Thursday, May 31, 2007

Most Common Cause of Progeria is a single-letter misspelling in a gene on chromosome 1 codes for lamin A protein key component of nuclear membrane

Researchers Identify Gene for Premature Aging Disorder
Progeria Gene Discovery May Help Solve Mysteries of Normal
WASHINGTON, D.C., April 16, 2003 - A team led by the National Human Genome Research Institute today announced the discovery of the genetic basis of a disorder that causes the most dramatic form of premature aging, a finding that promises to shed new light on the rare disease, as well as on normal human aging.

In their study, to be released online next week in the journal Nature, researchers identified the genetic mutations responsible for Hutchinson-Gilford progeria syndrome (HGPS), commonly referred to as progeria. Derived from the Greek word for old age, "geras," progeria is estimated to affect one in 8 million newborns worldwide. There currently are no diagnostic tests or treatments for the progressive, fatal disorder.

Francis S. Collins, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI) and leader of the research team, said, "This genetic discovery represents the first piece in solving the tragic puzzle of progeria. Without such information, we in the medical community were at loss about where to focus our efforts to help these children and their families. Now, we finally know where to begin."

Dr. Collins added, "The implications of our work may extend far beyond progeria to each and every human being. What we learn about the molecular basis of this model of premature aging may provide us with a better understanding of what occurs in the body as we all grow older."

In addition to NHGRI, the multi-institution research team included scientists from the Progeria Research Foundation; the New York State Institute for Basic Research in Developmental Disabilities in Staten Island, N.Y.; the University of Michigan in Ann Arbor; and Brown University in Providence, R.I.

W. Ted Brown, M.D., Ph.D., co-author of the study and chairman of the Department of Human Genetics at the Institute for Basic Research, said, "Many people consider progeria to be the most dramatic example of a genetic disease that clearly resembles accelerated aging. The children appear to have an aging rate that is 5 to 10 times what is normal." Dr. Brown is widely regarded as the world's leading clinical expert on progeria.

Children with progeria usually appear normal at birth. However, within a year, their growth rate slows and their appearance begins to change. Affected children typically become bald with aged-looking skin and pinched noses. They often suffer from symptoms typically seen in elderly people, especially severe cardiovascular disease. Death occurs on average at age 13, usually from heart attack or stroke.

Leslie Gordon, M.D., Ph.D., medical director of the Progeria Research Foundation (PRF) and executive director of the PRF Genetics Consortium, said, "Isolating this gene is just the beginning. It is our goal to find treatments and possibly a cure for this rare, life-threatening disease that robs children of their adulthood. The Progeria Research Foundation will continue to lead the fight against progeria."

In 2001, PRF co-hosted a workshop with various institutes and centers of the National Institutes of Health (NIH), including the National Institute on Aging and the Office of Rare Diseases. The workshop brought together leading scientists from around the world to identify promising areas of research in progeria. This partnership eventually led to funding for progeria research and the formation of the PRF Genetics Consortium, a group of 20 scientists whose common goal is to find the genetic cause of progeria and to develop ways of treating the disease. Six of those scientists are co-authors of the study to be published in Nature.

Dr. Collins commended the collaborative efforts, saying, "The Progeria Research Foundation's commitment and cooperation played a key role in the hunt for the disease gene. They brought the urgent need to find this gene to the attention of the biomedical research community."

Earlier this week, Dr. Collins, as leader of the Human Genome Project, announced the successful completion of the international project's effort to sequence the 3 billion letters that make up the human genetic instruction book. "Free and unrestricted access to the human genome sequence is greatly speeding the pace of disease gene discovery. Finding the gene for progeria would have been impossible without the tools provided by the Human Genome Project," said Dr. Collins, who still spends some of his time in a small research lab at the National Institutes of Health (NIH). "This was a particularly challenging project for the gene hunters, since there are no families in whom the disease has recurred, and geneticists generally depend on such families to track the responsible gene. This was a detective story with very few clues."

Taking advantage of an array of genomic technologies - from whole-genome scans to high-throughput sequencing of targeted DNA regions - researchers determined the most common cause of progeria is a single-letter "misspelling" in a gene on chromosome 1 that codes for lamin A, a protein that is a key component of the membrane surrounding the cell's nucleus. Specifically, the researchers found that 18 out of 20 children with classic progeria harbored exactly the same misspelling in the lamin A (LMNA) gene, a substitution of just a single DNA base - a change from cytosine (C) to thymine (T) - among the gene's 25,000 base pairs. In addition, one of the remaining progeria patients had a different single base substitution - guanine (G) to adenine (A) - just two bases upstream. In every instance, the parents were found to be normal indicating that the misspelling was a new, or "de novo," mutation in the child.

At first glance, the point substitution in the LMNA gene would appear to have no effect on the production of lamin A protein. "Initially, we could hardly believe that such a small substitution was the culprit. How could these bland-looking mutations lead to such terrible consequences in the body?" said NHGRI's Maria Eriksson, Ph.D., a post-doctoral fellow in Dr. Collins' lab and the first author of the study.

However, when Dr. Eriksson conducted laboratory tests on cells from progeria patients, she found that the minute change in the LMNA gene's DNA sequence dramatically changed the way in which the sequence was spliced by the cell's protein-making machinery. The end result was the production of an abnormal lamin A protein that is missing a stretch of 50 amino acids near one of its ends.

To determine what effect abnormal lamin A has upon cells, the NHGRI-led team used fluorescent antibodies to track lamin A in skin cells taken from progeria patients known to have the common misspelling, as well as skin cells taken from unaffected people. The studies showed that about half of the cells from the progeria patients had misshapen nuclear membranes, compared with less than 1 percent of the cells from the unaffected controls.

"We suspect that this instability of the nuclear membrane may pose major problems for tissues subjected to intense physical stress - tissues such as those found in the cardiovascular and musculoskeletal systems, which are so severely affected in progeria," said Dr. Eriksson, noting that nuclear instability ultimately may lead to widespread death of cells.

Researchers hope to move their new findings into the clinic almost immediately with the development of a genetic test for progeria. Such a test will help doctors diagnose or rule out progeria in young children much earlier than their current method of looking at outward physical changes.

The new findings also may have implications for the treatment of progeria, with the newfound understanding of progeria's molecular roots pointing to possible therapeutic approaches. For example, researchers plan to explore the possibility that statins and/or other drugs known to inhibit a step in protein processing, known as farnesylation, might reduce the production of abnormal lamin A in progeria patients. Another avenue for identifying possible therapies involves screening large libraries of chemical molecules with the hope of finding a compound that can reverse the nuclear membrane irregularities seen in the cells of progeria patients.

"It is impossible to predict how soon our findings will translate into treatments for children suffering from progeria. We and other researchers across the nation will be working hard to find ways of helping them. Unfortunately, as we have witnessed with other genetic discoveries, the road from the lab to the clinic is not always swift or smooth," Dr. Collins said.

More also remains to be done to determine what role the LMNA gene may play in the normal aging process. "Aging clearly has a strong genetic component. Discovery of this key genetic mutation that causes progeria may lead to a much clearer understanding of what causes aging in us all. Eventually, this information may lead to improvements in health care for our aging population," said Dr. Brown.

Researchers plan to look at the LMNA genes of people who are exceptionally long-lived to see if there are any variants of the gene associated with longevity. Other studies might focus on determining whether repeated damage to the LMNA gene over the course of a lifetime may influence the rates at which people age.

"Our hypothesis is that LMNA may help us solve some of the great mysteries of aging," Dr. Collins said. "However, it will probably take more than one genetic key to unlock the secrets to a biological process as complex as aging. There are probably a host of other genes related to aging still waiting to be discovered."

Another interesting footnote to the recent findings is that different mutations in other regions of the LMNA gene previously have been shown to be responsible for a half-dozen other rare, genetic disorders. Those disorders are: Emery-Dreifuss muscular dystrophy type 2; limb girdle muscular dystrophy type 1B; Charcot-Marie-Tooth disorder type 2B1; the Dunnigan type of familial partial lipodystrophy; mandibuloacral dysplasia; and a familial form of dilated cardiomyopathy.

