RBBP7-Related X-linked Spermatogenic Maturation Arrest

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

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

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

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

1. Hemizygous germline RBBP7 LoF variant, e.g. p.W401Mfs5 in the sixth WD40 blade. There is no second X allele to compensate. (Demonstrated genetically.)*
2. → 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.)
3. → 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.)
4. → 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.)
5. → 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.)
6. 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).
7. → results in germ cell depletion with early (spermatogonial/meiotic) maturation arrest: few spermatogonia, no spermatocytes or spermatids. (Human histology.)
8. → leads to non-obstructive azoospermia, small testes and raised FSH (loss of inhibin-B feedback is inferred), and therefore male infertility.
9. 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):

Suggested CL terms:

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:

• 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

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

1. 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.
2. The Leydig cell tumor association rests on a single patient. Treat it as a hypothesis, not an established phenotype frequency.
3. 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.
4. No ClinGen classification exists. gene_disease_validity should stay absent.
5. 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.

All extracted references resolved successfully.

Term Validation

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

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.