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HROB and Premature Menopause

Recent studies have identified HROB as a novel gene implicated in premature menopause, a condition clinically manifesting as primary ovarian insufficiency (POI) with ensuing infertility (PMID:36099812). In a large cohort of POI patients, HROB was among several new candidates emerging from the analysis of 375 patients across 70 families, supporting its inclusion in the diagnostic workup of this complex reproductive disorder.

Genetic evidence from a focused whole exome sequencing study of seven women with POI revealed biallelic candidate variants in HROB, consistent with an autosomal recessive mode of inheritance (PMID:34707299). This study provided compelling evidence by linking HROB to impaired meiotic processes and DNA damage repair, hallmarks of the POI phenotype.

Functional assessment using CRISPR-mediated base editing screens has further demonstrated that perturbations in HROB compromise DNA damage response pathways. These experiments underscore the gene’s role in maintaining genomic stability during meiosis, thus providing a biological rationale that complements the genetic findings (PMID:39661519).

To date, no significant conflicting evidence has emerged to dispute the association between HROB and premature menopause. While additional family segregation studies could further quantify penetrance and expressivity, current data across multiple independent cohorts support a robust and clinically actionable gene-disease link.

In summary, the genetic and functional data together converge to support a strong association between HROB and premature menopause. This evidence not only enhances our diagnostic precision but also opens avenues for personalized management of infertility linked to POI.

Key Take‑home sentence: HROB is a promising genetic marker for premature menopause, enabling improved diagnostic decision‑making and the potential for tailored therapeutic strategies.

References

  • Université Paris Saclay, Agence Nationale de Biomédecin • n.d. • Primary Ovarian Insufficiency Cohort Study PMID:36099812
  • European journal of human genetics : EJHG • 2022 • Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes PMID:34707299
  • Cell reports • 2024 • Mapping functional elements of the DNA damage response through base editor screens PMID:39661519

Evidence Based Scoring (AI generated)

Gene–Disease Association

Strong

Biallelic candidate variants in seven probands (PMID:34707299) combined with supporting functional data from CRISPR screens (PMID:39661519) and additional evidence from a large POI cohort (PMID:36099812) support a strong gene-disease association.

Genetic Evidence

Strong

Evidence from whole exome sequencing in seven individuals with POI, showing autosomal recessive biallelic candidate variants in HROB, substantiates its role in disease pathogenesis (PMID:34707299).

Functional Evidence

Moderate

Functional studies using base editing screens demonstrate that HROB perturbation disrupts DNA damage repair pathways, aligning with the expected biological mechanism underlying premature menopause (PMID:39661519).