Paternal age effect

The paternal age effect is the statistical relationship between paternal age at conception and biological effects on the child.[1] Such effects can relate to birthweight, congenital disorders, life expectancy, and psychological outcomes.[2] A 2009 review concludes that the absolute risk for genetic anomalies in offspring is low, and states that "there is no clear association between adverse health outcome and paternal age but longitudinal studies are needed."[3]

On the other hand, the genetic quality of sperm, as well as its volume and motility, all typically decrease with age,[4] leading the population geneticist James F. Crow to claim that the "greatest mutational health hazard to the human genome is fertile older males".[5]

The paternal age effect was first proposed implicitly by Weinberg in 1912,[6] and explicitly by Penrose in 1955.[7] DNA-based research started more recently, in 1998, in the context of paternity testing.

Health effects

Evidence for a paternal age effect has been proposed for a number of conditions, diseases and other effects. In many of these, the statistical evidence of association is weak, and the association may be related by confounding factors, or behavioral differences. Conditions proposed to show correlation with paternal age include the following:[3]

Single-gene disorders

Advanced paternal age is associated with a higher risk for certain single-gene disorders caused by mutations of the FGFR2, FGFR3, and RET genes.[8] These conditions are Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, achondroplasia, thanatophoric dysplasia, multiple endocrine neoplasia type 2, and multiple endocrine neoplasia type 2b.[8] The most significant effect concerns achondroplasia (a form of dwarfism), which occurs in about 1 in 1,875 children fathered by men over 50, compared to 1 in 15,000 in the general population.[9] However, the risk for achondroplasia is still considered clinically negligible.[10] The FGFR genes may be particularly prone to a paternal age effect due to selfish spermatogonial selection, whereby the influence of spermatogonial mutations in older men is enhanced because cells with certain mutations have a selective advantage over other cells (see § DNA mutations).[11]

Pregnancy effects

Several studies have reported that advanced paternal age is associated with an increased risk of miscarriage.[12] The strength of the association differs between studies.[13] It has been suggested that these miscarriages are caused by chromosome abnormalities in the sperm of aging men.[12] An increased risk for stillbirth has also been observed for pregnancies fathered by men over 45.[13]

Birth outcomes

A systematic review published in 2010 concluded the risk of low birthweight in infants with paternal age is "saucer-shaped" (U-shaped); that is, the highest risks occur at low and at high paternal ages.[14] Compared with a paternal age of 25–28 years as a reference group, the odds ratio for low birthweight was approximately 1.1 at a paternal age of 20 and approximately 1.2 at a paternal age of 50.[14] There was no association of paternal age with preterm births or with small for gestational age births.[14]

Mental illness

Schizophrenia is associated with advanced paternal age with 12 out of 14 studies supporting a relationship.[15] Paternal age older than 55 is a moderate risk factor for schizophrenia.[16] Most studies examining autism spectrum disorder (ASD) and advanced paternal age have demonstrated an association between the two, although there also appears to be an increase with maternal age.[17]

The risk of bipolar disorder ("manic depression") particularly for early-onset disease, is J-shaped, with the lowest risk for children of 20- to 24-year-old fathers, a twofold risk for younger fathers, and a threefold risk for fathers >50 years old. There is no similar relationship with maternal age.[18]

Cancers

Paternal age may be associated with an increased risk of breast cancer,[19] but the association is weak and there are confounding effects.[3]

Diabetes mellitus

High paternal age has been suggested as a risk factor for type 1 diabetes,[20] but research findings are inconsistent and a clear association has not been established.[21][22]

Down syndrome

It appears that a paternal-age effect exists with respect to Down syndrome, but is very small in comparison to the maternal-age effect.[23]

Intelligence

In 2005, Malaspina and colleagues detected a U-shaped relationship between paternal age and low intelligence quotients (IQs) in 44,175 people from Israel.[24] The highest IQ was found at paternal ages of 25-44; fathers younger than 25 and older than 44 tended to have children with lower IQs.[24] Malaspina et al. also reviewed the literature and found that "at least a half dozen other studies ... have demonstrated significant associations between paternal age and human intelligence."[24]

A 2009 study examined children at 8 months, 4 years, and 7 years and found that paternal age was associated with poorer scores in almost all neurocognitive tests used, but that maternal age was associated with better scores on the same tests.[25] An editorial accompanying the paper emphasized the importance of controlling for socioeconomic status in studies of paternal age and intelligence.[26] A 2010 paper from Spain provided further evidence that average paternal age is elevated in cases of intellectual disability.[27]

