Our Results Show That All Mutations Were Inherited From the Father, Advanced Paternal Age Was Found in Sporadic Cases of Noonan Syndrome

Published by the University of Chicago Press

--------------------------------------------------------------------------------
Title Paternal Germline Origin and Sex-Ratio Distortion in Transmission of PTPN11 Mutations in Noonan Syndrome
Author(s) Marco Tartaglia, Viviana Cordeddu, Hong Chang, Adam Shaw, Kamini Kalidas, Andrew Crosby, Michael A. Patton, Mariella Sorcini, Ineke van der Burgt, Steve Jeffery, and Bruce D. Gelb
Identifiers The American Journal of Human Genetics, volume 75 (2004), pages 492–497
DOI: 10.1086/423493
PubMed ID: 15248152

Availability This site: PS | HTML | PDF (89.5k)
Copyright © 2004, The American Society of Human Genetics.
Abstract Germline mutations in PTPN11the gene encoding the nonreceptor protein tyrosine phosphatase SHP-2represent a major cause of Noonan syndrome (NS), a developmental disorder characterized by short stature and facial dysmorphism, as well as skeletal, hematologic, and congenital heart defects. Like many autosomal dominant disorders, a significant percentage of NS cases appear to arise from de novo mutations. Here, we investigated the parental origin of de novo PTPN11 lesions and explored the effect of paternal age in NS. By analyzing intronic portions that flank the exonic PTPN11 lesions in 49 sporadic NS cases, we traced the parental origin of mutations in 14 families. Our results showed that all mutations were inherited from the father, despite the fact that no substitution affected a CpG dinucleotide. We also report that advanced paternal age was observed among cohorts of sporadic NS cases with and without PTPN11 mutations and that a significant sex-ratio bias favoring transmission to males was present in subjects with sporadic NS caused by PTPN11 mutations, as well as in families inheriting the disorder.

--For those British men whose children had a PTPN11
mutation (n p 15), the mean Z score was 0.93 (P !
.001). For the fathers of children with NS but without
a PTPN11 mutation (n p 43), the mean Z score was
0.62 (P ! .001). For comparison with other studies of
advanced paternal age, we noted that the average paternal
age of the PTPN11-related cohort was 35.6 years,
which was 6.1 years older than the population average
for the children’s average year of birth (1980). For the
PTPN11-negative cohort, the average paternal age was
33.4 years, which was 4.0 years older than the population
average for the children’s average year of birth
(1981).
------------------------------------------------------------------------------

De Novo Mutations It is interesting that the NCI locates the germline mutation in the woman

Slide 16 De Novo Mutations


Inherited mutations had to start somewhere, and that somewhere is a de novo mutation. A de novo mutation is a new mutation that occurs in a germ cell and is then passed on to an offspring. All germline mutations started as a de novo mutation in some ancestor. De novo mutations are common in a few inherited cancer susceptibility syndromes.

July 2001 to April 2007 and No One Knows About the Male Biological Clock. Why?

Judy Foreman is a Lecturer on Medicine at Harvard Medical School. Her column appears every other week. Past columns are available on www.myhealthsense.com

07/03/2001

For years, many prospective parents - and doctors as well - have blithely assumed that, if an older couple's baby has birth defects, it's most likely because of the woman's advancing age.



But, increasingly, scientists are discovering that, by focusing almost exclusively on mothers-to-be, they might have been barking up the wrong genome. A man, or more accurately his sperm, also has a biological clock. And it's ticking can be just as spooky as a woman's, perhaps even more so because its virtually impossible to do prenatal tests to pick up all the possible genetic mutations in sperm.

"There's always been this myth that fathers can be fathers until they die, and that would be fine. It's always the mother who had to be young," said Dr. Eric Vilain, a geneticist and pediatrician at the University of California at Los Angeles. But that's because the risks associated with advancing paternal age have been routinely "underestimated."
Over the years, geneticists have linked a number of other diseases to advancing paternal age, including achondroplasia, or dwarfism; Marfan's syndrome, which can lead to the fatal rupture of a major blood vessel; and Apert's syndrome, or the malformation of the skull, hands and feet.