Prior to coming to NIH to lead the Human Genome Project in 1993, Dr. Collins had established a reputation as a relentless gene hunter using an approach that he named "positional cloning." In contrast to previous methods for finding genes, positional cloning enabled scientists to identify disease genes without knowing in advance what the functional abnormality underlying the disease might be. Dr. Collins' lab, together with collaborators, applied the new approach in 1989 in their successful quest for the long-sought gene responsible for cystic fibrosis. Other major discoveries soon followed, including identification of the genes for neurofibromatosis; Huntington's disease; multiple endocrine neoplasia type 1; one type of adult acute leukemia; and Alagille syndrome.

NHGRI is one of the 27 institutes and centers at the NIH, which is an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its Web site:


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Monday, May 28, 2007


1: Am J Med Genet. 1988 Dec;31(4):845-52. Links
Prevalence of dominant mutations in Spain: effect of changes in maternal age distribution.Martinez-Frias ML, Herranz I, Salvador J, Prieto L, Ramos-Arroyo MA, Rodriguez-Pinilla E, Cordero JF.
Estudio Colaborativo Espanol de Malformaciones Congenitas (ECEMC), Facultad de Medicina, Universidad Complutense, Madrid, Spain.

We studied the birth prevalence of autosomal dominant mutations in Spain and estimated how a decrease in maternal age distribution may lead to reduction in dominant mutations. The data were collected by the Estudio Colaborativo Espanol de Malformaciones Congenitas from April, 1976, to December, 1985. Among 553,270 liveborn infants monitored during the period, 66 infants with autosomal dominant conditions were identified. These included Apert, Crouzon, Hay-Wells, Treacher-Collins, Robinow, Stickler, Adams-Oliver, and the blepharophimosis syndromes, achondroplasia, cleidocranial dysostosis, and thanatophoric dysplasia. The overall rate of autosomal dominant conditions was 1.2 per 10,000 liveborn infants. Thirteen (20%) had an affected relative, and 52 (79%) had a negative family history. One case was excluded because of insufficient family data. The rate of autosomal dominant mutations was 0.9 per 10,000 liveborn infants, or 47 per 1 million gametes. A reduction in the maternal age distribution of mothers age 35 years and older from the current 10.8% to 4.9%, as in Atlanta, Georgia, would reduce the rate of Down syndrome in Spain by 33% and through a change in parternal age distribution may lead to a reduction in dominant mutations of about 9.6%. This suggests that a public health campaign to reduce older maternal age distribution in Spain may also lead to a reduction in dominant mutations and emphasizes the potential that a direct campaign for fathers to complete their families before age 35 years may have a small, but measurable, effect in the primary prevention of dominant mutations.

PMID: 3239577 [PubMed - indexed for MEDLINE]

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Friday, May 18, 2007

Paternal Age 4 years older than general population in Paternal Germline Origin of PTPN11 Mutations in Noonan Syndrome

Paternal Germline Origin and Sex-Ratio Distortion in Transmission of
PTPN11 Mutations in Noonan Syndrome

Marco Tartaglia,1,2 Viviana Cordeddu,1 Hong Chang,4 Adam Shaw,5 Kamini Kalidas,5
Andrew Crosby,5 Michael A. Patton,5 Mariella Sorcini,1 Ineke van der Burgt,6 Steve Jeffery,5
and Bruce D. Gelb2,3
1Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanita`, Rome; Departments of 2Pediatrics and 3Human Genetics,
Mount Sinai School of Medicine, New York; 4Health Institute, Division of Clinical Care Research, Tufts–New England Medical Center, Boston;
5Division of Medical Genetics, St. George’s Hospital Medical School, London; and 6Department of Medical Genetics, University Hospital
Maastricht, Maastricht, The Netherlands
Germline mutations in PTPN11—the gene encoding the nonreceptor protein tyrosine phosphatase SHP-2—represent
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............

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

The data presented here provide the first evidence for
a paternal origin of de novo PTPN11 mutations in NS
and for their association with advanced paternal age.
This finding confirms previous studies supporting a predominance
of paternal origin of point mutations in the
majority of autosomal dominant diseases. It is clear that
this predominance does not reflect some genetic quirk
isolated to the FGFR genes, nor does it necessitate a
restricted molecular diversity of mutations, as observed
in some disorders (e.g., achondroplasia). The higher level
of DNA methylation in spermatagonia—compared with
that in oogonia—which would predict increased substitutions
at CpG dinucleotides, has been suggested as an
important contributing factor. .....

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Our results show some mechanistic interaction between new dystrophin gene mutations, paternal inheritance, and skewed X inactivation

1: Am J Hum Genet. 1994 Jun;54(6):989-1003. Links
Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females.
Pegoraro E, Schimke RN, Arahata K, Hayashi Y, Stern H, Marks H, Glasberg MR, Carroll JE, Taber JW, Wessel HB, et al.
Department of Molecular Genetics, University of Pittsburgh, School of Medicine, PA 15261.

Duchenne muscular dystrophy is one of the most common lethal monogenic disorders and is caused by dystrophin deficiency. The disease is transmitted as an X-linked recessive trait; however, recent biochemical and clinical studies have shown that many girls and women with a primary myopathy have an underlying dystrophinopathy, despite a negative family history for Duchenne dystrophy. These isolated female dystrophinopathy patients carried ambiguous diagnoses with presumed autosomal recessive inheritance (limb-girdle muscular dystrophy) prior to biochemical detection of dystrophin abnormalities in their muscle biopsy. It has been assumed that these female dystrophinopathy patients are heterozygous carriers who show preferential inactivation of the X chromosome harboring the normal dystrophin gene, although this has been shown for only a few X:autosome translocations and for two cases of discordant monozygotic twin female carriers. Here we study X-inactivation patterns of 13 female dystrophinopathy patients--10 isolated cases and 3 cases with a positive family history for Duchenne dystrophy in males. We show that all cases have skewed X-inactivation patterns in peripheral blood DNA. Of the nine isolated cases informative in our assay, eight showed inheritance of the dystrophin gene mutation from the paternal germ line. Only a single case showed maternal inheritance. The 10-fold higher incidence of paternal transmission of dystrophin gene mutations in these cases is at 30-fold variance with Bayesian predictions and gene mutation rates. Thus, our results suggest some mechanistic interaction between new dystrophin gene mutations, paternal inheritance, and skewed X inactivation. Our results provide both empirical risk data and a molecular diagnostic test method, which permit genetic counseling and prenatal diagnosis of this new category of patients.

PMID: 8198142 [PubMed - indexed for MEDLINE

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It is confirmed that approximately 1/3 of all cases of X-linked Duchenne muscular dystrophy are new mutants, the remainder being sons of carriers

6/10 cases of haemophilia-B the de novo mutations in the carriers mothers were found to be of paternal origin

1: Eur J Haematol. 1992 Mar;48(3):142-5. Links
Origin of mutation in sporadic cases of haemophilia-B.Kling S, Ljung R, Sjorin E, Montandon J, Green P, Giannelli F, Nilsson IM.
Department for Coagulation Disorders, University of Lund, Malmo General Hospital, Sweden.

Of the 45 haemophilia-B patients registered at the haemophilia centre in Malmo, Sweden, 24 are the sole members of their families to be affected, and in 13 of these 24 cases, ascendant relatives are available for study. Detection of the gene defect showed the mutation to be de novo in the proband in 3 of these 13 cases, and inherited from a carrier mother in the remaining 10 cases. All 10 carrier mothers were shown to have de novo mutations, as the patients' grandfathers were phenotypically and/or haematologically normal, and the grandmothers were non-carriers. Seven restriction fragment length polymorphisms (RFLPs) of the factor IX gene were used to determine whether the de novo mutations of the 10 carrier mothers were of paternal or maternal origin. In 6/10 cases, the RFLP patterns were informative, and indicated the mutation to be of paternal origin.