Life expectancy

A 2008 paper found a U-shaped association between paternal age and the overall mortality rate in children (i.e., mortality rate up to age 18).[28] Although the relative mortality rates were higher, the absolute numbers were low, because of the relatively low occurrence of genetic abnormality. The study has been criticized for not adjusting for maternal health, which could have a large effect on child mortality.[29] The researchers also found a correlation between paternal age and offspring death by injury or poisoning, indicating the need to control for social and behavioral confounding factors.[30]

In 2012 a study showed that greater age at paternity tends to increase telomere length in offspring for up to two generations. Since telomere length has effects on health and mortality, this may have effects on health and the rate of aging in these offspring. The authors speculated that this effect may provide a mechanism by which populations have some plasticity in adapting longevity to different social and ecological contexts.[31]

Fertility

Older men have decreased pregnancy rates, increased time to pregnancy, and increased infertility at a given point in time.[32] When controlling for the age of the female partner, comparisons between men under 30 and men over 50 found relative decreases in pregnancy rates between 23% and 38%.[32]

Associated social characteristics

Father's age versus risk of death in France[33]
Age at birthBefore child's 18th birthday
25 2.2%
30 3.3%
35 5.4%
40 8.3%
45 12.1%

Later age at parenthood is associated with a more stable family environment, with older parents being less likely to divorce or change partners.[33] Older parents also tend to occupy a higher socio-economic position and report feeling more devoted to their children and satisfied with their family.[33] On the other hand, the risk of the father dying before the child becomes an adult increases with paternal age.[33]

Mechanisms

Several hypothesized chains of causality exist whereby increased paternal age may lead to health effects.[13][34]

DNA mutations

In contrast to oogenesis, the production of sperm cells is a lifelong process.[13] Each year after puberty, spermatogonia (precursors of the spermatozoa) divide meiotically about 23 times.[34] By the age of 40, the spermatogonia will have undergone about 660 such divisions, compared to 200 at age 20.[34] Copying errors sometimes happen during the DNA replication preceding these cell divisions, which can lead to new (de novo) mutations in the sperm DNA.[11] A study of 78 Icelandic families found that each additional year in the age of the father causes about two new mutations in the child.[35] Regarding the increased risk at very young paternal ages, an international study indicates that the DNA mutation rate in very young fathers may also be elevated.[36]

The selfish spermatogonial selection hypothesis proposes that the influence of spermatogonial mutations in older men is further enhanced because cells with certain mutations have a selective advantage over other cells.[34][37] Such an advantage would allow the mutated cells to increase in number through clonal expansion.[34][37] In particular, mutations that affect the RAS pathway, which regulates spermatogonial proliferation, appear to offer a competitive advantage to spermatogonial cells, while also leading to diseases associated with paternal age.[37]

Epigenetic changes

DNA methylation

The production of sperm cells involves DNA methylation, an epigenetic process that regulates the expression of genes.[34] Improper genomic imprinting and other errors sometimes occur during this process, which can affect the expression of genes related to certain disorders, increasing the offspring's susceptibility.[38] The frequency of these errors appears to increase with age.[38] This could explain the association between paternal age and schizophrenia.[38]

Telomere length

Telomeres are genetic sequences that protect the structures of chromosomes.[39] As men age, most telomeres shorten, but sperm telomeres increase in length.[13] The offspring of older fathers have longer telomeres in both their sperm and white blood cells.[13][39] Because people with longer telomeres are at decreased risk for age-related diseases, higher paternal age may also be associated with certain health benefits.[13] This mechanism may have evolved because the environment of children born to older fathers is likely to have a higher expected age of reproduction.[39]

Semen

A 2001 review on variation in semen quality and fertility by male age concluded that older men had lower semen volume, lower sperm motility, and a decreased percent of normal sperm.[32] One common factor is the abnormal regulation of sperm once a mutation arises. It has been seen that once taking place, the mutation will almost always be positively selected for and over time will lead to the mutant sperm replacing all non-mutant sperm. In younger males, this process is corrected and regulated by the growth factor receptor-RAS signal transduction pathway.[40]

A 2014 review indicated that increasing male age is associated with declines in many semen traits, including semen volume and percentage motility. However, this review also found that sperm concentration did not decline as male age increased.[41]