Retinoblastoma, an eye cancer; neurofibromatosis, or fleshy growths of abnormal nerve tissue; and some types of prostate cancer also have been linked with older fathers. And some diseases caused by genes on the X-chromosome, among them hemophilia, Duchenne muscular dystrophy and Hunter syndrome, have been linked to advanced age not of a child's father but of his maternal grandfather. In these cases, an older man passes on a defective gene on the X chromosome to his daughter, who, like Queen Victoria, becomes an unaffected carrier who can pass the disease to her sons.

When certain diseases caused by genetic defects show up in a family for the first time, the odds are seven to 10 times greater that the mutation has occurred in the DNA of the father rather than that of the mother, said Dr. Victor McKusick, professor of%2

Sung-Tae Cho, the killer's father.....He Was a "Country Bumpkin" and Considerably Older Than Cho's Mother

Sung-Tae Cho, the killer's father, came from a poor rural area. He was a "country bumpkin" and considerably older than Cho's mother, Hyang-Im Kim, the daughter of a refugee, said Cho's great-aunt, Kim Yan-Soon. "We practically forced her to getung married."



Father's age:


South Korea's largest newspaper Chosun Ilbo reported that Cho's family was poor when they lived in a Seoul suburb and decided to emigrate to seek a better life.

The family lived in a rented, basement apartment - usually the cheapest unit in a multi-apartment building, the newspaper reported quoting building owner Lim Bong-ae, 67. Police identified the shooter's father as Cho Seong-tae, 61.

"I didn't know what (Cho's father) did for a living. But they lived a poor life," Lim told the newspaper. "While emigrating, (Cho's father) said they were going to America because it is difficult to live here and that it's better to live in a place where he is unknown."

Meanwhile, South Korean President Roh Moo-hyun held a special meeting with aides today to discuss the shooting, as the public expressed shame over a South Korean citizen being identified as the gunman.

Rwas to speak publicly about the tragedy later in the day, his office said, without elaborating on what the president discussed at the meeting with aides.

-------------------------------------------------------------------------------------

Sung Cho, 61, and Hyang Cho, 56, kept a low profile in the small town, attending services at the Korean Presbyterian Church and planting lettuce in the backyard of their home.

THE OPTIMAL TIME FOR A MAN TO FATHER A CHILD IS 25 OR SO

"The optimal time for a man to father a healthy child is the same as for a woman — 25 or so," says Dolores Malaspina, a psychiatry professor at New York University and coauthor of the study.

Do the benefits of loving older fathers outweigh the risks? Take a survey of the street people, of the victims and see. Who else could answer this questions except the offspring?


Is the firm that hired the firm that produced and wrote this video selling something?

Paternal Age Effect and Disorders Known in 1999

It is now 2007 and most of the public has no idea of this.


Table II. Long-term effects of paternal ageing on offspring from table on page 2373 of Long –term effects of delayed parenthood by J.J. Tarin, J. Brines, and A. Cano

Dominant disorders
Wilms tumour, thanatophoric dysplasia, retinitis pigmentosa, osteogenisis imperfecta type IIA, acrodysostosis, achondroplasia, Apert’s disease, fibrodysplasia ossificans progressiva, aniridia, bilateral retinoblastoma, multiple exostoses, Marfan’s, Lesch-Nyan’s, Pfeiffer’s, Wardenburg’s, Treacher-Collins, Soto’s, and Crouzon’s syndromes, basel cell nevus, cleidocranial dysostosis, polyposis coli, oculodentodigital syndrome, Costello syndrome , progeria, Recklinghausen’s neurofibromatosis, tuberous sclerosis and renal polycystic kidney disease.