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1: Am J Hum Genet. 1992 Jan;50(1):164-73. Links
Parental origin of factor IX gene mutations, and their distribution in the gene.Ludwig M, Grimm T, Brackmann HH, Olek K.
Institute of Experimental Haematology and Blood Transfusion, Bonn, Germany.

Genomic amplification followed by direct sequencing enabled us to establish the causative mutation in 67 unrelated hemophilia B patients of predominantly German origin. With the detection of the mutation, extensive pedigree analysis has become feasible. We therefore anticipated that determination of the origin of mutation could be achieved in a comparatively great number of families. Although these investigations often were restricted by the availability of blood samples from the maternal grandparents or great-grandparents, we were able to prove a de novo mutation in 9 of 20 families with sporadic hemophilia B and in 3 of 20 families with a history of the disease. This could be achieved with the aid of RFLP analysis and, in one case, where the mutation is still unknown, with the aid of biochemical and immunological factor IX assays. Since the maternal grandfather was decreased in two of these families, the germ line of origin could not be determined precisely. In the remaining families, the female and male germ lines turned out to be the origin of mutation in six and four cases, respectively, and an effect of paternal age on the mutations observed could not be excluded. Furthermore, our data indicate that the hemophilia B gene pool is mainly renewed byvariable mutations.

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8 of the 61 Hemophilia A Families Found to Have a Somatic Mosaicism (0.2-25%)


: Am J Hum Genet. 2001 Jul;69(1):75-87. Epub 2001 Jun 14. Links
Somatic mosaicism in hemophilia A: a fairly common event.Leuer M, Oldenburg J, Lavergne JM, Ludwig M, Fregin A, Eigel A, Ljung R, Goodeve A, Peake I, Olek K.
Department of Clinical Biochemistry, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.

Mutations in the large gene of clotting factor VIII (FVIII) are the most common events leading to severe human bleeding disorder. The high proportion of de novo mutations observed in this gene raises the possibility that a significant proportion of such mutations does not derive from a single germ cell but instead should be attributed to a germline or somatic mosaic originating from a mutation during early embryogenesis. The present study explores this hypothesis by using allele-specific PCR to analyze 61 families that included members who had sporadic severe hemophilia A and known FVIII gene defects. The presence of somatic mosaicisms of varying degrees (0.2%-25%) could be shown in 8 (13%) of the 61 families and has been confirmed by a mutation-enrichment procedure. All mosaics were found in families with point mutations (8 [25%] of 32 families). In the subgroup of 8 families with CpG transitions, the percentage with mosaicism increased to 50% (4 of 8 families). In contrast, no mosaics were observed in 13 families with small deletions/insertions or in 16 families with intron 22 inversions. Our data suggest that mosaicism may represent a fairly common event in hemophilia A. As a consequence, risk assessment in genetic counseling should include consideration of the possibility of somatic mosaicism in families with apparently de novo mutations, especially families with the subtype of point mutations.

PMID: 11410838 [PubMed




Haemophilia. 2003 Sep;9(5):584-7. Links
Exclusion of mosaicism in Spanish haemophilia A families with inversion of intron 22.Tizzano EF, Cornet M, Domenech M, Baiget M.
Department of Genetics, Hospital of Sant Pau, Barcelona, Spain.

Inversion of intron 22, the most frequent mutation event in haemophilia A (HA), was tested in our HA families to diagnose the females at risk of being carriers, to trace the origin of the mutation and to investigate the presence of germinal or somatic mosaicism. A total of 166 females belonging to 54 families with inversion, were analysed. All but one of the mothers tested were carriers and the inversion originated almost exclusively in male germ cells. Somatic or germline mosaicisms were excluded in 53 of these women and in 20 grandfathers, suggesting that such mosaicisms may be a rare event in families with inversion of intron 22.



Thromb Haemost. 1995 Jan;73(1):6-9. Links
Inversion of intron 22 in isolated cases of severe hemophilia A.Tizzano EF, Domenech M, Baiget M.
Molecular Genetics Unit, Santa Creu i Sant Pau Hospital, Barcelona, Spain.

Inversion involving intron 22 is the commonest type of mutation causing severe hemophilia A (HA). We investigated 15 families with isolated cases and 5 families with two or three brothers as the only affected members with hemophilia A, in order to determine the carrier status of the mothers, the origin of the mutation and the presence of germinal mosaicism. Our results show that all mothers tested were carriers of the inversion. In addition, three families whose unique hemophilic member was not available for analysis, were screened for the inversion. In one of these last families, the mother was diagnosed as a carrier and her sister and her niece as non-carriers. DNA haplotype analysis in 8 families with grandparents available for study demonstrated that the inversion originated almost exclusively in male germ cells. These findings have important relevance for genetic counselling in families with an isolated case or to exclude germinal mosaicism. Inversion analysis should constitute the first step in molecular diagnosis of severe hemophilia A.

PMID: 7740498 [PubMed - indexed for MEDLINE]


Hemophilias and the Age of the Maternal Grandfather at the carrier Mother Birth

Haemophilia. 2003 Nov;9(6):717-20. Links
Germ-line origin of intron 1 inversion in two haemophilia A families.Acquila M, Pasino M, Santoro C, Lanza T, Molinari AC, Bottini F, Bicocchi MP.
Haemostasis and Haemophilia Laboratory, IV Paediatric Department, G Gaslini Institute, Genova, Italy.

Factor VIII gene inversion of intron 1 has recently been reported to be the mutation responsible for haemophilia A in about 5% of severe cases. In our series of patients, which is made up of 77 Italian cases negative for intron 22 inversion, the mutation was found in three sporadic and in one familial patients, with an overall frequency of 5.2%. The carrier status of the patients' female relatives was assessed by mutation analysis and showed that only two-thirds of cases could be considered truly sporadic. The germ-line origin of the mutation was investigated in the two sporadic families by haplotype analysis on genomic DNA of the patients' maternal grandparents. These studies indicated that both mutation events had occurred in the germ cell lines of the patients' healthy grandfather, suggesting that, as already demonstrated for the inversion of intron 22, the male germ cell line is more susceptible to the intrachromosome recombination which leads to the inversion of intron 1.

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Thursday, May 17, 2007


Genetic concerns for the subfertile male in the era of ICSI
Edward D. Kim 1, Farideh Z. Bischoff 2, Larry I. Lipshultz 1, Dolores
J. Lamb 1 3 *
1Scott Department of Urology, Baylor College of Medicine, Houston, TX, U.S.A.
2Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, U.S.A.
3Department of Cell Biology, Baylor College of Medicine, Houston, TX, U.S.A.

email: Dolores J. Lamb (

*Correspondence to Dolores J. Lamb, Scott Department of Urology, Baylor College of Medicine, 1 Baylor Plaza, Room 440E, Houston, TX 77030, U.S.A.

ICSI • male infertility • genes • genetic defects

The treatment of severe male factor infertility has seen remarkable advances in the last five years with the introduction and widespread use of intracytoplasmic sperm injection (ICSI). Although ICSI represents one of the most important advances in the treatment of the subfertile male, significant concerns exist regarding the potential for transmission of abnormal genes to the offspring because many of the natural barriers to conception have been bypassed. Because these couples were not able to conceive prior to ICSI, the long-term genetic consequences in these offspring are largely undefined at this time. Genetic abnormalities related to male infertility need to be considered in terms of being (1) causative for male infertility and (2) potentially transmissible to the offspring. Reasons for pursuing a genetic evaluation include (1) establishing a diagnosis, (2) establishing a possible genetic origin, (3) clarifying the pattern of inheritance, and (4) providing information on natural history, variation and expression. The three most common known genetic factors related to male infertility are cystic fibrosis gene mutations leading to congenital absence of the vas deferens, Y-chromosome microdeletions leading to spermatogenic impairment, and karyotype abnormalities. When congenital bilateral absence of the vas deferens with azoospermia is encountered, cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations are commonly the underlying cause. When testicular failure is manifest by azoospermia or severe oligoszoospermia, Y-chromosome microdeletions may be present in approximately 10-15 per cent of otherwise normal appearing men. Karyotyping can uncover potentially transmissible genetic abnormalities in the infertile male including structural chromosomal disorders such as Klinefelter's (classic 47, XXY), mixed gonadal dysgenesis, chromosomal translocations and XYY syndromes. Finally, potential male infertility genes in animal models are reviewed. Without question, advances in clinical and basic research raise scientific and social issues that must be addressed. Copyright © 1998 John Wiley & Sons, Ltd.


