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At least 19 recordsLinked to original sources
PubMed2003

Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases.

I estimate per nucleotide rates of spontaneous mutations of different kinds in humans directly from the data on per locus mutation rates and on sequences of de novo nonsense nucleotide substitutions, deletions, insertions, and complex events at eight loci causing autosomal dominant diseases and 12 loci causing X-linked diseases. The results are in good agreement with indirect estimates, obtained by comparison of orthologous human and chimpanzee pseudogenes. The average direct estimate of the combined rate of all mutations is 1.8x10(-8) per nucleotide per generation, and the coefficient of variation of this rate across the 20 loci is 0.53. Single nucleotide substitutions are approximately 25 times more common than all other mutations, deletions are approximately three times more common than insertions, complex mutations are very rare, and CpG context increases substitution rates by an order of magnitude. There is only a moderate tendency for loci with high per locus mutation rates to also have higher per nucleotide substitution rates, and per nucleotide rates of deletions and insertions are statistically independent on the per locus mutation rate. Rates of different kinds of mutations are strongly correlated across loci. Mutational hot spots with per nucleotide rates above 5x10(-7) make only a minor contribution to human mutation. In the next decade, direct measurements will produce a rather precise, quantitative description of human spontaneous mutation at the DNA level.

Codon, Nonsense↗
PubMed2003

The Iranian Human Mutation Gene Bank: a data and sample resource for worldwide collaborative genetics research.

As Human Genome Project exploration continues, the necessity of having a broader spectrum of genomic DNA material from different nationalities to study various aspects of hereditary disease becomes more obvious. The existence of high genetic polymorphism within and between different communities in the world makes it necessary for the gene hunters to investigate many different populations. Iran, a large country with close to 66 million people, is a land of different nationalities, tribes, and religions that offers a highly heterogeneous gene pool to the genetics researcher. The purity of many different races in this country has been highly conserved by geographical borders and by an ancient culture that has always encouraged intrafamilial marriages. All these have created a population that is remarkably heterogeneous yet high in consanguinity rate. During the last five years of investigation we have established a DNA bank, the Iranian Human Mutation Gene Bank (www.IHMGB.com), which contains all genetic diseases studied in Iran that have the Mendelian mode of inheritance. Some of the samples are assigned to common or novel mutations and others belong to patients with clinical profiles associated with particular genetic diseases but undefined mutation. This bank stores samples of DNA from the patient and his/her first-degree relatives together with a comprehensive pedigree and clinical profile for each sample. To facilitate collaboration with other scientists around the world with the same interests, we decided to present our experimental projects online. This DNA bank provides opportunities for us to collaborate with scientists outside Iran. It offers a sample resource to research scientists around the world, at no charge, for the purpose of investigating the various aspects of genetic disorders from prenatal diagnosis to gene structure and function. It is strongly stressed that no commercial benefit is involved in the establishment of this DNA bank and the DNA samples are free of charge. However, to meet our goals and to respect ethical values, DNA samples can only be used under certain conditions stated in the User Consent Form.

Consanguinity↗
PubMed2004

What have rare genetic syndromes taught us about the pathophysiology of the common forms of obesity?

Obesity is a central feature for several congenital syndromes, including Prader-Willi, Angelman, Bardet-Biedl, Cohen, Alström, and Börjeson-Forssman-Lehmann syndromes, and Albright's hereditary osteodystrophy. Although a role for the central nervous system, including the hypothalamus-pituitary axis, has been suggested for the etiology of obesity in these syndromes, the pathophysiologic pathways are as yet not well defined, and in many cases may identify currently unknown mechanisms. Nevertheless, many of the causative genes and unusual mechanisms, including parental imprinting of genes and complex patterns of inheritance, have been identified. We review the latest advances in understanding congenital syndromes in which obesity is purely genetic, drawing on comparisons to genetic studies of obesity in the human population as well as to those in experimental and agricultural animal models. An understanding of the genetic basis for these syndromes will provide a more comprehensive picture of the mechanisms that control food intake and energy balance in humans.