X-linked recessive diseases
Haemophilia A and Duchenne’s muscular dystrophy

Non-cytogenetic congential defects
Congential cataracts, reduction defects of the upper limb, nasal aplasia, pulmonic and urethtal stenosis, perauricular cyst, cleft palate,1 neural tube defects

Athetoid /dystonic cerebral palsy and congenital hemiplegia

Psychotic disorders

Decreased learning capacity and/or mental retardation




Moreover, (i) the activities of antioxidant enzymes within the seminal plasma and spermatozoa from older men may be reduced and so spermatozoa may be more vulnerable to mutational changes than spermatozoa from younger men; and (ii) late spermatids, and immature and mature spermatozoa do not have a DNA repair system.

posted by concerned heart at 8:37 PM | 0 comments

------------------------------------------------------------------------------

Breast Cancer Risk Was Found to Rise With The Age of Each Parent Maybe Independently

1: J Clin Epidemiol. 1989;42(2):151-7. Links
Epidemiologic evidence of perinatal influence in the etiology of adult cancers.Janerich DT, Hayden CL, Thompson WD, Selenskas SL, Mettlin C.
Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT 06510.

Using data from 5489 cancer patients and 2647 patients without cancer we investigated whether parental age at the birth of the patient or the patient's rank within his sibship was related to the risk of cancer during adulthood. An increase of 10 years in maternal age was associated with an increase of 24% for the incidence of breast cancer (odds ratio = 1.24%; 95% CI = 1.09-1.41); the corresponding increase for paternal age was 19% (odds ratio = 1.19; 95% CI = 1.07-1.33). There was some evidence that the age of each parent may make an independent contribution to the risk of breast cancer. For certain types of genito-urinary cancers, the risk was higher when the parents were relatively young at the birth of the patient. These cancers included tumors arising in the prostate (odds ratios = 0.71 and 0.55 for maternal and paternal ages, respectively), testis (odds ratios = 0.57 and 0.52), penis (odds ratios = 0.37 and 0.45), kidney (odds ratios = 0.66 and 0.60), and bladder (odds ratio = 0.79 and 0.85). The associations for cancer of the prostate and bladder were stronger among patients who were diagnosed at a relatively young age. No statistically significant effects were found for birth order relative to adult cancers. The authors conclude that environmental factors that affect the parents or that operate in the perinatal period may have stronger influences on the incidence of adult cancers than have been previously recognized.

PMID: 2918324 [PubMed - indexed for MEDLINE]

FORBES ON FERTILITY: FISCH, "WHY WOULD YOU THINK THE SPERM OR TESTICLES DON'T AGE?"

Allison Van Dusen, 04.11.07, 12:01 AM ET

Dr. Samuel Pang, medical director of the Reproductive Science Center of New England, estimates that about one third of his patients' difficulties is due to a woman's health problem and another third is due to a problem with a man's sperm.

Having problems conceiving? You're not alone. Find out how others are coping here.
The other third consists of couples whose age is affecting their ability to conceive, a group that's growing as more people delay having children until later in life. Doctors say maternal age in particular is one of the most important factors couples need to consider.

"Sociologically we've changed, but our biology hasn't changed very much," says Dr. Richard Scott, director of Reproductive Medicine Associates of New Jersey. "Women make a lifetime supply of eggs when they're in the fetus. When they're gone, they're gone."

In fact, a woman's fertility starts to measurably decline around age 27, due to the depletion and aging of her eggs. For those under 30, it's estimated that the chance of getting pregnant in any one cycle is 20% to 30%. By age 40, it falls to 5%, according to the American Fertility Association.

Guys, Listen Up
But it's not just women who need to pay attention to the ticking of the clock, says Dr. Harry Fisch, director of the Male Reproductive Center at New York-Presbyterian Hospital/Columbia University Medical Center and author of The Male Biological Clock.

Men over 35 are twice as likely to be infertile as those under 25. Studies also are showing that, as with older women, older men are more likely to have children with birth defects due to the decreased genetic quality of their sperm.

"Every cell in the body ages," Fisch says. "Why would you think the sperm or testicles don't age?"

PATERNAL AGE ABOVE 35 IS ASSOCIATED WITH AN INCREASED RISK OF SCHIZOPHRENIA AND MANY OTHER GENETIC DISORDERS AND DISEASES

Eur Psychiatry. 2007 Jan;22(1):22-6. Epub 2006 Dec 4. Links
Paternal ages below or above 35 years old are associated with a different risk of schizophrenia in the offspring.Wohl M, Gorwood P.
INSERM U675, 16 rue Henri Huchard 75018 Paris, France.