X-linked effects

Some classify the paternal age effect as one of two different types. One effect is directly related to advanced paternal age and autosomal mutations in the offspring. The other effect is an indirect effect in relation to mutations on the X chromosome which are passed to daughters who are then at risk for having sons with X-linked diseases.[42]

History

In 1912, Wilhelm Weinberg, a German physician, was the first person to hypothesize that non-inherited cases of achondroplasia could be more common in last-born children than in children born earlier to the same set of parents.[43] Weinberg "made no distinction between paternal age, maternal age and birth order" in his hypothesis. In 1953, Krooth used the term "paternal age effect" in the context of achondroplasia, but mistakenly thought the condition represented a maternal age effect.[43][44]:375 The paternal age effect for achondroplasia was described by Lionel Penrose in 1955. At a DNA level, the paternal age effect was first reported in 1998 in routine paternity tests.[45]

Scientific interest in paternal age effects is relevant because the average paternal age increased in countries such as the United Kingdom,[46] Australia,[47] and Germany,[48] and because birth rates for fathers aged 30–54 years have risen between 1980 and 2006 in the United States.[49] Possible reasons for the increases in average paternal age include increasing life expectancy and increasing rates of divorce and remarriage.[48] Despite recent increases in average paternal age, however, the oldest father documented in the medical literature was born in 1840: George Isaac Hughes was 94 years old at the time of the birth of his son by his second wife, a 1935 article in the Journal of the American Medical Association stated that his fertility "has been definitely and affirmatively checked up medically," and he fathered a daughter in 1936 at age 96.[48]:329[50][51] In 2012, two 96-year-old men, Nanu Ram Jogi and Ramjit Raghav, both from India, claimed to have fathered children that year.,[52][53]

Medical assessment

The American College of Medical Genetics recommends obstetric ultrasonography at 18–20 weeks gestation in cases of advanced paternal age to evaluate fetal development, but it notes that this procedure "is unlikely to detect many of the conditions of interest." They also note that there is no standard definition of advanced paternal age;[54] it is commonly defined as age 40 or above, but the effect increases linearly with paternal age, rather than appearing at any particular age.[55] According to a 2006 review, any adverse effects of advanced paternal age "should be weighed up against potential social advantages for children born to older fathers who are more likely to have progressed in their career and to have achieved financial security."[46]

Geneticist James F. Crow described mutations that have a direct visible effect on the child's health and also mutations that can be latent or have minor visible effects on the child's health; many such minor or latent mutations allow the child to reproduce, but cause more serious problems for grandchildren, great-grandchildren and later generations.[5]

