SYCE1 – Premature Menopause

Evidence from multiple independent studies supports a strong association between loss‐of‐function variants in SYCE1 and premature menopause. Several case reports from consanguineous families have identified homozygous nonsense and frameshift mutations in SYCE1, notably the mutation c.721C>T (p.Gln241Ter) (PMID:25062452), that segregate with ovarian insufficiency in affected sisters and other relatives.

Additional multi‐patient studies have independently detected recessive variants in SYCE1 among patients with premature ovarian insufficiency, reinforcing the role of SYCE1 in the reproductive phenotype. In these studies, affected individuals consistently showed biallelic alterations and a clear autosomal recessive inheritance pattern, with segregation confirmed by family‐based analyses (PMID:34718620).

Genetic screening in diverse cohorts, including consanguineous pedigrees and sporadic cases, has further demonstrated the recurrence of deleterious SYCE1 variants. The gross deletion identified in one familial study (PMID:31925770) and the point mutations corroborated in independent reports underscore the wide mutational spectrum contributing to the phenotype.

Functional studies add a key layer of support by showing that SYCE1 loss disrupts the synaptonemal complex assembly, thereby impairing homologous chromosome pairing during meiosis. Mouse models engineered with the human equivalent of the c.721C>T mutation have recapitulated the ovarian insufficiency phenotype, and in vitro assays reveal loss of SYCE1 protein expression consistent with a null effect (PMID:32402064) and further supported by studies on SC protein function (PMID:27997882).

Collectively, both the genetic and functional data demonstrate robust concordance between SYCE1 loss‐of‐function and the clinical presentation of premature menopause. The aggregation of multiple unrelated probands, clear segregation patterns, and loss‐of-function evidence provides a compelling case for a strong gene–disease association.

Key take‑home sentence: The integration of segregation data, recurrent recessive mutations, and functional validation in models supports the clinical utility of SYCE1 testing in patients with premature menopause for improved diagnostic decision‑making and genetic counseling.

References

• The Journal of clinical endocrinology and metabolism • 2014 • Exome sequencing reveals SYCE1 mutation associated with autosomal recessive primary ovarian insufficiency PMID:25062452
• Reproductive sciences (Thousand Oaks, Calif.) • 2020 • Consanguineous Familial Study Reveals that a Gross Deletion that Includes the SYCE1 Gene Region Is Associated with Premature Ovarian Insufficiency PMID:31925770
• The Journal of clinical endocrinology and metabolism • 2022 • Variations of C14ORF39 and SYCE1 Identified in Idiopathic Premature Ovarian Insufficiency and Nonobstructive Azoospermia PMID:34718620
• Molecular human reproduction • 2020 • Familial primary ovarian insufficiency associated with an SYCE1 point mutation: defective meiosis elucidated in humanized mice PMID:32402064
• Cytogenetic and genome research • 2016 • Mutations in Genes Coding for Synaptonemal Complex Proteins and Their Impact on Human Fertility PMID:27997882

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