BACKGROUND: A link between older age of fatherhood and an increased risk of schizophrenia was detected in 1958. Since then, 10 studies attempted to replicate this result with different methods, on samples with different origins, using different age classes. Defining a cut-off at which the risk is significantly increased in the offspring could have an important impact on public health. METHODS: A meta-analysis (Meta Win) was performed, assessing the mean effect size for each age class, taking into account the difference in age class references, and the study design. RESULTS: An increased risk is detected when paternal age is below 20 (compared to 20-24), over 35 (compared to below 35), 39 (compared to less than 30), and 54 years old (compared to less than 25). Interestingly, 35 years appears nevertheless to be the lowest cut-off where the OR is always above 1, whatever the age class reference, and the smallest value where offspring of fathers below or above this age have a significantly different risk of schizophrenia. CONCLUSION: No threshold can be precisely defined, but convergent elements indicate ages below or above 35 years. Using homogeneous age ranges in future studies could help to clarify a precise threshold.

PMID: 17142012 [PubMed - indexed for MEDLINE]

Paternal Age Equal of Greater than 35 years found associated with a 49% higher risk of ALL

Br J Cancer. 2002 Feb 1;86(3):356-61. Links
Association of early life factors and acute lymphoblastic leukaemia in childhood: historical cohort study.Murray L, McCarron P, Bailie K, Middleton R, Davey Smith G, Dempsey S, McCarthy A, Gavin A.
Northern Ireland Cancer Registry, Department of Epidemiology and Public Health, The Queens University, Belfast, Riddel Hall, Stranmillis Road, Belfast BT9 5EE, UK. l.murray@qub.ac.uk
In a historical cohort study of all singleton live births in Northern Ireland from 1971-86 (n=434,933) associations between early life factors and childhood acute lymphoblastic leukaemia were investigated. Multivariable analyses showed a positive association between high paternal age (> or =35 years) and acute lymphoblastic leukaemia (relative risk=1.49; 95% confidence interval (CI)=0.96--2.31) but no association with maternal age. High birth weight (> or =3500 g) was positively associated with acute lymphoblastic leukaemia (relative risk=1.66; 95% CI=1.18--2.33). Children of mothers with a previous miscarriage or increased gestation (> or =40 weeks) had reduced risks of ALL (respective relative risks=0.49; 95% CI=0.29--0.80, and 0.67; 95% CI=0.48--0.94). Children born into more crowded households (> or =1 person per room) had substantially lower risks than children born into less crowded homes with also some evidence of a lower risk for children born into homes with three adults (relative risks=0.56; 95% CI=0.35-0.91 and 0.58; 95% CI=0.21-1.61 respectively). These findings indicate that several early life factors, including living conditions in childhood and maternal miscarriage history, influence risk of acute lymphoblastic leukaemia in childhood. Copyright 2002 The Cancer Research Campaign

PMID: 11875699 [PubMed - indexed for MEDLINE]

Central Nervous System Early Childhood Cancer Incidence Increases with Paternal Age

1: Int J Epidemiol. 2006 Dec;35(6):1495-503. Epub 2006 Sep 28. Links
Parental age and risk of childhood cancers: a population-based cohort study from Sweden.Yip BH, Pawitan Y, Czene K.
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 171 77 Stockholm, Sweden.

BACKGROUND: Frequent germ line cells mutations were previously demonstrated to be associated with aging. This suggests a higher incidence of childhood cancer among children of older parents. A population-based cohort study of parental ages and other prenatal risk factors for five main childhood cancers was performed with the use of a linkage between several national-based registries. METHODS: In total, about 4.3 million children with their parents, born between 1961 and 2000, were included in the study. Multivariate Poisson regression was used to obtain the incidence rate ratios (IRR) and 95% confidence interval (CI). Children <5 years of age and children 5-14 years of age were analysed independently. RESULTS: There was no significant result for children 5-14 years of age. For children <5 years of age, maternal age were associated with elevated risk of retinoblastoma (oldest age group's IRR = 2.39, 95%CI = 1.17-4.85) and leukaemia (oldest age group's IRR = 1.44, 95%CI = 1.01-2.05). Paternal age was significantly associated with leukaemia (oldest age group's IRR = 1.31, 95%CI = 1.04-1.66). For central nervous system cancer, the effect of paternal age was found to be significant (oldest age group's IRR = 1.69, 95%CI = 1.21-2.35) when maternal age was included in the analysis. CONCLUSION: Our findings indicate that advanced parental age might be associated with an increased risk of early childhood cancers.

