Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors.

: Nat Genet. 2009 Oct 25. [Epub ahead of print]
Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors.
Goriely A, Hansen RM, Taylor IB, Olesen IA, Jacobsen GK, McGowan SJ, Pfeifer SP, McVean GA, Meyts ER, Wilkie AO.
Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Genes mutated in congenital malformation syndromes are frequently implicated in oncogenesis, but the causative germline and somatic mutations occur in separate cells at different times of an organism's life. Here we unify these processes to a single cellular event for mutations arising in male germ cells that show a paternal age effect. Screening of 30 spermatocytic seminomas for oncogenic mutations in 17 genes identified 2 mutations in FGFR3 (both 1948A>G, encoding K650E, which causes thanatophoric dysplasia in the germline) and 5 mutations in HRAS. Massively parallel sequencing of sperm DNA showed that levels of the FGFR3 mutation increase with paternal age and that the mutation spectrum at the Lys650 codon is similar to that observed in bladder cancer. Most spermatocytic seminomas show increased immunoreactivity for FGFR3 and/or HRAS. We propose that paternal age-effect mutations activate a common 'selfish' pathway supporting proliferation in the testis, leading to diverse phenotypes in the next generation including fetal lethality, congenital syndromes and cancer predisposition.
PMID: 19855393 [PubMed - as supplied by publisher]

Revealed: why children of older men are more likely to have health problems

Revealed: why children of older men are more likely to have health problems
Oxford study identifies mutant cells affecting sperm
By Steve Connor, Science Editor
Monday, 26 October 2009

Scientists may have discovered the reason why older men are at greater risk than younger men of fathering a child who develops serious health problems such as congenital deformities, autism, or schizophrenia.
Researchers at Oxford University have found that older men are more likely to harbour a rare form of testicular tumour which may also cause genetic mutations in the DNA of their children, who inherit the faults through their father's sperm. Professor Andrew Wilkie, who led the study published in the journal Nature Genetics, said that clumps of tumour-producing cells form in the testicular tissue which produces the "germ cells" that give rise to sperm.
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"We think most men develop these tiny clumps of mutant cells in their testicles as they age. They are rather like moles in the skin, usually harmless in themselves," Professor Wilkie said. "But by being located in the testicle, they also make sperm, causing children to be born with a variety of serious conditions."
Professor Wilkie said that the latest study, which was funded by the Wellcome Trust, could help to explain the origin of several serious conditions affecting children, including achondroplasia, which is commonly known as dwarfism, as well as stillbirths.
The work may also help scientists to find the many genes that are involved in common diseases where there is a strong genetic component, such as autism and schizophrenia.
Until recently, it was assumed that only women have to worry about having children in later life but a number of studies in the past decade have shown that as the quality of a man's sperm decreases with age, the risk of him fathering a child with serious health problems increases.
The overall risk for an older father of having a child with a birth defect is estimated to be about 4 per cent, compared with a "background" risk of about 3 per cent. One study carried out in Israel suggested that men who became fathers at the age of 40 or older were nearly six times as likely to have a child with autism compared with men younger than 30 when they became fathers.
Research into schizophrenia suggests that the risk of the illness doubled among the children of older fathers compared with the children of men who became fathers in their 20s.

Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors

Letter abstract
Nature Genetics Published online: 25 October 2009 doi:10.1038/ng.470
Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors
Anne Goriely1, Ruth M S Hansen1, Indira B Taylor1, Inge A Olesen2, Grete Krag Jacobsen3, Simon J McGowan4, Susanne P Pfeifer5, Gilean A T McVean5, Ewa Rajpert-De Meyts2 & Andrew O M Wilkie1
Abstract
Genes mutated in congenital malformation syndromes are frequently implicated in oncogenesis1, 2, but the causative germline and somatic mutations occur in separate cells at different times of an organism's life. Here we unify these processes to a single cellular event for mutations arising in male germ cells that show a paternal age effect3. Screening of 30 spermatocytic seminomas4, 5 for oncogenic mutations in 17 genes identified 2 mutations in FGFR3 (both 1948A>G, encoding K650E, which causes thanatophoric dysplasia in the germline)6 and 5 mutations in HRAS. Massively parallel sequencing of sperm DNA showed that levels of the FGFR3 mutation increase with paternal age and that the mutation spectrum at the Lys650 codon is similar to that observed in bladder cancer7, 8. Most spermatocytic seminomas show increased immunoreactivity for FGFR3 and/or HRAS. We propose that paternal age-effect mutations activate a common 'selfish' pathway supporting proliferation in the testis, leading to diverse phenotypes in the next generation including fetal lethality, congenital syndromes and cancer predisposition.Top of page
Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Department of Growth & Reproduction, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
Department of Pathology, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
Computational Biology Research Group, Oxford, UK.
Department of Statistics, University of Oxford, Oxford, UK.
Correspondence to: Andrew O M Wilkie1 e-mail: awilkie@hammer.imm.ox.ac.uk