Digital Object Identifier (DOI)

10.1002/(SICI)1097-0223(199812)18:13<1349::AID-PD504>3.0.CO;2-# About DOI

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Monday, May 14, 2007

Turner Syndrome Scotland had a Paternal Age Effect and England did not ONE MECHANISM OF ORIGIN MAY BE INCREASING PATERNAL AGE

1: Clin Genet. 1989 Jul;36(1):53-8. Links
An aetiological study of isochromosome-X Turner's syndrome.Carothers AD, De Mey R, Daker M, Boyd E, Connor M, Ellis PM, Stevenson D.

Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, U.K.

In an attempt to resolve conflicting evidence from the literature concerning the existence of a paternal age effect in 46,X,i(Xq) Turner's syndrome, we have analysed data on all known cases ascertained in the main population centres of Scotland and on others ascertained in England, using population controls matched for year of birth. There was a significant (P = 0.02) increase of 2.3 years in the mean paternal age of the Scottish cases, and a smaller and non-significant increase in their mean maternal age. Logistic regression analysis confirmed that the primary association was with paternal, rather than maternal, age. For the English cases, however, there were small and non-significant decreases in their mean maternal and paternal ages. The differences between the two groups were also significant, but cannot be explained by any likely source of ascertainment bias. We therefore conclude that there is no evidence for a universal paternal age effect in this condition, but that at least one mechanism of origin, occurring with variable frequency, may be associated with increased paternal age. Using data from this and earlier published studies, we estimate the incidence of individuals with a 46,X,i(Xq) cell line to be between 3.3 and 13 per 10(5) female livebirths.


Clin Endocrinol (Oxf). 2004 Feb;60(2):272. Links
The prevalence of diabetes mellitus in the parents of women with Turner's syndrome.Bakalov VK, Cooley MM, Troendle J, Bondy CA.


J Pediatr Endocrinol Metab. 2002 Sep-Oct;15(8):1203-6. Links
Type 1 diabetes mellitus in a 3 1/2 year-old girl with Turner's syndrome.Gonc EN, Ozon A, Alikasifoglu A, Kandemir N.
Pediatric Endocrinology Unit, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Turner's syndrome is associated with autoimmune disorders. Autoimmune endocrinopathy in Turner's syndrome seems to be limited to autoimmune thyroiditis. A small number of patients with Turner's syndrome has also been associated with celiac disease, inflammatory bowel disease and juvenile rheumatoid arthritis. Type 1 diabetes mellitus in Turner's syndrome has been rarely reported. We present here the youngest patient with Turner's syndrome who developed type 1 diabetes mellitus. At the age of 3.5 years she was hospitalized with diabetic ketoacidosis. Anti-islet cell and anti-insulin antibodies were positive and C-peptide level was low. When she was investigated for recurrent urinary tract infections, horseshoe kidney was detected by ultrasonography. Karyotype analysis revealed 45,XO. She has been followed for 2 years with an insulin dose of 0.9 U/kg per day. The prevalence of type 1 diabetes mellitus associated with Turner's syndrome is still unknown.

PMID: 14725692 [PubMed - indexed for MEDLINE]


1: Clin Exp Rheumatol. 1998 Jul-Aug;16(4):489-94. Links
Comment in:
Clin Exp Rheumatol. 2000 Mar-Apr;18(2):267-8.
Juvenile arthritis in Turner's syndrome: a multicenter study.Zulian F, Schumacher HR, Calore A, Goldsmith DP, Athreya BH.
Department of Pediatrics, University of Padova, Italy.

OBJECTIVE: Turner's syndrome (TS) is a disorder associated with characteristic defects in the X chromosome. Autoimmune conditions such as thyroiditis, inflammatory bowel diseases and diabetes have been described in association with TS. METHODS: We have studied the association between TS and juvenile arthritis (JA) by using a survey in which 28 pediatric rheumatology centers (15 in the USA, 10 in Europe, and 3 in Canada) participated. RESULTS: Eighteen cases of TS in a population of approximately 15,000 JRA patients have been found. Two different patterns of arthritis were present: polyarticular (7) and oligoarticular (11). Children with polyarticular disease had early onset, seronegative, progressively deforming arthritis and growth retardation. Those with oligoarticular arthritis had a benign course and were ANA+ (8/11). The oligoarticular children had varying karyotypes whereas almost all of the polyarthritic patients shared the same 45X0 karyotype (6/7). The light and electron microscopic studies of synovium performed in two patients showed chronic inflammation and hyperplasia of the synovial lining cells, vascular proliferation and infiltration with lymphocytes, plasma cells and mononuclear phagocytes. CONCLUSION: Juvenile arthritis is a new autoimmune condition association with Turner's syndrome. The prevalence seems to be at least six times greater than would be expected if the two conditions were only randomly associated. This is the first description of the synovium in Turner's syndrome; no differences from other forms of juvenile rheumatoid arthritis were found.

Clin Exp Rheumatol. 1997 Nov-Dec;15(6):701-3. Links
Delayed diagnosis of juvenile rheumatoid arthritis in a girl with Turner's syndrome.Foeldvari I, Wuesthof A.
University Children's Hospital, Hamburg, Germany.

Although increased risk for autoimmune diseases has been documented in Turner's syndrome (TS), the involvement of juvenile rheumatoid arthritis (JRA) has rarely been reported. A detailed case description of JRA associated with Turner's syndrome is presented as the second such case report in the literature. The arthritis was diagnosed 8 years after its onset due to the confounding of its symptoms with those of TS

1: Am J Med Genet. 2000 Jun 12;96(3):312-6. Links
Female with autistic disorder and monosomy X (Turner syndrome): parent-of-origin effect of the X chromosome.Donnelly SL, Wolpert CM, Menold MM, Bass MP, Gilbert JR, Cuccaro ML, Delong GR, Pericak-Vance MA.
Department of Medicine and Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA.

We have ascertained and examined a patient with autistic disorder (AD) and monosomy X (Turner syndrome). The patient met Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)/International Classification of Diseases (ICD-10) criteria for AD verified by the Autism Diagnostic Interview-Revised. The patient exhibited both social and verbal deficits and manifested the classical physical features associated with monosomy X. Skuse et al. [1997: Nature 387:705-708] reported three such cases of AD and monosomy X in their study of Turner syndrome and social cognition. They observed that monosomy X females with a maternally inherited X chromosome had reduced social cognition when compared with monosomy X females with a paternally inherited X chromosome. All three cases of AD and monosomy X were maternally inherited. Based on their data, they suggested that there was a gene for social cognition on the X chromosome that is imprinted and not expressed when the X chromosome is of maternal origin. Thus, we conducted parent-of-origin studies in our AD/monosomy X patient by genotyping X chromosome markers in the patient and her family. We found that the patient's X chromosome was of maternal origin. These findings represent the fourth documented case of maternal inheritance of AD and monosomy X and provide further support for the hypothesis that parent-of-origin of the X chromosome influences social cognition.


Nature. 1997 Jun 12;387(6634):705-8. Links
Comment in:
Nature. 1997 Jun 12;387(6634):652-3.
Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function.Skuse DH, James RS, Bishop DV, Coppin B, Dalton P, Aamodt-Leeper G, Bacarese-Hamilton M, Creswell C, McGurk R, Jacobs PA.
Behavioural Sciences Unit, Institute of Child Health, London, UK.