Angelman Syndrome↗
PubMed2004

Preimplantation genetic diagnosis.

Preimplantation genetic diagnosis (PGD) was introduced at the beginning of the 1990s as an alternative to prenatal diagnosis, to prevent termination of pregnancy in couples with a high risk for offspring affected by a sex-linked genetic disease. At that time, embryos obtained in vitro were tested to ascertain their sex, and only female embryos were transferred. Since then, techniques for genetic analysis at the single-cell level, involving assessment of first and second polar bodies from oocytes or blastomeres from cleavage-stage embryos, have evolved. Fluorescence in-situ hybridisation (FISH) has been introduced for the analysis of chromosomes and PCR for the analysis of genes in cases of monogenic diseases. In-vitro culture of embryos has also improved through the use of sequential media. Here, we provide an overview of indications for, and techniques used in, PGD, and discuss results obtained with the technique and outcomes of pregnancies. A brief review of new technologies is also included.

Chromosome Aberrations↗
PubMed2005

ESHRE PGD Consortium data collection V: cycles from January to December 2002 with pregnancy follow-up to October 2003.

The fifth report of the ESHRE PGD Consortium is presented (data collection V). For the first time, the cycle data were collected for one calendar year (2002) in the following October, so that data collection was complete for pregnancies and babies. The data were collected using a Filemaker Pro database and divided into referrals, cycles, pregnancies and babies. There are currently 66 active centres registered with the consortium; however, the data presented here were obtained from 43 centres and included 1603 referrals, 2219 cycles, 485 pregnancies and 382 babies born. The cycle data were divided into preimplantation genetic diagnosis (PGD) for inherited disorders (including chromosome abnormalities, sexing for X-linked disease and monogenic disorders), aneuploidy screening (PGS) and the use of PGD for social sexing. Data collection V is compared with the previous cumulative data collection (I-IV), which comprised 4058 PGD/PGS cycles that reached oocyte retrieval.

Aneuploidy↗
PubMed2006

ESHRE PGD Consortium data collection VI: cycles from January to December 2003 with pregnancy follow-up to October 2004.

The sixth report of the ESHRE PGD Consortium is presented, relating to cycles collected for the calendar year 2003 and follow-up of the pregnancies and babies born up to October 2004. Since the beginning of the data collections, there has been a steady rise in the number of cycles, pregnancies and babies reported. For this report, 50 centres participated, reporting on 2984 cycles, 501 pregnancies and 373 babies born. Five hundred and twenty-nine cycles were reported for chromosomal abnormalities, 516 cycles were reported for monogenic diseases, 137 cycles were reported for sexing for X-linked diseases, 1722 cycles were reported for preimplantation genetic screening (PGS) and 80 cycles were reported for social sexing. Data VI is compared to the cumulative data for data collections I-V.

Abortion, Spontaneous↗
PubMed2006

How does the mode of inheritance of a genetic condition influence families? A study of guilt, blame, stigma, and understanding of inheritance and reproductive risks in families with X-linked and autosomal recessive diseases.

PURPOSE: While the mode of inheritance of a genetic condition has long been considered to have not only medical, but also psychosocial consequences for families, this supposition has never been tested. METHODS: We surveyed 112 members of 51 families (59% response) with chronic granulomatous disease to determine the influence of mode of inheritance on parents', siblings', and patients' (1) knowledge of inheritance and reproductive risk; (2) concern about risk to future family-members; (3) feelings of guilt and blame; and (4) feelings of stigmatization. Ninety-six members of 51 families (49% response) with Duchenne/Becker muscular dystrophy and spinal muscular atrophy types II/III were also studied. RESULTS: X-linked families had better understanding of inheritance (P < 0.001) and reproductive risks (P < 0.01). X-linked mothers worried more about risks to future generations; other autosomal-recessive family members were as worried. X-linked mothers were more likely to feel guilty (P < 0.01) and blame themselves (P < 0.001). X-linked fathers blamed their child's mother (P < 0.05) and X-linked mothers felt more blamed by the father (P < 0.01). X-linked family-members were more likely to consider being a carrier stigmatizing (P < 0.05). CONCLUSION: When providing genetic counseling, attention should be given to guilt and blame in X-linked families and understanding reproductive risks in autosomal recessive families.

