From late fatherhood to prenatal screening of monogenic disorders: evidence and ethical concerns

• Published in: Human reproduction update 2021-10, Vol.27 (6), p.1056-1085
• Main Authors: Zhytnik, Lidiia, Peters, Maire, Tilk, Kadi, Simm, Kadri, Tõnisson, Neeme, Reimand, Tiia, Maasalu, Katre, Acharya, Ganesh, Krjutškov, Kaarel, Salumets, Andres
• Format: Article
• Language: English
• Subjects: Aneuploidy; Child; Female; Humans; Informed Consent; Male; Morals; Paternal Age; Pregnancy; Prenatal Diagnosis - methods
• ISSN: 1355-4786; 1460-2369
• DOI: 10.1093/humupd/dmab023

Abstract BACKGROUND With the help of ART, an advanced parental age is not considered to be a serious obstacle for reproduction anymore. However, significant health risks for future offspring hide behind the success of reproductive medicine for the treatment of reduced fertility associated with late parenthood. Although an advanced maternal age is a well-known risk factor for poor reproductive outcomes, understanding the impact of an advanced paternal age on offspring is yet to be elucidated. De novo monogenic disorders (MDs) are highly associated with late fatherhood. MDs are one of the major sources of paediatric morbidity and mortality, causing significant socioeconomic and psychological burdens to society. Although individually rare, the combined prevalence of these disorders is as high as that of chromosomal aneuploidies, indicating the increasing need for prenatal screening. With the help of advanced reproductive technologies, families with late paternity have the option of non-invasive prenatal testing (NIPT) for multiple MDs (MD-NIPT), which has a sensitivity and specificity of almost 100%. OBJECTIVE AND RATIONALE The main aims of the current review were to examine the effect of late paternity on the origin and nature of MDs, to highlight the role of NIPT for the detection of a variety of paternal age-associated MDs, to describe clinical experiences and to reflect on the ethical concerns surrounding the topic of late paternity and MD-NIPT. SEARCH METHODS An extensive search of peer-reviewed publications (1980–2021) in English from the PubMed and Google Scholar databases was based on key words in different combinations: late paternity, paternal age, spermatogenesis, selfish spermatogonial selection, paternal age effect, de novo mutations (DNMs), MDs, NIPT, ethics of late fatherhood, prenatal testing and paternal rights. OUTCOMES An advanced paternal age provokes the accumulation of DNMs, which arise in continuously dividing germline cells. A subset of DNMs, owing to their effect on the rat sarcoma virus protein–mitogen-activated protein kinase signalling pathway, becomes beneficial for spermatogonia, causing selfish spermatogonial selection and outgrowth, and in some rare cases may lead to spermatocytic seminoma later in life. In the offspring, these selfish DNMs cause paternal age effect (PAE) disorders with a severe and even life-threatening phenotype. The increasing tendency for late paternity and the subsequent high risk of PAE disorders indicate