the association with high paternal age

Am J Med Genet A. 2012 Mar 9. doi: 10.1002/ajmg.a.35246. [Epub ahead of print]

Clinical epidemiology of skeletal dysplasias in South America.

Barbosa-Buck CO, Orioli IM, da Graça Dutra M, Lopez-Camelo J, Castilla EE, Cavalcanti DP.

Source

Faculdade de Ciências Médicas, Departamento de Genética Médica, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, Brazil.

Abstract

Currently accepted birth prevalence for osteochondrodysplasias (OCD) of about 2/10,000 is based on few studies from small series of cases. We conducted a study based on more than 1.5 million births. OCD cases were detected from 1,544,496 births occurring and examined in 132 hospitals of ECLAMC (Latin American Collaborative Study of Congenital Malformations) between 2000 and 2007. Cases were detected and registered according to a pre-established protocol, and then ranked in four diagnostic evidence levels (DEL), according to available documentation. For the analysis of risk factors, a healthy control sample born in the same period was used. OCD was diagnosed in 492 newborns, resulting in a prevalence per 10,000 of 3.2 (95% CI: 2.9-3.5). Perinatal lethality (stillbirths plus early neonatal deaths) occurred in 50% of cases. Prenatal ultrasound diagnosis was made in 73% of cases (n = 359). Among 211 cases from the best documented group (DEL-1) and according to international classification, 33% of cases fit into the G-25 (osteogenesis imperfecta), 29% in Group-1 (FGFR3), and 8% in Group-18 (Bent bones). The prevalence of the main OCD types were: OI-0.74 (0.61-0.89); thanatophoric dysplasia-0.47 (0.36-0.59); and achondroplasia-0.44 (0.33-0.55). Paternal age (31.2 ± 8.5), parity (2.6), and parental consanguinity rate (5.4%) were higher in cases than in controls (P < 0.001). In conclusion, the OCD overall prevalence of 3.2 per 10,000 found seems to be more realistic than previous estimates. This study also confirmed the high perinatal mortality, and the association with high paternal age, parity, and parental consanguinity rate. © 2012 Wiley Periodicals, Inc.

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Neuron. 2011 Dec 22;72(6):951-63.

High frequencies of de novo CNVs in bipolar disorder and schizophrenia.

Malhotra D, McCarthy S, Michaelson JJ, Vacic V, Burdick KE, Yoon S, Cichon S, Corvin A, Gary S, Gershon ES, Gill M, Karayiorgou M, Kelsoe JR, Krastoshevsky O, Krause V, Leibenluft E, Levy DL, Makarov V, Bhandari A, Malhotra AK, McMahon FJ, Nöthen MM, Potash JB, Rietschel M, Schulze TG, Sebat J.

Source

Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA.

Abstract

While it is known that rare copy-number variants (CNVs) contribute to risk for some neuropsychiatric disorders, the role of CNVs in bipolar disorder is unclear. Here, we reasoned that a contribution of CNVs to mood disorders might be most evident for de novo mutations. We performed a genome-wide analysis of de novo CNVs in a cohort of 788 trios. Diagnoses of offspring included bipolar disorder (n = 185), schizophrenia (n = 177), and healthy controls (n = 426). Frequencies of de novo CNVs were significantly higher in bipolar disorder as compared with controls (OR = 4.8 [1.4,16.0], p = 0.009). De novo CNVs were particularly enriched among cases with an age at onset younger than 18 (OR = 6.3 [1.7,22.6], p = 0.006). We also confirmed a significant enrichment of de novo CNVs in schizophrenia (OR = 5.0 [1.5,16.8], p = 0.007). Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases.
Copyright © 2011 Elsevier Inc. All rights reserved.

Am J Hum Genet. 2012 Feb 10;90(2):175-200.

Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease.

Goriely A, Wilkie AO.

Source

Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.

Abstract

Advanced paternal age has been associated with an increased risk for spontaneous congenital disorders and common complex diseases (such as some cancers, schizophrenia, and autism), but the mechanisms that mediate this effect have been poorly understood. A small group of disorders, including Apert syndrome (caused by FGFR2 mutations), achondroplasia, and thanatophoric dysplasia (FGFR3), and Costello syndrome (HRAS), which we collectively term "paternal age effect" (PAE) disorders, provides a good model to study the biological and molecular basis of this phenomenon. Recent evidence from direct quantification of PAE mutations in sperm and testes suggests that the common factor in the paternal age effect lies in the dysregulation of spermatogonial cell behavior, an effect mediated molecularly through the growth factor receptor-RAS signal transduction pathway. The data show that PAE mutations, although arising rarely, are positively selected and expand clonally in normal testes through a process akin to oncogenesis. This clonal expansion, which is likely to take place in the testes of all men, leads to the relative enrichment of mutant sperm over time-explaining the observed paternal age effect associated with these disorders-and in rare cases to the formation of testicular tumors. As regulation of RAS and other mediators of cellular proliferation and survival is important in many different biological contexts, for example during tumorigenesis, organ homeostasis and neurogenesis, the consequences of selfish mutations that hijack this process within the testis are likely to extend far beyond congenital skeletal disorders to include complex diseases, such as neurocognitive disorders and cancer predisposition.
Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PMID:

22325359

[PubMed - in process]

Am J Med Genet A. 2012 Feb 2. doi: 10.1002/ajmg.a.34413. [Epub ahead of print]

The importance of advanced parental age in the origin of neurofibromatosis type 1.

Snajderova M, Riccardi VM, Petrak B, Zemkova D, Zapletalova J, Mardesic T, Petrakova A, Lanska V, Marikova T, Bendova S, Havlovicova M, Kaluzova M.