Turner's syndrome is a sporadic disorder of human females in which all or part of one X chromosome is deleted. Intelligence is usually normal but social adjustment problems are common. Here we report a study of 80 females with Turner's syndrome and a single X chromosome, in 55 of which the X was maternally derived (45,X[m]) and in 25 it was of paternal origin (45,X[p]). Members of the 45,X[p] group were significantly better adjusted, with superior verbal and higher-order executive function skills, which mediate social interactions. Our observations suggest that there is a genetic locus for social cognition, which is imprinted and is not expressed from the maternally derived X chromosome. Neuropsychological and molecular investigations of eight females with partial deletions of the short arm of the X chromosome indicate that the putative imprinted locus escapes X-inactivation, and probably lies on Xq or close to the centromere on Xp. If expressed only from the X chromosome of paternal origin, the existence of this locus could explain why 46,XY males (whose single X chromosome is maternal) are more vulnerable to developmental disorders of language and social cognition, such as autism, than are 46,XX females.


Pathol Int. 2007 Apr;57(4):219-23. Links
Sudden death of a young woman due to aortic dissection caused by Turner's syndrome.Mimasaka S, Ohtsu Y, Tsunenari S, Matsukawa A, Hashiyada M, Takahashi S, Funayama M.
Department of Forensic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

A 24-year-old woman was found dead in her bed. There had been an episode of fainting with cervicodynia 1 day before death but no significant past medical history, except for menstrual irregularities. Post-mortem examination revealed that death was due to hemopericardium caused by rupture of the ascending aorta by thoracic aortic dissection (Stanford type A). Microscopically, weakness of the aorta was due to cystic medial necrosis. On external examination, short stature, a short neck and multiple pigmented nevi were observed, while internal examination revealed coarctation of the aorta and funicular ovaries. Examination of the X chromatin showed a decrease in numbers of Barr bodies in the tissues, and a 45,X/46,XX mosaicism was suspected. It is concluded that the cause of death was aortic dissection due to Turner's syndrome.

PMID: 17316418 [PubMed - indexed for MEDLINE]

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Saturday, May 12, 2007



The occurrence of new mutants in the X-linked recessive Lesch-Nyhan disease.
U Francke, J Felsenstein, S M Gartler, B R Migeon, J Dancis, J E Seegmiller, F Bakay, and W L Nyhan
This article has been corrected. See Am J Hum Genet. 1976 May; 28(3): 311.
This article has been cited by other articles in PMC.
AbstractIn a population at equilibrium for a sex-linked lethal, one-third of the genes for that lethal must arise anew each generation. Therefore, one-third of all cases of Lesch-Nyhan disease, a severe X-linked recessive lethal disorder, should be new mutants. To test this hypothesis, we have collected 47 families, 20 with a single proband and 27 with multiple affected males in which the patients' mothers and other female relatives had been studied for heterozygosity. Available carrier detection tests identify heterozygous for HPRT deficiency in hair roots and skin fibroblasts. Only four mothers were found not to be carriers. This result deviates significantly from expected (P less than .001). Statistical tests for ascertainment effects indicated absence of bias for multiple proband families but strong bias in favor of families with many heterozygous females. When the analysis was limited to single proband families, the deviation from expected was still significant (P less than .01). The incidence of new mutants among the heterozygous mothers, as determined by the ratio of +/+ to +/- maternal grandmothers, should be one-half (see Appendix). Of all 20 maternal grandmothers studied, five were +/+ and 15 were +/- (P less than .05). Considering only the single proband families, the ratio of 5 +/+ to 8 +/- was not significantly different from expected. In four of the five cases in which the heterozygous mother of an affected individual was a new mutation, the age of her parents was considerably higher than the mean parental age in the population. This raises the possibility of a paternal age effect on X-linked mutations. There appears to be a true deficiency of new mutatnts among males but not among females. Data on additional Lesch-Nyhan families are needed before conclusions regarding a possible higher mutation rate in males can be drawn.Full textFull text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.6M), or see the PubMed citation or the full text of some References or click on a page below to browse page by page.















137Selected ReferencesThis list contains those references that cite another article in PMC or have a citation in PubMed. It may not include all the original references for this article.LESCH M, NYHAN WL. A FAMILIAL DISORDER OF URIC ACID METABOLISM AND CENTRAL NERVOUS SYSTEM FUNCTION. Am J Med. 1964 Apr;36:561–570. [PubMed]
Seegmiller JE, Rosenbloom FM, Kelley WN. Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis. Science. 1967 Mar 31;155(770):1682–1684. [PubMed]
Shapiro SL, Sheppard GL Jr, Dreifuss FE, Newcombe DS. X-linked recessive inheritance of a syndrome of mental retardation with hyperuricemia. Proc Soc Exp Biol Med. 1966 Jun;122(2):609–611. [PubMed]
Migeon BR, Der Kaloustian VM, Nyhan WL, Yough WJ, Childs B. X-linked hypoxanthine-guanine phosphoribosyl transferase deficiency: heterozygote has two clonal populations. Science. 1968 Apr 26;160(826):425–427. [PubMed]
Salzmann J, DeMars R, Benke P. Single-allele expression at an X-linked hyperuricemia locus in heterozygous human cells. Proc Natl Acad Sci U S A. 1968 Jun;60(2):545–552. [PubMed]
Gartler SM, Scott RC, Goldstein JL, Campbell B. Lesch-Nyhan syndrome: rapid detection of heterozygotes by use of hair follicles. Science. 1971 May 7;172(983):572–574. [PubMed]
Silvers DN, Cox RP, Balis ME, Dancis J. Detection of heterozygote in Lesch-Nyhan disease by hair-root analysis. N Engl J Med. 1972 Feb 24;286(8):390–395. [PubMed]
Francke U, Bakay B, Nyhan WL. Detection of heterozygous carriers of the Lesch-Nyhan syndrome by electrophoresis of hair root lysates. J Pediatr. 1973 Mar;82(3):472–478. [PubMed]
Migeon BR. Studies of skin fibroblasts from 10 families with HGPRT deficiency, with reference in X-chromosomal inactivation. Am J Hum Genet. 1971 Mar;23(2):199–210. [PubMed]
Itiaba K, Banfalvi M, Crawhall JC, Mongeau JG. Family studies of a Lesch-Nyhan patient from an isolated Canadian community. Am J Hum Genet. 1973 Mar;25(2):134–140. [PubMed]
Francke U, Bakay B, Connor JD, Coldwell JG, Nyhan WL. Linkage relationships of X-linked enzymes glucose-6-phosphate dehydrogenase and hypoxanthine guanine phosphoribosyltransferase: recombination in female offspring of compound heterozygotes. Am J Hum Genet. 1974 Jul;26(4):512–522. [PubMed]
Migeon BR. X-linked hypoxanthine-guanine phosphoribosyl transferase deficiency: detection of heterozygotes by selective medium. Biochem Genet. 1970 Jun;4(3):377–383. [PubMed]
Hagemeijer AM, Dodinval P, Andrien JM. Syndrome de Lesch-Nyhan. Détection des hétérozygotes par sélection biochimique des cellules mutants et autoradiographie. Humangenetik. 1972;15(2):126–135. [PubMed]
de Bruyn CH, Oei TL, ter Haar BG. Studies on hair roots for carrier detection in hypoxanthine-quanine phosphoribosyl transferase deficiency. Clin Genet. 1974;5(5):449–456. [PubMed]
McKeran RO, Andrews TM, Howell A, Gibbs DA, Chinn S, Watts WE. The diagnosis of the carrier state for the Lesch--Nyhan syndrome. Q J Med. 1975 Apr;44(174):189–205. [PubMed]
Felix JS, DeMars R. Detection of females heterozygous for the Lesch-Nyhan mutation by 8-azaguanine-resistant growth of cultured fibroblasts. J Lab Clin Med. 1971 Apr;77(4):596–604. [PubMed]
Fujimoto, Wilfred Y.; Seegmiller, J Edwin. Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency: Activity in Normal, Mutant, and Heterozygote-Cultured Human Skin Fibroblasts. Proc Natl Acad Sci U S A. 1970 Mar;65(3):577–584. [PubMed]
Chase GA, Murphy EA. Risk of recurrence and carrier frequency for X-linked lethal recessives. Hum Hered. 1973;23(1):19–26. [PubMed]
Gartler SM, Francke U. Half chromatid mutations: transmission in humans? Am J Hum Genet. 1975 Mar;27(2):218–223. [PubMed]



1: J Genet Hum. 1988 Jun;36(3):239-45. Links
[Marfan disease][Article in French]
Briard ML, Chauvet ML, Kaplan J.
Clinique et Unite de Recherches de Genetique Medicate, INSERM U.12, Hopital
des Enfants, Malades, Paris.

