Department of OB/GYN and Reproductive Sciences, School of Medicine, University of Pittsburgh, 204 Craft Avenue, Room A206, Pittsburgh, PA, 15213, USA.
The Turek Clinics, 55 Francisco St., Suite 300, San Francisco, CA, 94133, USA.
J Assist Reprod Genet. 2018 Jun;35(6):933-941. doi: 10.1007/s10815-018-1148-y. Epub 2018 Mar 9.
To examine current evidence of the known effects of advanced paternal age on sperm genetic and epigenetic changes and associated birth defects and diseases in offspring.
Review of published PubMed literature.
Advanced paternal age (> 40 years) is associated with accumulated damage to sperm DNA and mitotic and meiotic quality control mechanisms (mismatch repair) during spermatogenesis. This in turn causes well-delineated abnormalities in sperm chromosomes, both numerical and structural, and increased sperm DNA fragmentation (3%/year of age) and single gene mutations (relative risk, RR 10). An increase in related abnormalities in offspring has also been described, including miscarriage (RR 2) and fetal loss (RR 2). There is also a significant increase in rare, single gene disorders (RR 1.3 to 12) and congenital anomalies (RR 1.2) in offspring. Current research also suggests that autism, schizophrenia, and other forms of "psychiatric morbidity" are more likely in offspring (RR 1.5 to 5.7) with advanced paternal age. Genetic defects related to faulty sperm quality control leading to single gene mutations and epigenetic alterations in several genetic pathways have been implicated as root causes.
Advanced paternal age is associated with increased genetic and epigenetic risk to offspring. However, the precise age at which risk develops and the magnitude of the risk are poorly understood or may have gradual effects. Currently, there are no clinical screenings or diagnostic panels that target disorders associated with advanced paternal age. Concerned couples and care providers should pursue or recommend genetic counseling and prenatal testing regarding specific disorders.
探讨高龄父亲对精子遗传和表观遗传变化以及后代相关出生缺陷和疾病的已知影响的现有证据。
对已发表的 PubMed 文献进行综述。
高龄（>40 岁）与精子 DNA 损伤以及在精子发生过程中细胞分裂和减数分裂质量控制机制（错配修复）的累积损伤有关。这反过来又导致精子染色体的明显异常，包括数目和结构异常，以及精子 DNA 碎片化（每年增加 3%）和单基因突变（相对风险，RR 10）增加。还描述了后代相关异常的增加，包括流产（RR 2）和胎儿丢失（RR 2）。罕见的单基因疾病（RR 1.3 至 12）和先天性畸形（RR 1.2）在后代中的发生率也显著增加。目前的研究还表明，自闭症、精神分裂症和其他形式的“精神疾病”在高龄父亲的后代中更有可能发生（RR 1.5 至 5.7）。与精子质量控制缺陷相关的遗传缺陷导致几个遗传途径中的单基因突变和表观遗传改变，被认为是根本原因。
高龄父亲与后代遗传和表观遗传风险增加有关。然而，风险发展的确切年龄和风险的程度尚不清楚，或者可能有逐渐的影响。目前，没有针对与高龄父亲相关的疾病的临床筛查或诊断小组。有此担忧的夫妇和医护人员应就特定疾病进行遗传咨询和产前检测。