See also

References

  1. ↑ "paternal age effect". Retrieved 2015-05-28.
  2. ↑ Amaral, David; Dawson, Geraldine; Geschwind, Daniel (2011-06-17). Autism Spectrum Disorders. Oxford University Press, USA. ISBN 9780195371826.
  3. 1 2 3 H. Tournaye, "Male Reproductive Ageing," in Bewley, Ledger, and Nikolaou, eds., Reproductive Ageing, Cambridge University Press (2009), ISBN 9781906985134 (accessed 15 November 2013)
  4. ↑ Gurevich, Rachel (June 10, 2008). "Does Age Affect Male Fertility?". About.com:Fertility. About.com. Retrieved 14 February 2010.
  5. 1 2 Crow, James F. (August 5, 1997). "The high spontaneous mutation rate: Is it a health risk?". Proceedings of the National Academy of Sciences 94 (16): 8380–8386. doi:10.1073/pnas.94.16.8380. PMC 33757. PMID 9237985. Retrieved 29 March 2013.
  6. ↑ Weinberg, W (1912). "Zur Vererbung des Zwergwuchses. (On the inheritance of dwarfism)". Arch Rassen-u Gesell Biol 9: 710–718.
  7. ↑ Penrose, LS (1955). "Parental age and mutation". Lancet 269: 312–313. doi:10.1016/s0140-6736(55)92305-9. PMID 13243724.
  8. 1 2 Toriello HV, Meck JM (2008). "Statement on guidance for genetic counseling in advanced paternal age". Genet. Med. 10 (6): 457–60. doi:10.1097/GIM.0b013e318176fabb. PMC 3111019. PMID 18496227.
  9. ↑ Kovac JR, Addai J, Smith RP, Coward RM, Lamb DJ, Lipshultz LI (2013). "The effects of advanced paternal age on fertility". Asian J. Androl. 15 (6): 723–8. doi:10.1038/aja.2013.92. PMC 3854059. PMID 23912310.
  10. ↑ Czeizel AE, Czeizel B, Vereczkey A (2013). "The participation of prospective fathers in preconception care". Clin Med Insights Reprod Health 7: 1–9. doi:10.4137/CMRH.S10930. PMC 3888083. PMID 24453513.
  11. 1 2 Ramasamy R, Chiba K, Butler P, Lamb DJ (2015). "Male biological clock: a critical analysis of advanced paternal age". Fertil. Steril. 103: 1402–6. doi:10.1016/j.fertnstert.2015.03.011. PMID 25881878.
  12. 1 2 Abbas HA, Rafei RE, Charafeddine L, Yunis K (2015). "Effects of Advanced Paternal Age on Reproduction and Outcomes in Offspring". NeoReviews 16 (2): e69 –e83. doi:10.1542/neo.16-2-e69.
  13. 1 2 3 4 5 6 7 Sharma R, Agarwal A, Rohra VK, Assidi M, Abu-Elmagd M, Turki RF (2015). "Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring" (PDF). Reprod. Biol. Endocrinol. 13 (1): 35. doi:10.1186/s12958-015-0028-x. PMID 25928123.
  14. 1 2 3 Shah PS; Knowledge Synthesis Group on determinants of preterm/low birthweight births (2010). "Paternal factors and low birthweight, preterm, and small for gestational age births: a systematic review". Am J Obstet Gynecol 202 (2): 103–23. doi:10.1016/j.ajog.2009.08.026. PMID 20113689.
  15. ↑ Kirkpatrick, B; Messias, E; Harvey, PD; Fernandez-Egea, E; Bowie, CR (November 2008). "Is schizophrenia a syndrome of accelerated aging?". Schizophrenia bulletin 34 (6): 1024–32. doi:10.1093/schbul/sbm140. PMID 18156637.
  16. ↑ Torrey EF, Buka S, Cannon TD, Goldstein JM, Seidman LJ, Liu T, Hadley T, Rosso IM, Bearden C, Yolken RH (2009). "Paternal age as a risk factor for schizophrenia: how important is it?". Schizophr Res 114 (1–3): 1–5. doi:10.1016/j.schres.2009.06.017. PMID 19683417.
  17. ↑ Kolevzon A, Gross R, Reichenberg A (2007). "Prenatal and perinatal risk factors for autism: a review and integration of findings". Arch Pediatr Adolesc Med 161 (4): 326–333. doi:10.1001/archpedi.161.4.326. PMID 17404128.
  18. ↑ Frans EM, Sandin S, Reichenberg A, Lichtenstein P, Långström N, Hultman CM (2008). "Advancing Paternal Age and Bipolar Disorder". Arch Gen Psychiatry 65 (9): 1034–1040. doi:10.1001/archpsyc.65.9.1034. PMID 18762589.
  19. ↑ Xue F, Michels KB (2007). "Intrauterine factors and risk of breast cancer: a systematic review and meta-analysis of current evidence". Lancet Oncol 8 (12): 1088–100. doi:10.1016/S1470-2045(07)70377-7. PMID 18054879.