After reviewing the main features of the Marfan syndrome (musculoskeletal, ocular, cardiovascular, pulmonary abnormalities), its autosomal dominant inheritance with high penetrance but variable phenotype and presence of "soft" conditions preventing an easy diagnosis, the authors report their own data relevant to 73 probands: ratio of each clinical manifestation, state of 34% of familial cases and display of a paternal age effect in the sporadic cases. The pathogenic defect is unknown as like the location of the gene. The difficulties of the genetic counseling are then approached: unpredictability of the severity and of the prognosis in the unborn children of an affected patient, benefit of the echocardiography in the management of people at risk.

PMID: 3411304 [PubMed - indexed for MEDLINE]

1: Humangenetik. 1972;16(1):77-82. Links
Human mutations and paternal age.Tunte W.
PMID: 4647446 [PubMed - indexed for MEDLINE

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1: Am J Med Genet. 1995 Nov 6;59(2):209-17. Links
Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta.Orioli IM, Castilla EE, Scarano G, Mastroiacovo P.
Departamento de Genetica, Universidade Federal do Rio de Janeiro, Brazil

The paternal ages of nonfamilial cases of achondroplasia (AC) (n = 78), thanatophoric dysplasia (TD) (n = 64), and osteogenesis imperfecta (OI) (n = 106), were compared with those of matched controls, from an Italian Indagine Policentrica Italiana sulle Malformazioni Congenite and a South American Estudio Colaborativo Latinoamericano de Malformaciones Congenitas series. The degree of paternal age effect on the origin of these dominant mutations differed among the three conditions. Mean paternal age was highly elevated in AC, 36.30 +/- 6.74 years in the IPIMC, and 37.19 +/- 10.53 years in the ECLAMC; less consistently elevated in TD, 33.60 +/- 7.08 years in the IPIMC, and 36.41 +/- 9.38 years in the ECLAMC; and only slightly elevated in OI in the ECLAMC, 31.15 +/- 9.25 years, but not in the IPIMC, 32.26 +/- 6.07 years. Increased maternal age or birth order in these conditions disappeared when corrected for paternal age. Approximately 50% of AC and TD cases, and only 30% of OI cases, were born to fathers above age 35 years. For AC and TD, the increase in relative incidence with paternal age fitted an exponential curve. The variability of paternal age effect in these new mutations could be due, among other reasons, to the high proportion of germ-line mosaicism in OI parents, or to the localization of the AC gene, mapped to the 4p16.3 region, in the neighborhood of an unstable DNA area

Reviewed June 2006
What is thanatophoric dysplasia?
Thanatophoric dysplasia is a severe skeletal disorder characterized by extremely short limbs and folds of extra (redundant) skin on the arms and legs. Other features of this condition include a narrow chest, short ribs, underdeveloped lungs, and an enlarged head with a large forehead and prominent, wide-spaced eyes.

Researchers have described two major forms of thanatophoric dysplasia, type I and type II. Type I thanatophoric dysplasia is distinguished by the presence of curved thigh bones and flattened bones of the spine (platyspondyly). Type II thanatophoric dysplasia is characterized by straight thigh bones and a moderate to severe skull abnormality called a cloverleaf skull

The term thanatophoric is Greek for "death bearing." Infants with thanatophoric dysplasia are usually stillborn or die shortly after birth from respiratory failure; however, a few affected individuals have survived into childhood with extensive medical help.

How common is thanatophoric dysplasia?
This condition occurs in 1 in 20,000 to 50,000 newborns. Type I thanatophoric dysplasia is more common than type II.

What genes are related to thanatophoric dysplasia?
Mutations in the FGFR3 gene cause thanatophoric dysplasia.

What genes are related to thanatophoric dysplasia?
Mutations in the FGFR3 gene cause thanatophoric dysplasia.

Both types of thanatophoric dysplasia result from mutations in the FGFR3 gene. This gene provides instructions for making a protein that is involved in the development and maintenance of bone and brain tissue. Mutations in this gene cause the FGFR3 protein to be overly active, which leads to the severe disturbances in bone growth that are characteristic of thanatophoric dysplasia. It is not known how FGFR3 mutations cause the brain and skin abnormalities associated with this disorder.

How do people inherit thanatophoric dysplasia?
Thanatophoric dysplasia is considered an autosomal dominant disorder because one mutated copy of the FGFR3 gene in each cell is sufficient to cause the condition. Virtually all cases of thanatophoric dysplasia are caused by new mutations in the FGFR3 gene and occur in people with no history of the disorder in their family. No affected individuals are known to have had children; therefore, the disorder has not been passed to the next generation.


1: Am J Med Genet. 1988 Dec;31(4):815-20. Links
Thanatophoric dysplasia: an autosomal dominant condition?Martinez-Frias ML, Ramos-Arroyo MA, Salvador J.
Estudio Colaborativo Espanol de Malformaciones Congenitas, Facultad de Medicina, Universidad Complutense, Madrid, Spain.

We present 13 cases of thanatophoric dysplasia collected in the Spanish Collaborative Study of Congenital Malformations from a total population of 517,970 births. The incidence (live and stillbirth) was 2.7 per 100,000 births. All cases were sporadic, and there was no evidence of parental consanguinity. Parental age was significantly higher as compared with control parents. These findings suggest the occurrence of autosomal dominant mutation, with an overall mutation rate of 1.34 X 10(-5) in our population, which is close to that observed in achondroplasia.

PMID: 3239573 [PubMed - indexed for MEDLINE]

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Thursday, May 10, 2007

1998 a 29 YEAR OLD MOTHER AND A SIXTY YEAR OLD FATHER HAVE a SON WITH de novo complex chromosomal rearrangement

He was hypotonic and he could neither stand
up nor walk. Speech was lacking. A mild facial dysmorphy
was noted, including a long face, a large nose with anteverted
nostrils, micrognathy, a pronounced philtrum, long teeth and
low set ears. There was neither visceral malformation nor
anomaly in standard laboratory investigations such as
electroencephalography, electromyography or skeletal X-ray