PMID: 17008361 [PubMed - in process]

Brain cancer was found to increase 25% with rising paternal age, Leukemia increased with maternal age

Childhood brain cancer and leukemia incidence found to increase with parental age.


1: Epidemiology. 1999 May;10(3):271-5. Links
Parental age as a risk factor of childhood leukemia and brain cancer in offspring.Hemminki K, Kyyronen P, Vaittinen P.
Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden.

We use here the Swedish Family-Cancer Database to analyze the time trends in childhood leukemia and brain cancer between 1960 and 1994 and the effect of parental age on childhood leukemia and brain cancer of some 1500 cases each. The database includes all persons born in Sweden after 1940 with their biological parents, over 6 million individuals, whose cancers were retrieved from the Swedish Cancer Registry from years 1958-1994. Incidence in cancer increased from 1960 to 1994; low grade astrocytoma accounted for most of the increase, whereas high grade astrocytoma has not increased in incidence. There has been a moderate increase in leukemia to about 1980. We found a parental age effect for both leukemia and brain cancer, with the former (of about 50% excess in those over 35 years) being mediated by maternal age and the latter (of about 25% excess) by paternal age. Accumulation of chromosomal aberrations and mutations during the maturation of germ cells is a likely mechanism for these findings. They can help to explain partially the secular trends of these malignancies and the excess risks in offspring of the well educated.

PMID: 10230837 [PubMed - indexed for MEDLINE]

Alzheimer's and Advanced Parental Age in a Study in Japan in 1989

1: Arch Neurol. 1989 Jan;46(1):38-9. Links
A community-based study of parental age at the birth of patients with dementia of the Alzheimer type.Urakami K, Adachi Y, Takahashi K.
Division of Neurology, Tottori University School of Medicine, Yonago, Japan.

The association of dementia of the Alzheimer type (DAT) with parental age at the birth of patients who develop DAT was investigated in a community-based study in Japan. Both maternal and paternal ages of patients who have developed DAT are significantly higher than those in controls and multi-infarct dementia. This study suggests that advanced age may become a cause of chromosome abnormality, and advanced parental age at subjects' birth may be a possible risk factor in DAT.

Decline in Fertility and Serious Birth Defects Associated With Advanced Paternal Age

: Urol Clin North Am. 1994 Aug;21(3):549-56. Links
Reproductive function in the aging male.Meacham RB, Murray MJ.
Division of Urology, University of Colorado Health Sciences Center, Denver.

Although the association between advanced paternal age and serious birth defects has received less attention than the effect of maternal age on such defects, this association has been demonstrated. This, as well as the potential decline in fertility among older men, should be borne in mind by men electing to defer establishing a family.

The Father's Age as a Risk Factor for Autism

Published and should be read on the EBD Blog
part of the paper is republished below, the entire paper contains excellent links to research papers pertaining to this subject.


The average age of fatherhood is increasing in the US and in Western Europe. Some research shows f older fathers are at increased risk for diseases and conditions (Bray et al., 2006). Some experts predict an upswing in cases of schizophrenia will accompany the increasing average paternal age. “The actual percentage of cases with paternal germ line-derived schizophrenia in a given population will depend on the demographics of paternal childbearing age, among other factors. With an upswing in paternal age, these cases would be expected to become more prevalent” (Malaspina et al., 2006). Approximately 25-33% of all cases of schizophrenia may be due to the father’s age at conception, according to Malaspina (2006). Malaspina sees a connection between advancing paternal age and neural functioning difficulties in people with autism and with schizophrenia. According to Tarin et al. (1998), there are well over 30 known conditions that the offspring of older fathers are more at risk for (see chart on paternal aging in the linked article).

