Significantly increased load of hereditary cancer–linked germline variants in infertile men

Human Reproduction Open, Journal Year: 2025, Volume and Issue: 2025(2)

Published: Jan. 1, 2025

What is the load and profile of hereditary cancer-linked germline variants in infertile compared to fertile men? This study showed almost 5-fold enrichment disease-causing findings cancer genes men (6.9% vs 1.5%, P = 2.3 × 10-4). Epidemiological studies have revealed that with low sperm count a 2-fold higher risk developing during their lifetime. Our recent observed 4-fold increased prevalence monogenic infertility general male population (8% 2%). Shared molecular etiologies been proposed. retrospective analyzed likely pathogenic (LP/P) 157 522 323 recruited ESTonian ANDrology (ESTAND) cohort. All participants (n 845) had phenotyped at an Andrology Clinic. Identification LP/P gene panel was performed from exome sequencing dataset generated for passed automated filtering process, final manual assessment pathogenicity, experimental confirmation using Sanger sequencing. Retrospective health records were available 36 out 41 (88%) findings. Infertile presented nearly (36 cases, 6.9%) subjects (5 323, 1.5%; odds ratio (OR) 4.7, 95% CI 1.81-15.5; 10-4) spanning over 24 genes. The not significantly different between azoospermic oligozoospermic cases. There also no history cryptorchidism. By time study, six carrying diagnosed tumor. Family members affected documented 10 14 cases pedigree data.Nearly half (17 36) carried belonging Fanconi anemia (FA) pathway involved maintenance genomic integrity mitosis meiosis, repair DNA double-stranded breaks, interstrand crosslinks. Overall, FA-pathway BRCA2 (monoallelic) FANCM (biallelic) most frequently loci (five per gene).LP/P pleiotropic linked human development (TSC1, PHOX2B, WT1, SPRED1, NF1, LZTR1, HOXB13) identified several patients syndromic phenotypes. Four cryptorchid carriers MLH1, MSH2, MSH6 implicated Lynch syndrome. Future will reveal whether this observation by chance or replicable finding.Most show high expression one more testicular cell types, mouse models 15 reported exhibit sub- infertility. These data support shared genetic etiology impaired spermatogenesis cancer. A fraction could explain as comorbidity submitted National Center Biotechnology Information (NCBI) ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/). white European ancestry living Estonia. Thus, results might apply other ethnic groups. Due young age (median 34.4 years), true incidence lifetime be assessed. As clinical all men, it possible evaluate genotype-phenotype links. absence family precluded nature potential de novo occurrence. Infertility affects about 7-10% worldwide. In spermatogenic failure gradually entering diagnostics setup andrology, analyzing workup offer additional benefits. Male factor typically 30s, often before onset its symptoms. Early knowledge predisposition enables timely screening multidisciplinary management options, potentially improving prognosis. provide failure. funded Estonian Research Council grant PRG1021 (M.L. M.P.). authors declare conflicts interest.

Language: Английский

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Sperm from infertile, oligozoospermic men have elevated mutation rates

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 22, 2024

Abstract Male infertility is associated with elevated rates of aneuploidy and DNA breaks in spermatozoa germline precursors. This common condition not well understood poor individual familial somatic health relative to fertile men. To further understand the extent source genome instability, we used error-corrected duplex sequencing test whether impaired spermatogenesis relatively poorer oligozoospermic men are linked single nucleotide de novo mutation frequencies their sperm blood, respectively. We observed a significant 1.34 2.01-fold increase age-adjusted infertile, Conversely, consistently blood were found. Gain-of-function mutations clonal Mendelian disorders accumulate age at similar rate normozoospermic These results implicate hypermutation as hallmark feature oligozoospermia point age-independent processes affecting spermatogonial stem cell biology that may underlie spermatogenic impairment before after puberty. Our findings also underscore importance investigating tissue-specific mechanisms driving association between reduced reproductive infertile

Language: Английский

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Male Fertility as a Proxy for Health

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(18), P. 5559 - 5559

Published: Sept. 19, 2024

Male fertility is affected by a wide range of medical conditions that directly and indirectly affect spermatogenesis. As such, it can be useful as both an indicator current health predictive factor for future outcomes. Herein, we discuss the literature regarding association between male systemic exposures. We review connection genetics, medications, diet, environmental pollutants, well its effects on oncologic, cardiovascular, autoimmune conditions. Understanding this interplay will allow more care providers to engage in counseling not only improve men’s reproductive outcomes but also their overall health.

Language: Английский

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Reproductive medicine news. Digest of publications, issue 3

Bulletin of Reproductive Health, Journal Year: 2024, Volume and Issue: 3(2), P. 4 - 10

Published: July 2, 2024

This issue of reproductive medicine news presents the most relevant meta-analysis data, as well innovative methods in treatment diseases system, presented leading international periodicals 2024. The main conclusions clinical recommendations European Society for Human Reproduction on management married couples with recurrent implantation failures are also briefly formulated.

Language: Английский

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