Human Reproduction vol.13 no.7 pp.1801–1803, 1998
Advanced paternal age and de-novo complex
chromosomal rearrangement in offspring
B.Benzacken1,4, J.P.Siffroi2, B.Straub2,
C.Le Bourhis2, S.Sauvion3, J.Gaudelus3,
J.P. Dadoune2 and J.P.Wolf1
1Laboratoire d’Histologie, Embryologie, Cytoge´ne´tique et Biologie
de la Reproduction, Hoˆpital Jean Verdier, 93140, Bondy,
2Laboratoire d’Histologie, Biologie de la Reproduction et
Cytoge´ne´tique, Hoˆpital Tenon, Paris and 3Service de Pe´diatrie,
Hopital Jean Verdier, 93140, Bondy, France
4To whom correspondence should be addressed
We report one case of a de-novo complex chromosomal
rearrangement (CCR), t(1;5;13)ins(14;13), in an abnormal
19-month-old boy. Clinical features associated were a mild
facial dysmorphy and a psychomotor retardation. Parental
ages were, respectively, 29 years for the mother and
60 years for the father. We point out the usefulness of
fluorescence in-situ hybridization in elucidating CCRs, and
discuss the possible correlation between the existence of a
chromosomal aberration and advanced paternal age.
Key words: complex chromosomal rearrangement/fluorescence
in-situ hybridization/mental retardation/reproduction/paternal
Complex chromosomal rearrangements (CCRs) are defined as
reciprocal exchanges between three or more chromosomes.
They are rare events in human pathology and only about 100
CCRs have been reported as constitutional findings (Batista
et al., 1994). The involvement of several chromosomes and
the high number of breakpoints can make cytogenetic diagnosis
very difficult when classical banding techniques or highresolution
methods only are used. Here we report the molecular
study by fluorescence in–situ hybridization (FISH) of an
apparently balanced 4-chromosome CCR in an abnormal child.
Advanced paternal age, as a possible causal factor, is discussed.
Case report
The proband was a boy, born from a 29-year-old healthy
mother and from a 60-year-old father. The parents were
unrelated, and they already had a normal child. Pregnancy,
labour and delivery were uneventful; birthweight was 3830 g,
length 53 cm and head circumference 37 cm.
At 19 months, the child was referred for a psychomotor
retardation evaluation. He was 80 cm high and weighed
© European Society for Human Reproduction and Embryology 1801
10.1 kg (–1SD). He was hypotonic and he could neither stand
up nor walk. Speech was lacking. A mild facial dysmorphy
was noted, including a long face, a large nose with anteverted
nostrils, micrognathy, a pronounced philtrum, long teeth and
low set ears. There was neither visceral malformation nor
anomaly in standard laboratory investigations such as
electroencephalography, electromyography or skeletal X-ray
Cytogenetic investigations were performed on blood cell
cultures using R-banding and bromodeoxyuridine (BrdU)
incorporation. The karyotype revealed a complex chromosomal
rearrangement involving chromosomes 1, 5, 13 and 14 with
at least five breakpoints (Figure 1). Molecular study by FISH,
using whole chromosome paint probes (Biosys®, France),
allowed the precise identification, first, of a complex translocation
implicating the long arms of chromosomes 1, 5 and 13
and, second, of an insertion of a part of the long arm of
chromosome 13 into the long arm of chromosome 14 (Figure 1).
Therefore, the proband’s karyotype was apparently balanced,
46,XY,t(1;5;13)(q32.2;q14;q12).ish t(1;5;13)(wcp131; wcp11;
wcp51)ins(14;13)(q12.2;q12q31).ish ins (14;13)(wcp131;
The parents’ and brother’s karyotypes were normal even
after high-resolution cytogenetic techniques. According to this
result, no analysis by FISH was necessary in the parents.
In order to determine parental origin of this CCR, polymorphisms
of the 13 and 14 acrocentric chromosomes’ short
arms and of the secondary constriction of chromosome 1 were
analysed in the proband and his parents. Only the latter was
informative: indeed, parental chromosomes 1 were distinguishable
by the size of their secondary constrictions, and the
comparison with the translocated chromosome 1 in the proband
allowed us to assume that CCR had arisen during paternal
spermatogenesis (Figure 2).
Since continual divisions of spermatogonia throughout adult
life may result in structural rearrangements of chromosomes
which may persist in a clone, it seems reasonable to consider
that pregnancies from elderly fathers, especially those who are
more than 50 years old, present genetically increased risk and
that fetal karyotype analyses can be proposed in these cases.

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Wednesday, May 9, 2007


1: Br J Cancer. 1993 Apr;67(4):813-8. Links
Wilms' tumour and parental age: a report from the National Wilms' Tumour Study.Olson JM, Breslow NE, Beckwith JB.
Department of Biostatistics, University of Washington, Seattle 98195.

Age distributions of parents at birth of patients registered in the National Wilms' Tumour Study were compared to those of the general population. An increasing incidence of sporadic Wilms' tumour with increasing paternal age was found, with a relative risk of 2.1 of tumour in children of fathers over 55 compared to children of fathers younger than 20. A similar effect for maternal age was found, with a relative risk of 1.4 in children of mothers over 40 compared to children of mothers younger than 20. The maternal age effect was much weaker among patients registered later in the study; in the later, more completely ascertained cohort, paternal age appears to be the major contributor to the parental age effect. Little difference in paternal age distribution was found between patients with bilateral and unilateral tumour and between male and female patients. In contrast, patients with reported associated congenital anomalies, patients with evidence of nephrogenic rests, and patients with early or late age-of-onset of tumour had parents who were, on average, substantially older than the remainder. These findings lend support to the idea that many Wilms' tumours result from new germline mutations. Further, the histologic composition of such tumours may

1: Med Pediatr Oncol. 1992;20(4):284-91. Links
Genetics and epidemiology of Wilms' tumor: the French Wilms' tumor study.Bonaiti-Pellie C, Chompret A, Tournade MF, Hochez J, Moutou C, Zucker JM, Steschenko D, Brunat-Mentigny M, Roche H, Tron P, et al.
Unite de Recherche d'Epidemiologie Genetique (U155 INSERM), Paris, France.
A complete family history was obtained for 501 patients with Wilms' tumor, treated in departments of pediatric oncology in whole France. The information was collected by self-questionnaire and/or by interview of parents. The proportion of bilateral cases is 4.6% and there are 12 patients (2.4%) with a positive family history of Wilms' tumor. The affected relatives are most often distant and no first degree relative was affected. Apart from the well-known associations with aniridia, hemihypertrophy, genitourinary anomalies, Beckwith-Wiedeemann, and Drash syndromes, there is also a significant excess of congenital heart defects (P = .008) which remains to be explained. Several findings support the bimutational hypothesis such as earlier diagnosis and increased parental age in bilateral cases. No particular anomalies and no increased frequency of childhood cancer were found in patients' relatives. The frequency of Wilms' tumor in relatives was estimated to be less than 0.4% in sibs, 0.06% in uncles and aunts, and 0.04% in first cousins. These figures are very different from those found in retinoblastoma and suggest that the mechanism may be more complex in Wilms' tumor. This conclusion is in agreement with molecular biology studies in tumors and linkage analysis in multiple case families which suggest that more than one locus is involved.

PMID: 1318995 [PubMed - indexed for MEDLINE]

Am J Hum Genet. 1990 July; 47(1): 155–160.
Copyright notice
Parental origin of de novo constitutional deletions of chromosomal band 11p13.
V Huff, A Meadows, V M Riccardi, L C Strong, and G F Saunders
Department of Biochemistry and Molecular Biology, University of Texas, M. D. Anderson Cancer Center, Houston 77030.
This article has been cited by other articles in PMC.
AbstractOne-half of all cases of Wilms tumor (WT), a childhood kidney tumor, show loss of heterozygosity at chromosomal band 11p13 loci, suggesting that mutation of one allele and subsequent mutation or loss of the homologous allele are important events in the development of these tumors. The previously reported nonrandom loss of maternal alleles in these tumors implied that the primary mutation occurred on the paternally derived chromosome and that it was "unmasked" by loss of the normal maternal allele. This, in turn, suggests that the paternally derived allele is more mutable than the maternal one. To investigate whether germinal mutations are seen with equal frequency in maternally versus paternally inherited chromosomes, we determined the parental origin of the de novo germinal 11p13 deletions in eight children by typing lymphocyte DNA from these children and from their parents for 11p13 RFLPs. In seven of the eight cases, the de novo deletion was of paternal origin. The one case of maternal origin was unremarkable in terms of the size or extent of the 11p13 deletion, and the child did develop WT. Transmission of 11p13 deletions by both maternal and paternal carriers of balanced translocations has been reported, although maternal inheritance predominates. These data, in addition to the general preponderance of paternally derived, de novo mutations at other loci, suggest that the increased frequency of paternal deletions we observed is due to an increased germinal mutation rate in males.Full textFull text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (862K), or see the PubMed citation or the full text of some