The diagnosis of autism is increasing in the US and elsewhere (Centers for Disease Control, 2006). In a population study of 1990 through 1999, a total of 669,995 children, Atladóttir and colleagues (2007) reported increased diagnosese of autism, Torrette Syndrome, and hyperkinetic disorder. Is there a connection between increased cases of disorders such as autism and increased average paternal age? Psychiatrist Michael Craig Miller (2006), editor of the Harvard Mental Health Letter is convinced there is. Although a connection between the two would be corelational (not causal), the relationship encourages examination of the possibility that something related to paternal age (e.g. mutations in gametes) may contribute to the occurrence of autism. If there is a potential causal relationship, the new study by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) Network would provide a valuable opportunity to test the hypothesis.

Observations of a connection between advanced paternal age and difficulties for offspring go way back. Earlier research looking for a link between maternal age and autism also found the average paternal age (34) was much higher than the average age in the general population (Gillberg, 1980). Geneticist James F. Crow (1997) cites Wilhelm Weinberg (1862-1937) as noticing, during his 42 years of medical practice and helping 3,500 births, that the mutation rate might be a function of paternal age.James F. Crow said,in 1997and on other occasions that the greatest mutational health hazard in the population is fertile old men.

DISORDERS LINKED TO PATERNAL AGE BEGIN TO SHOW UP AGES 33-35

"It makes sense that the mutations causing these diseases would occur more frequently in older men, and indeed that's what we saw for Apert syndrome," says Ethylin Jabs, M.D., director of the Center for Craniofacial Development and Disorders at Johns Hopkins.


Importantly, disorders linked to advancing paternal age begin to increase rapidly at about the same time as maternal risks increase -- age 33 to 35. Until now, the only evidence for paternal age effects has come from determining how many children with these diseases are born to fathers of various ages.



To obtain the first genetic explanation for these effects, the scientists studied sperm from about 60 men of various ages and looked for two genetic changes responsible for 99 percent of the cases of Apert syndrome. They found that men over 50 were, on average, three times as likely as men under 30 to have sperm with at least one of these changes. The mutations were not more common in blood samples as men aged.

The scientists say it's likely that the number of cell divisions that go into making a sperm plays a large role in the link between Apert syndrome and paternal age, and represents a fundamental difference between how aging egg and sperm can impact the health of a child.

"In the men we studied, these mutations had not been inherited, but rather collected over time in the reservoir of primitive cells that become sperm," says first author Rivka Glaser, a graduate student in human genetics at the Johns Hopkins School of Medicine.

Sperm, on the other hand, are continually produced throughout a male's lifetime from a reservoir of primitive cells. These primitive cells, like other kinds of so-called stem cells, can either replicate themselves or take a step closer to becoming a sperm, a process called differentiation. All told, these cells divide every 21 days after puberty, and at each cell division the opportunity exists for an error in copying the DNA.

"Literally hundreds of millions of sperm are made in each batch, so in most cases there are still many normal sperm available," says Jabs, also a professor of pediatrics. Their study showed that "high levels" of mutations among men who had no children with Apert syndrome amounted to roughly 3 sperm with the mutation among 100,000 sperm.

If an error is made in any of the steps toward becoming a sperm, the only cells affected are the resulting sperm for that batch. However, if an error appears in a primitive cell as it replicates itself and the mistake isn't fixed, the mutation will continue to be passed on to all of its progeny, including subsequent primitive cells and other batches of semen.

As men age, more of these primitive cells have collected mutations that cause Apert syndrome, leading to more sperm with the mutations in each batch of semen, the scientists suggest. The risk of having a child with Apert is about six times higher for a man age 52 than for someone who's 27.


Authors on the study are Glaser, Jabs, and Rebecca Schulman, of Johns Hopkins School of Medicine, and Karl Broman, of the Johns Hopkins Bloomberg School of Public Health.

The Paternal Age Effect

From Wikipedia

Paternal Age Effect
Scientists know that a woman’s age at the time she conceives can affect her offspring’s genetic make-up. Women age 35 and older are at greater risk of delivering a child with a genetic disorder, such as Down Syndrome, due to an incorrect number of chromosomes. Less well known is that a man’s age also affects his offspring. In what is called the paternal age effect, men 35 years and older have a greater probability than younger men of fathering a child with some kind of genetic defect.