Source

Department of Pediatrics, 2nd Medical School and University Hospital Motol, Charles University, Prague, Czech Republic.

Abstract

Von Recklinghausen neurofibromatosis (NF1) is an autosomal dominant disorder with a prevalence about 1/3,000 (1/2,000-1/5,000 in various population-based studies). About 30-50% of cases are sporadic, resulting from a new mutation. NF1 is fully penetrant by mid-childhood, stigmata, and medical problems (neurological, dermatological, endocrine, ophthalmological, oncological) are highly variable. Advanced paternal age (APA) has been known to increase the risk of new germline mutations that contribute to the presence of a variety of genetic diseases in the human population. The trend in developed countries has been toward higher parental age due to various reasons. In a cross-sectional study, in two university hospital centers, data on parental age of 103 children (41 female) born between 1976 and 2005 with sporadic NF1 were analyzed. Parental age at birth was compared with the Czech general population matched to birth year. The mean NF1 sporadic case paternal age at birth was 32.0 years (95% CI 30.7-33.3 years) compared with 28.8 years (95% CI 28.6-29.1 years) in the general population (P < 0.001). The mean maternal age at birth was 27.4 years (95% CI 26.3-28.5 years) compared with 25.8 years (95% CI 25.5-26.0 years) in the general population (P < 0.05). The case-control difference in the father's age was higher than it was for the mother's age. Sporadic NF1 cases accounted for 35.6% of our entire NF1 cohort. We confirmed an association of advanced parental and particularly paternal age with the occurrence of sporadic NF1. © 2012 Wiley Periodicals, Inc.

National PostNews CanadaGraphicsInternetScience & HealthU.S.World

News

Delaying parenthood has serious medical risks for both men and women, study warns

Postmedia News Jan 17, 2012 – 9:48 AM ET

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Babies born to fathers of “advanced paternal age” — defined as 40 and older at the time of conception — are at increased risk of genetic disorders, as well as schizophrenia, autism and some forms of cancer, according to the authors

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By Sharon Kirkey
Men, and not just women, need to be aware of the “reproductive consequences” of postponing parenthood, new national guidelines on the risks of delayed child-bearing warn.
Though women especially should recognize that their “fecundity and fertility” starts to decline precipitously after 32, a man’s semen quality and fertility also worsens with age, according to guidelines endorsed by the Society of Obstetricians and Gynaecologists of Canada.

Postponing parenthood could have serious consequences, warns new study

Postponing parenthood could have serious consequences, warns new study







By Sharon Kirkey, Postmedia News January 17, 2012 10:13 AM















9





•Story
•Photos ( 1 )














The new guideline to doctors comes amid growing concerns about the number of women delaying childbearing. In Canada, 11 per cent of first births now occur in women aged 35 and older, up from five per cent in 1987.

Photograph by: Thinkstock, canada.com


Men, and not just women, need to be aware of the "reproductive consequences" of postponing parenthood, new national guidelines on the risks of delayed child-bearing warn.


Though women especially should recognize that their "fecundity and fertility" starts to decline precipitously after 32, a man's semen quality and fertility also worsens with age, according to guidelines endorsed by the Society of Obstetricians and Gynaecologists of Canada.


Read more: http://www.canada.com/health/Postponing+parenthood+could+have+serious+consequences+warns+study/6007363/story.html#ixzz1jjoxmhNe

James Crow Dies

James Crow Dies

January 11, 2012




James Crow, who was a population geneticist at the University of Wisconsin-Madison, has died, reports The New York Times. He was 95. Crow studied mutational load, and was part of on a National Academy of Sciences committee that assessed mutational damage to the populations of Hiroshima and Nagasaki following the use of atomic bombs there. He also was on a committee that paved the way for using DNA forensics in court. The Times notes that when Crow began teaching in the 1940s and 1950s, the field of genetics underwent rapid changes. "When anxious students asked Dr. Crow what would be in the exams, he would tell them that the questions were the same every year but that the answers were different," the Times says.

Neuron. 2011 Dec 22;72(6):951-63. High Frequencies of De Novo CNVs in Bipolar Disorder and Schizophrenia.

Neuron. 2011 Dec 22;72(6):951-63.

High Frequencies of De Novo CNVs in Bipolar Disorder and Schizophrenia.

Malhotra D, McCarthy S, Michaelson JJ, Vacic V, Burdick KE, Yoon S, Cichon S, Corvin A, Gary S, Gershon ES, Gill M, Karayiorgou M, Kelsoe JR, Krastoshevsky O, Krause V, Leibenluft E, Levy DL, Makarov V, Bhandari A, Malhotra AK, McMahon FJ, Nöthen MM, Potash JB, Rietschel M, Schulze TG, Sebat J.


Source

Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 12824, USA.


Abstract

While it is known that rare copy-number variants (CNVs) contribute to risk for some neuropsychiatric disorders, the role of CNVs in bipolar disorder is unclear. Here, we reasoned that a contribution of CNVs to mood disorders might be most evident for de novo mutations. We performed a genome-wide analysis of de novo CNVs in a cohort of 788 trios. Diagnoses of offspring included bipolar disorder (n = 185), schizophrenia (n = 177), and healthy controls (n = 426). Frequencies of de novo CNVs were significantly higher in bipolar disorder as compared with controls (OR = 4.8 [1.4,16.0], p = 0.009). De novo CNVs were particularly enriched among cases with an age at onset younger than 18 (OR = 6.3 [1.7,22.6], p = 0.006). We also confirmed a significant enrichment of de novo CNVs in schizophrenia (OR = 5.0 [1.5,16.8], p = 0.007). Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases.

Copyright © 2011 Elsevier Inc. All rights reserved.