Scientists discover link between older dads and genetic diseases

From The Times

October 26, 2009
Scientists discover link between older dads and genetic diseases
Mark Henderson

http://www.timesonline.co.uk/tol/news/science/genetics/article6889878.ece");
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Scientists have moved a step closer to understanding why older fathers are more likely to have children with certain genetic diseases.
They have discovered a surprising genetic link between the formation of benign testicular tumours called spermocytic seminomas and several rare growth disorders, which are more common among the children of older fathers.
The abnormal testicular cells that form these rare tumours also produce sperm carrying mutant genes that cause serious inherited diseases, research at the University of Oxford and Copenhagen University Hospital in Denmark has shown.
The findings offer important new insights into the origin of several rare genetic disorders, including a cause of dwarfism called achondroplasia, and also promise to illuminate more common conditions such as autism, schizophrenia and breast cancer.

All three of these are known to be affected by genetics, and to be more prevalent among the children of older fathers, but few of the DNA mutations responsible have yet been identified. Scientists behind the research believe that abnormal testicular cells of the sort that develop into tumours could be partially responsible.
Professor Andrew Wilkie, of the University of Oxford, who led the research, said: “What we have seen so far may just be the tip of a large iceberg of mildly harmful mutations being introduced into our genome. These mutations would be too weak and too rare to be picked up by our current technology, but their sheer number would have a cumulative effect, leading to disease.
“It may be that process we have identified might contribute to part of the excess risk for older fathers to have children with higher risks of, for example, breast cancer, schizophrenia, or autism. We have no direct evidence for this as yet.”
Details of the research are published in the journal Nature Genetics . Professor Wilkie’s team, which is funded by the Wellcome Trust, is now planning further research to investigate whether testicular abnormalities might be linked to conditions such as autism and schizophrenia.
Spermatocytic seminomas are rare tumours of the testes, almost always benign, which affect about one in 100,000 men. They are caused by the accumulation of genetic mutations in testicular cells, which can sometimes then divide to trigger tumours.
“We think most men develop these tiny clumps of mutant cells in their testicles as they age,” Professor Wilkie said. “They are rather like moles in the skin, usually harmless in themselves. But by being located in the testicle, they also make sperm - causing children to be born with a variety of serious conditions.”
The new study, has identified genetic mutations of the sort that cause achondroplasia and other rare inherited conditions in cells from spermatocytic seminomas. It appears that these mutations help the tumour cells to divide, but cause abnormal growth when transmitted to the offspring via sperm. “We call them ‘selfish’ because the mutations benefit the germ cell but are harmful to offspring,” Professor Wilkie said.
As the mutations cause the tumour cells to profilerate in the testes, they also increase the chances that a sperm that fertilises an egg will be abnormal.
The results will help doctors to explain to parents why children have developed these disorders, and to advise them about the risks of having further children. In most cases, these families will not have a high risk of having another affected child, though it will be higher than in the general population.
“The major implication is for older fathers,” Professor Wilkie said. “We already knew that men in their 50s have a risk of having children with various individually rare genetic disorders — achondroplasia is a well known one — about tenfold higher than men in their early 20s.
“Adding all these risks together, the total additional risk is still only a fraction of 1 per cent because each of these disorders is rare.”

Advanced paternal age: How old is too old?

J Epidemiol Community Health. 2006 October; 60(10): 851–853.
doi: 10.1136/jech.2005.045179. PMCID: PMC2566050

