confusion)

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome	Count
References checked	8
Resolved	8
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	8
On topic	3
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	31
Resolved	30
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	15
Terms named correctly	9
Terms named as a different term	0
Terms whose name is worth a second look	6

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:0042393 (1 mention) - the report calls it "histone binding (DECREASED)"; GO calls it histone binding
GO:0036098 (1 mention) - the report calls it "male germ-line stem cell population maintenance [verify]"; GO calls it male germ-line stem cell population maintenance**
GO:0007283 (1 mention) - the report calls it "spermatogenesis [verify]"; GO calls it spermatogenesis**
GO:0006335 (1 mention) - the report calls it "DNA replication-dependent chromatin assembly [verify]"; GO calls it DNA replication-dependent chromatin assembly**
CL:0000014 (1 mention) - the report calls it "germ line stem cell [verify]"; CL calls it germ line stem cell**
NCBITaxon:7227 (1 mention) - the report calls it "D. melanogaster"; NCBITaxon calls it Drosophila melanogaster

Prefixes with no resolver

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

30 of 31 terms resolved to a current term; the rest could not be looked up either way.

RBBP7-Related X-linked Spermatogenic Maturation Arrest

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1. Disease Information

2. Etiology

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7. Anatomical Structures Affected

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14. Other Species / Natural Disease

15. Model Organisms

Evidence Summary and Caveats

Sources

Reference Validation

Term Validation

Terms whose name is worth a second look

Prefixes with no resolver