  20. ↑ Bishop DB, O'Connor PJ, Desai J (2010). "Diabetes". Chronic Disease Epidemiology and Control (3rd ed.). Washington, DC: American Public Health Association. p. 301. ISBN 9780875531922.
  21. ↑ Cardwell CR, Stene LC, Joner G, et al. (2010). "Maternal age at birth and childhood type 1 diabetes: a pooled analysis of 30 observational studies". Diabetes 59 (2): 486–94. doi:10.2337/db09-1166. PMC 2809958. PMID 19875616.
  22. ↑ Stene LC, Harjutsalo V, Moltchanova E, Tuomilehto J (2011). "Epidemiology of Type 1 Diabetes". In Holt RIG, Cockram C, Flyvbjerg A, Goldstein BJ. Textbook of Diabetes. John Wiley & Sons. p. 39.
  23. ↑ Girirajan S (2009). "Parental-age effects in Down syndrome" (PDF). J Genet 88 (1): 1–7. doi:10.1007/s12041-009-0001-6. PMID 19417538.
  24. 1 2 3 Malaspina D, Reichenberg A, Weiser M, Fennig S, Davidson M, Harlap S, Wolitzky R, Rabinowitz J, Susser E, Knobler HY (2005). "Paternal age and intelligence: implications for age-related genomic changes in male germ cells". Psychiatr Genet 15 (2): 117–25. doi:10.1097/00041444-200506000-00008. PMID 15900226.
  25. ↑ Saha S, Barnett AG, Foldi C, Burne TH, Eyles DW, Buka SL, McGrath JJ (2009). Brayne, Carol, ed. "Advanced Paternal Age Is Associated with Impaired Neurocognitive Outcomes during Infancy and Childhood". PLoS Med 6 (3): e40. doi:10.1371/journal.pmed.1000040. PMC 2653549. PMID 19278291.
  26. ↑ Cannon M (2009). "Contrasting Effects of Maternal and Paternal Age on Offspring Intelligence: The clock ticks for men too". PLoS Med 6 (3): e42. doi:10.1371/journal.pmed.1000042. PMC 2653550. PMID 19278293.
  27. ↑ Lopez-Castroman J, Gómez DD, Belloso JJ, Fernandez-Navarro P, Perez-Rodriguez MM, Villamor IB, Navarrete FF, Ginestar CM, Currier D, Torres MR, Navio-Acosta M, Saiz-Ruiz J, Jimenez-Arriero MA, Baca-Garcia E (2010). "Differences in maternal and paternal age between schizophrenia and other psychiatric disorders". Schizophr Res 116 (2–3): 184–90. doi:10.1016/j.schres.2009.11.006. PMID 19945257.
  28. ↑ Zhu JL, Vestergaard M, Madsen KM, Olsen J (2008). "Paternal age and mortality in children". Eur J Epidemiol 23 (7): 443–7. doi:10.1007/s10654-008-9253-3. PMID 18437509.
  29. ↑ "In this particular study, no adjustment was made for the health of the mother, and this could have had a large effect on child mortality." National Health Service (UK), "Older Dads and the Death of Children," (accessed 15 November 2013)
  30. ↑ Tournaye 2009, p. 102
  31. ↑ Eisenberg, Dan T.A.; Hayes, M. Geoffrey; Kuzawa, Christopher W. (June 11, 2012). "Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants". Proc Natl Acad Sci U S A. 109 (26): 10251–10256. doi:10.1073/pnas.1202092109. Retrieved 28 June 2014.
  32. 1 2 3 Kidd SA, Eskenazi B, Wyrobek AJ (2001). "Effects of male age on semen quality and fertility: a review of the literature". Fertil Steril 75 (2): 237–48. doi:10.1016/S0015-0282(00)01679-4. PMID 11172821.
  33. 1 2 3 4 Schmidt L, Sobotka T, Bentzen JG, Nyboe Andersen A (2012). "Demographic and medical consequences of the postponement of parenthood". Hum. Reprod. Update 18 (1): 29–43. doi:10.1093/humupd/dmr040. PMID 21989171.
  34. 1 2 3 4 5 6 Malaspina D, Gilman C, Kranz TM (2015). "Paternal age and mental health of offspring". Fertil. Steril. 103: 1392–6. doi:10.1016/j.fertnstert.2015.04.015. PMID 25956369.
  35. ↑ Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, Gudjonsson SA, Sigurdsson A, Jonasdottir A, Jonasdottir A, Wong WS, Sigurdsson G, Walters GB, Steinberg S, Helgason H, Thorleifsson G, Gudbjartsson DF, Helgason A, Magnusson OT, Thorsteinsdottir U, Stefansson K (2012). "Rate of de novo mutations and the importance of father's age to disease risk". Nature 488 (7412): 471–5. doi:10.1038/nature11396. PMC 3548427. PMID 22914163.
  36. ↑ Forster P, Hohoff C, Dunkelmann B, Schürenkamp M, Pfeiffer H, Neuhuber F, Brinkmann B (2015). "Elevated germline mutation rate in teenage fathers". Proc R Soc B 282 (1803): 1–6. doi:10.1098/rspb.2014.2898. PMC 4345458. PMID 25694621.