Copyright ©2006 BMJ Publishing Group Ltd.
Advanced paternal age: How old is too old?
Isabelle Bray and David Gunnell, George Davey Smith
I Bray, D Gunnell, G Davey Smith, Department of Social Medicine, University of Bristol, UK
Correspondence to: Dr I Bray
Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, UK; Issy.Bray@bristol.ac.uk
Accepted March 25, 2006.
This article has been cited by other articles in PMC.
Top
Abstract
Time trends in paternal age
All births
Reasons for increasing age at parenthood
Risks associated with advanced paternal age
Conclusions
References AbstractAverage paternal age in the UK is increasing. The public health implications of this trend have not been widely anticipated or debated. This commentary aims to contribute to such a debate. Accumulated chromosomal aberrations and mutations occurring during the maturation of male germ cells are thought to be responsible for the increased risk of certain conditions with older fathers. Growing evidence shows that the offspring of older fathers have reduced fertility and an increased risk of birth defects, some cancers, and schizophrenia. Adverse health outcomes should be weighed up against advantages for children born to older parents, mindful that these societal advantages are likely to change over time.
Keywords: paternal age, DNA damage, fertility, abnormalities, schizophrenia
Top
Abstract
Time trends in paternal age
All births
Reasons for increasing age at parenthood
Risks associated with advanced paternal age
Conclusions
References Changing patterns of education, employment, and marriage mean that the average age of childbearing for women is increasing, resulting in higher risks of adverse reproductive outcomes.1,2 It has recently been suggested that the decade 25–35 years is the optimal age for women in Westernised societies to have their children balancing education, career, and family.3 In England and Wales, the mean age at childbearing increased from 26.4 years in 1974 to 29.3 years in 2002.1 Healthcare systems have responded to the increased risk associated with delaying maternity by offering screening for congenital abnormalities and treatment for infertility.4,5 Meanwhile, the average paternal age is also increasing. The mean age of fathers in England and Wales increased from 29.2 years in 1980 to 32.1 in 2002.6 The public health implications of this trend have not been widely anticipated or debated.
Top
Abstract
Time trends in paternal age
All births
Reasons for increasing age at parenthood
Risks associated with advanced paternal age
Conclusions
References Time trends in paternal ageBirths within marriage
In 1993, fathers aged <35 years accounted for 74% of live births within marriage in England and Wales, while only 25% of such births were to fathers aged 35–54 years. Ten years later, these percentages were 60% and 40%. Figure 1 1 illustrates these trends. If this trend continues, the proportion of fathers >35 years will further increase.
Figure 1Trends in paternal age for live births within marriage in England and Wales, 1993–2003: (A) decreasing trends <35 years, (B) increasing trends 35–54 years. Source: Series FM1 no 32 (ONS, 2003). (Births to fathers (more ...)

Top
Abstract
Time trends in paternal age
All births
Reasons for increasing age at parenthood
Risks associated with advanced paternal age
Conclusions
References All birthsData on time trends in paternal ages for all births in England and Wales are not available, and it could be argued that the increasing proportion of births occurring outside marriage will lead to declining paternal ages as the fathers of such children are younger than those for children born to married couples. Figure 2 2 shows the age distribution of fathers for all births in England and Wales in 2003, which reaches a maximum at age 32. While this approximately normal distribution is mirrored closely for the 60% of births that occurred within marriage, the paternal ages for births outside marriage is more uniform between the ages of 22 and 33 years, with a lower mean age at fatherhood. Between 1993 and 2003 the percentage of births occurring outside marriage increased steadily from 32% to 41%. However, the demographic composition of the group having children outside marriage is changing.
Figure 2Distribution of paternal age for births in England and Wales in 2003: total births* and live births within and outside marriage to fathers aged 13–49. Source: Series FM1 no 32 (ONS, 2003). *All births within marriage, (more ...)