list contains those references that cite another article in PMC or have a citation in PubMed. It may not include all the original references for this article.Breslow NE, Beckwith JB. Epidemiological features of Wilms' tumor: results of the National Wilms' Tumor Study. J Natl Cancer Inst. 1982 Mar;68(3):429–436. [PubMed]
Breslow N, Beckwith JB, Ciol M, Sharples K. Age distribution of Wilms' tumor: report from the National Wilms' Tumor Study. Cancer Res. 1988 Mar 15;48(6):1653–1657. [PubMed]
Bunin GR, Nass CC, Kramer S, Meadows AT. Parental occupation and Wilms' tumor: results of a case-control study. Cancer Res. 1989 Feb 1;49(3):725–729. [PubMed]
Butler MG, Meaney FJ, Palmer CG. Clinical and cytogenetic survey of 39 individuals with Prader-Labhart-Willi syndrome. Am J Med Genet. 1986 Mar;23(3):793–809. [PubMed]
Chamberlin J, Magenis RE. Parental origin of de novo chromosome rearrangements. Hum Genet. 1980;53(3):343–347. [PubMed]
Compton DA, Weil MM, Jones C, Riccardi VM, Strong LC, Saunders GF. Long range physical map of the Wilms' tumor-aniridia region on human chromosome 11. Cell. 1988 Dec 2;55(5):827–836. [PubMed]
Dao DD, Schroeder WT, Chao LY, Kikuchi H, Strong LC, Riccardi VM, Pathak S, Nichols WW, Lewis WH, Saunders GF. Genetic mechanisms of tumor-specific loss of 11p DNA sequences in Wilms tumor. Am J Hum Genet. 1987 Aug;41(2):202–217. [PubMed]
Dryja TP, Mukai S, Petersen R, Rapaport JM, Walton D, Yandell DW. Parental origin of mutations of the retinoblastoma gene. Nature. 1989 Jun 15;339(6225):556–558. [PubMed]
Ejima Y, Sasaki MS, Kaneko A, Tanooka H. Types, rates, origin and expressivity of chromosome mutations involving 13q14 in retinoblastoma patients. Hum Genet. 1988 Jun;79(2):118–123. [PubMed]
Emanuel BS. Molecular cytogenetics: toward dissection of the contiguous gene syndromes. Am J Hum Genet. 1988 Nov;43(5):575–578. [PubMed]


Tuesday, May 8, 2007

1981 Genetic Disease in the offspring of older fathers-Good public health policy for both men and women to complete their family before age 40, ...


Obstetrics & Gynecology 1981;57:745-749
© 1981 by The American College of Obstetricians and Gynecologists


Genetic disease in the offspring of older fathers
JM Friedman

Autosomal dominant genetic diseases may result from the transmission of a trait by a carrier parent or from gene mutation in one of the gametes from which the child develops. The mean age of fathers of affected persons has been found to be greater than expected for several autosomal dominant diseases due to new mutations. To assess the clinical importance of this observation, the relative and absolute frequencies of offspring with autosomal dominant diseases due to mutation in the sperm from fathers of various ages have been calculated. The relative frequency of new autosomal dominant mutations in children increases logarithmically with paternal age during the usual years of fatherhood. The absolute frequency of autosomal dominant disease due to new mutations among the offspring of fathers who are 40 years of age or older is estimated to be at least 0.3 to 0.5%. This risk is many times greater than that for children of young fathers and is similar in magnitude to the risk of Down syndrome among the offspring of 35- to 40-year-old mothers. Thus, it is good public health policy to recommend that both men and women complete their family a before age 40, if possible.

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J.M. Friedman on the Epidemiology of Neurofibromatosis type 1

Epidemiology of neurofibromatosis type 1
J.M. Friedman *

email: J.M. Friedman ( *Correspondence to J.M. Friedman, UBC Department of Medical Genetics, BC Children's Hospital, 4500 Oak Street, Room C201, Vancouver, Canada V6H 3N1

Dr. Friedman is professor and head of the Department of Medical Genetics at the University of British Columbia and Children's and Women's Health Centre of British Columbia. He is a clinical geneticist.

NF1 • epidemiology • mutation

The prevalence of neurofibromatosis type 1 (NF1) is about 1/3,000. There are no known ethnic groups in which NF1 does not occur or is unusually common. The prevalence is somewhat higher in young children than in adults, a difference that probably results at least in part from the early death of some NF1 patients. NF1 is fully penetrant in adults, but many disease features increase in frequency or severity with age. The reproductive fitness of NF1 patients is reduced by about one-half. About half of all cases result from new mutations. The estimated rate of new NF1 mutations is unusually high, but the basis for this high mutation rate is not known. Am. J. Med. Genet. (Semin. Med. Genet.) 89:1-6, 1999. © 1999 Wiley-Liss, Inc.


Digital Object Identifier (DOI)



Original Article
Paternal age and sporadic neurofibromatosis 1: A case-control study and consideration of the methodologic issues
Greta R. Bunin 1 *, Michael Needle 1, Vincent M. Riccardi 2
1Department of Pediatrics, Division of Oncology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia
2The Neurofibromatosis Institute, La Crescenta, California

email: Greta R. Bunin (

*Correspondence to Greta R. Bunin, Children's Hospital of Philadelphia, Abramson Center, 34th St. & Civic Center Blvd., Philadelphia, PA 19104-4318

Funded by:
National Institutes of Health; Grant Number: HD28376
Texas Neurofibromatosis Foundation

epidemiologic methods • germline mutation • maternal age

Sporadic neurofibromatosis 1 (NF1) occurs in the absence of a family history of the disease and usually results from a new mutation in the germ cell of one of the parents, most commonly the father. Older paternal age may increase the risk for a new germinal NF1 mutation, but the results of studies to address this question conflict. We investigated paternal age in sporadic NF1 by using a case-control study design. Patients who were seen at two specialty NF clinics in Houston, Texas, born between 1970 and 1992 and living in the Houston area and surrounding counties, were studied. Birth certificates with information on the father were found for 89 cases. For each case, two birth certificates were chosen at random from the same year and county of birth. In this way, the control group of 178 individuals was formed. Fathers of patients with NF1 were 1.5 years older than fathers of control subjects at the birth of the child, but the difference was only of borderline statistical significance (P = 0.07). This paternal age difference was not changed by adjustment for socioeconomic status or maternal age. These and previous data are consistent with either a small paternal age effect in sporadic NF1 or a bias such as that resulting from the selection of cases and/or controls. Genet. Epidemiol. 14:507-516,1997. © 1997 Wiley-Liss, Inc.

Received: 23 July 1996; Revised: 2 December 1996; Accepted: 2 January 1997
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Monday, May 7, 2007


U-I researchers find genetic link to autism
Monday, May 7, 2007, 4:11 PM
By Darwin Danielson
University of Iowa researchers have found a genetic mutation that contributes to a brain disorder that inhibits a person's ability to communicate and develop social relationships. Dr. Thomas Wassink says the finding involving autism was part of a larger study of families which have children with the disorder.

Wassink says there was one family where they found "a piece of a chromosome missing in the middle of a really interesting gene, in two girls with autism from this family."

Wassink says they did further study to narrow down the gene mutation. Wassink says, "At some point in the embryonic development of the father, an abnormality occurred or a mutation arose in his primordial sperm cell." Wassink says the discovery of the mutation led to more research. He says the screened the gene, called "neurexin one," for mutations in about 400 other individuals with autism, but didn't find any additional mutations of the gene in people with autism. Wassink says it appears the mutations in the gene in this particular family are not a very common cause of autism.

Wassink says the exciting thing is that this is one of a groups of genes where mutations have been found in the proteins in the synapse that send messages between nerve cells. Wassink says this tells researchers that other genes and proteins in this particular synapse are worth looking at to screen for other mutations that might be related to autism.

Wassink says having a clue about where to look for the problem is important. He says there are well over 10,000 genes in the brain, and finding the right ones to look at is not easy. Wassink says this finding helps them look at a more specific set of genes. Wassink says the finding could eventually help with treatments for autism.

Wassink says it may indicate different types of medications to try in treating autism. Wassink, who is an associate professor of psychiatry, says this study does not show any link to an earlier study that indicated that the chances for autism increased with the age of the father. Wassink says age is not a factor in this finding.