  37. 1 2 3 Goriely A, Wilkie AOM (2013). ""Selfish spermatogonial selection": a novel mechanism for the association between advanced paternal age and neurodevelopmental disorders". Am. J. Psychiatry 170: 599–608. doi:10.1176/appi.ajp.2013.12101352. PMC 4001324. PMID 23639989.
  38. 1 2 3 Perrin MC, Brown AS, Malaspina D (2007). "Aberrant Epigenetic Regulation Could Explain the Relationship of Paternal Age to Schizophrenia". Schizophr Bull 33 (6): 1270–3. doi:10.1093/schbul/sbm093. PMC 2779878. PMID 17712030.
  39. 1 2 3 Wiener-Megnazi Z, Auslender R, Dirnfeld M (2012). "Advanced paternal age and reproductive outcome". Asian J. Androl. 14 (1): 69–76. doi:10.1038/aja.2011.69. PMC 3735149. PMID 22157982.
  40. ↑ Goriely, Anne; Wilkie, Andrew (2012). "Paternal Age Effect Mutations and Selfish Spermatogonial Selection: Causes and Consequences for Human Disease". The American Journal of Human Genetics 90 (2): 175–200. doi:10.1016/j.ajhg.2011.12.017. PMID 22325359.
  41. ↑ Johnson, Sheri L.; Dunleavy, Jessica; Gemmell, Neil J.; Nakagawa, Shinichi (January 2015). "Consistent age-dependent declines in human semen quality: A systematic review and meta-analysis". Ageing Research Reviews 19: 22–33. doi:10.1016/j.arr.2014.10.007.
  42. ↑ "Definition of Advanced paternal age".
  43. 1 2 Crow JF (2000). "The origins, patterns and implications of human spontaneous mutation" (PDF). Nature Reviews Genetics 1 (1): 40–7. doi:10.1038/35049558. PMID 11262873. Archived from the original (PDF) on October 29, 2013.
  44. ↑ Krooth RS (1953). "Comments on the estimation of the mutation rate for achondroplasia". American Journal of Human Genetics 5 (4): 373–6. PMC 1716528. PMID 13104383.
  45. ↑ Brinkmann B, Klintschar M, Neuhuber F, Huhne J, Rolf B (1998). "Mutation Rate in Human Microsatellites: Influence of the Structure and Length of the Tandem Repeat". Am J Hum Genet 62 (6): 1408–1415. doi:10.1086/301869. PMC 1377148. PMID 9585597.
  46. 1 2 Bray I, Gunnell D, Smith GD (2006). "Advanced paternal age: How old is too old?". J Epidemiol Community Health 60 (10): 851–3. doi:10.1136/jech.2005.045179. PMC 2566050. PMID 16973530.
  47. ↑ Australian Bureau of Statistics (11 November 2009). "3301.0 - Births, Australia, 2008. Summary of findings. Births". Retrieved 25 February 2010.
  48. 1 2 3 Kühnert B, Nieschlag E (2004). "Reproductive functions of the ageing male". Hum Reprod Update 10 (4): 327–39. doi:10.1093/humupd/dmh030. PMID 15192059.
  49. ↑ Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Kirmeyer S, Mathews TJ (2009). "Births: final data for 2006" (PDF). National Vital Statistics Reports (Hyattsville, MD: National Center for Health Statistics) 57 (7): 1–104. Retrieved 25 February 2010.
  50. ↑ Seymour FI, Duffy C, Koerner A (1935). "A case of authenticated fertility in a man, aged 94". J Am Med Assoc 105 (18): 1423–4. doi:10.1001/jama.1935.92760440002009a.
  51. ↑ "A father again at 96; North Carolinan's baby a sister to boy born two years ago". New York Times. 4 June 1936. p. 10.
  52. ↑ Nanu Ram Jogi fathers another child aged 96, article in the Times of India, 16 October 2012
  53. ↑ "World's oldest dad, 97, devastated after wife leaves him following disappearance of their son". The Daily Mail (London). 3 October 2013.
  54. ↑ Toriello HV, Meck JM; Professional Practice and Guidelines Committee, American College of Medical Genetics (2008). "Statement on guidance for genetic counseling in advanced paternal age". Genet Med 10 (6): 457–60. doi:10.1097/GIM.0b013e318176fabb. PMC 3111019. PMID 18496227.
  55. ↑ Frans E, MacCabe JH, Reichenberg A (2015). "Advancing paternal age and psychiatric disorders". World Psychiatry 14 (1): 91–3. doi:10.1002/wps.20190. PMC 4329902. PMID 25655163.

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