Maternal age data are available for all births (within and outside marriage) in England and Wales6 and they show that the proportion and number of births to women of 30 and over are increasing.
Top
Abstract
Time trends in paternal age
All births
Reasons for increasing age at parenthood
Risks associated with advanced paternal age
Conclusions
References Reasons for increasing age at parenthoodChanges in the population structure (different sizes of birth cohorts across the span of reproductive ages) explain the trend towards older parents to some extent,1 but there is no doubt that societal changes have led to both men and women beginning families later. Advances in reproductive technologies are also contributing to this trend.7 Some 3%–6% of births in most developed countries are now the result of assisted reproduction.8 While the UK government directs substantial efforts towards reducing teenage pregnancy rates, little guidance is given on the risks of delaying childbearing until advanced maternal age, and less still on the risks of advanced paternal age. In the USA, the American Society for Reproductive Medicine has begun to publicise the risks of delaying childbearing, although their Patient Guide on Age and Fertility9 focuses mainly on the mechanisms and risks of maternal, rather than paternal, aging.
Top
Abstract
Time trends in paternal age
All births
Reasons for increasing age at parenthood
Risks associated with advanced paternal age
Conclusions
References Risks associated with advanced paternal ageIt is thought that accumulation of chromosomal aberrations and mutations during the maturation of male germ cells are responsible for increasing risks of certain conditions with advancing paternal age. The amount of DNA damage in sperm of men aged 36–57 is three times that of men <35 years.8 There is a recent body of literature discussing the possible effects on reproductive outcomes, which has been summarised by Kühnert and Nieschlag.10
Fertility and birth
Regarding fertility, Kühnert and Nieschlag10 conclude that men start to contribute to the reduced fertility of a couple in their late 30s, and to a reduced fecundity in their early 40s. For example, a descriptive study of birth rates in married couples in Ireland before the widespread use of contraception found that the probability of birth decreased for men from 42–43 years of age.11 A more recent prospective cohort study of 5121 pregnant women in California concluded that the risk of spontaneous abortion increased with increasing paternal age, and found that the association was stronger for first trimester losses,12 while another prospective cohort study of 23821 pregnant women (based on the Danish national birth cohort) reported that the paternal age related risk of late fetal death was higher than the risk of early fetal death, and started to increase from age 45 years.13 It has been suggested that advanced paternal age (>50 years) increases the risk of preterm delivery and low birth weight,14 although others have found no such effect.15 Although aneuploidy is the leading genetic cause of pregnancy loss, there is no substantial evidence for an effect of paternal age on the presence of extra or missing chromosomes10 and the proportion of fetal deaths attributable to advanced paternal age is currently probably small.13
Birth defects, developmental illnesses, and childhood cancer
A Danish population based study of 1920 affected births of 1489014 live births concluded that paternal age is associated with cleft lip and cleft palate, independently of maternal age.16 Single gene mutations are the suggested mechanism. Many autosomal dominant diseases (for example, achondroplasia) have been shown to be associated with increasing paternal age.10 A population based study of childhood brain cancers reported to the Swedish Cancer Registry between 1960 and 1994 concluded that there is a paternal age affect, estimated to confer about 25% excess risk in fathers >35 years of age.17 A case‐control study of 10162 matched pairs reported a threefold increase in risk of retinoblastoma for fathers 45 years18 and a 50% increased risk of childhood acute lymphoblastic leukaemia for fathers aged 35 years or more was found in a historical cohort of 434933 live births.19 There is conflicting evidence regarding congenital heart defects, although it has been estimated that among offspring of men aged >35 years, about 5% of cases may be attributable to advanced paternal age.10
What is already known on the topic
The average paternal age in the UK in increasing, and the public health implications of this trend have not been widely anticipated or debated
Accumulation of chromosomal aberrations and mutations during the maturation of male germ cells are thought to be responsible for increasing risks of certain conditions with advancing paternal age
There is a growing literature on the effects for offspring of advanced paternal age. Risks include reduced fertility and increased risk of birth defects, schizophrenia, and cancer

Policy implications
Adverse health outcomes should be weighed up against potential social advantages and disadvantages for children born to older parents, mindful that these societal effects are likely to change over time

Illnesses in adulthood
Some diseases of complex aetiology such as schizophrenia are associated with advanced paternal age.10 This may be because of an increase in mutations arising in paternal germ cells, although the possibility of confounding (for example, by schizoid personality traits) cannot be ruled out.16 To illustrate the possible scale of the effects, results from a Swedish population based cohort study have been used to estimate that the increase in paternal age since 1980 could account for about 10% of new cases of schizophrenia diagnosed in the UK in 2002.20 Advanced paternal age is associated with increased risk of cancers in offspring (for example, breast, prostate, nervous system).10 There is less conclusive data regarding Alzheimer's disease.10
Top
Abstract
Time trends in paternal age
All births
Reasons for increasing age at parenthood
Risks associated with advanced paternal age
Conclusions
References ConclusionsA recent report concluded that “even if the genetic risk for progeny from older fathers is slightly increased, the risk to the individual is low”.9 But as our appreciation of the genetic contribution to disease risk develops it seems probable that, if the current trends in timing of fatherhood continue, the consequences at a population level may nevertheless be worth considering further. The adverse health outcomes discussed here 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. For example, data from the national child development study show that young fathers are more likely to come from economically disadvantaged families and to have lower educational attainment21; the labour force survey22 found increasing income with age for men up to their early 40s. Socioeconomic factors such as educational level and occupation are currently associated with many health outcomes. For example people from less affluent backgrounds are less likely to use prenatal care services23 but more likely to give birth to premature or low birthweight infants.24 However, potential social disadvantages of increased paternal age should also be considered, such as less energetic parents and decreased likelihood of the child benefiting from long term relationships with grandparents. Furthermore, as it becomes more common for men to become parents in later adulthood, the current (relatively affluent) socioeconomic composition of older fathers will change, and therefore the relative socioeconomic advantages of having an older father are likely to diminish. An evaluation of various scenarios may help to determine an optimal period of fatherhood balancing the social and economic advantages for the offspring of delayed paternity against the corresponding small, but increasingly well reported, genetic disadvantages. Such an evaluation would inform policy. Possible interventions might include health promotion advising people about the risk of delaying childbearing or changes at a societal level (for example, family benefits, flexible working) that encourage couples to have children earlier rather than later.
Contributors and sourcesAll authors contributed to the conception of the article. IB wrote the initial draft of the paper and subsequent drafts including comments from DG and GDS. All authors have seen and approved the final version. The article arises from a review of the literature and analysis of data available from the Office for National Statistics. All authors are epidemiologists with an interest in public health applications. DG and GDS are members of the Faculty of Public Health.
FootnotesCompeting interests: none.
Ethical approval: not needed.
Top
Abstract
Time trends in paternal age
All births
Reasons for increasing age at parenthood
Risks associated with advanced paternal age
Conclusions
References References1. Chamberlain J, Corbin T. Trends in reproductive epidemiology and women's health. In: Moody J, ed. Why mothers die 2000–2002—report on confidential enquiries into maternal deaths in the United Kingdom. London: RCOG Press at the Royal College of Obstetricians and Gynaecologists, 2004.
2. Bewley S, Davies M, Braude P. Which career first? BMJ 2005. 331589.
3. Heffner L J. Advanced maternal age—how old is too old? N Engl J Med 2005. 3511927–1929. [PubMed]
4. National Collaborating Centre for Women's and Children's Health. Fertility: assessment and treatment for people with fertility problems. London: NICE, 2004.
5. Nicolaides K H, Azar G, Byrne D. et al Fetal nuchal translucency: ultrasound screening for chromosomal defects in first trimester of pregnancy. BMJ 1992. 304867–869. [PubMed]
6. Office for National Statistics. Birth statistics: review of the registrar general on births and family building patterns in England and Wales. London: Stationery Office, 2002.
7. Blickstein I. Motherhood at or beyond the edge of reproductive age. International Journal Fertlilty and Womens Medicine 2003. 4817–24.
8. Aitken R J, Koopman P, Lewis S E M. Seeds of concern. Nature 2004. 43248–52. [PubMed]
9. American Society for Reproductive Medicine. Age and fertility: a guide for patients. Birmingham, AL: American Society for Reproductive Medicine 2003.
10. Kühnert B, Nieschlag E. Reproductive functions of the ageing male. Human Reproduction Update 2004. 10327–339. [PubMed]
11. Anderson B A. Male age and infertility. Result from Ireland prior to 1911. Population Index 1975. 41561–567.
12. Slama R, Bouyer J, Windham G. et al Influence of paternal age on the risk of spontaneous abortion. Am J Epidemiol 2005. 161816–823. [PubMed]
13. Anderson A‐M N, Hansen K D, Anderson P K. et al Advanced paternal age and risk of fetal death: a cohort study. Am J Epidemiol 2004. 1601214–1222. [PubMed]
14. Tough S C, Faber A J, Svenson L W. et al Is paternal age associated with an increased risk of low birthweight, preterm delivery, and multiple birth? Can J Public Health 2003. 9488–92. [PubMed]
15. Nahum G G, Stainslow H. Relationship of paternal factors to birth weight. J Rerod Med 2003. 48963–968.
16. Bille C, Skytthe A, Vach W. et al Parent's age and the risk of oral clefts. Epidemiology 2005. 16311–316. [PubMed]
17. Hemminki K, Kyyronen P, Vaittinen P. Parental age as a risk factor of childhood leukaemia and brain cancer in offspring. Epidemiology 1999. 10271–275. [PubMed]
18. Dockerty J D, Draper G, Vincent T. et al Case‐control study of parental age, parity and socioeconomic level in relation to childhood cancers. Int J Epidemiol 2001. 301428–1437. [PubMed]
19. Murray L, McCarron P, Bailie K. et al Association of early life factors and acute lymphoblastic leukaemia in childhood: historical cohort study. Br J Cancer 2002. 86356–361. [PubMed]
20. Sipos A, Rasmussen F, Harrison G. et al Paternal age and schizophrenia: a population based cohort study. BMJ 2004. 3291070–1073. [PubMed]
21. Kiernan K E. Becoming a young parent: a longitudinal study of associated factors. British Journal of Sociology 1997. 48406–408. [PubMed]
22. Office for National Statistics. Social trends 36. Income and health. Basingstoke: Palgrave Macmillan, 2006 .
23. D'Ascoli P T, Alexander G R, Peterson D J. et al Parental factors influencing patterns of prenatal care utilization. J Perinatol 1997. 17283–287. [PubMed]
24. Parker J D, Schoendorf K C, Kiely J L. Associations between measures of socioeconomic status and low birth weight, small for gestational age, and premature delivery in the United States. Ann Epidemiol 1994. 4271–278. [PubMed]

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