Attitude↗
PubMedDate not supplied

[Preimplantation genetic diagnosis of monogenic diseases].

Preimplantation genetic diagnosis (PGD) is an alternative to prenatal diagnosis allowing the detection of genetic diseases on IVF embryos before their transfer into the uterus and before the pregnancy. The aim of this procedure is to obtain unaffected or carrier embryos in order to avoid the burden of termination of pregnancy after prenatal diagnosis for couples at risk of transmitting particularly severe genetic disorders to their offspring. For monogenic diseases, PGD is most often based on single blastomere amplification by polymerase chain reaction (PCR). More than a decade after the first births, the possibilities of diagnosis for monogenic diseases have considerably increased. As for molecular biology and conventional diagnosis, the technologies and strategies for PGD are continually improved, with for instance introduction of fluorescent PCR or multiplex amplification. In this review, we describe several approaches for PGD of monogenic diseases, followed by an overview of the French practice, particularly in our lab.

Chromosome Disorders↗
PubMed2001

Predictive genetic testing in children.

Predictive genetic testing should only be performed on children if it is in their best interests. "Interests" include psychosocial elements. Predictive testing is performed on children when there are interventions to prevent disease or to detect and treat it early and it is necessary to begin these interventions in childhood. It is also performed for diseases known to commence in childhood. Predictive testing in children for adult-onset conditions for which there is no medical intervention is highly controversial. Competent children and adolescents can consent to predictive genetic testing. Predictive testing can result in harm, such as discrimination (eg, in insurance entitlement or employment) and stigmatisation. Predictive testing can have important non-medical benefits in terms of self-knowledge and life planning.

Australia↗
PubMed2005

Inborn errors of immunity to infection: the rule rather than the exception.

The immune system's function is to protect against microorganisms, but infection is nonetheless the most frequent cause of death in human history. Until the last century, life expectancy was only approximately 25 years. Recent increases in human life span primarily reflect the development of hygiene, vaccines, and anti-infectious drugs, rather than the adjustment of our immune system to coevolving microbes by natural selection. We argue here that most individuals retain a natural vulnerability to infectious diseases, reflecting a great diversity of inborn errors of immunity.

Animals↗
PubMedDate not supplied

The sheep model of in utero gene therapy.

Once its full clinical potential has been realized, hematopoietic stem cell based gene therapy (GT) promises to cure a wide array of both inborn and acquired diseases. For many genetic disorders, early onset and irreparable tissue and organ damage necessitate innovative methods that allow therapeutic intervention early in development, if a full cure is to be realized. Performing GT in utero would allow early correction prior to disease onset and is thus one of the few therapeutic modalities that could promise the birth of a healthy infant. Several features of the developing fetus may circumvent obstacles that have thus far been observed in GT trials. For example, the immune naïveté of the early gestational fetus may evade immune reactions to the vector and transgene product. Furthermore, fetal exposure to foreign antigens can result in sustained tolerance, suggesting that induction of tolerance to the vector/transgene product could allow postnatal treatment to be performed successfully. In addition to these immunologic advantages, the fetal hematopoietic system promises to be more amenable to retrovirus-mediated gene transfer than either the neonate or adult as a result of both proliferation and expansion of the stem/progenitor cell pool that take place during fetal development. To investigate whether these characteristics of the developing fetus could be used to advantage to efficiently transduce hematopoietic stem cells, we developed an approach to in utero GT, in which retroviral vectors were directly injected into the peritoneal cavity of preimmune fetal sheep. This approach resulted in the transfer and long-term (>5 years) expression of exogenous genes within the hematopoietic system of primary and secondary recipients, albeit at relatively low levels that would not likely be therapeutic in most diseases. These studies also demonstrated that the direct injection of retroviral vectors into preimmune fetal sheep results not only in the successful transduction of long-term engrafting hematopoietic stem cells, but also in the widespread distribution of vector to all other tissues examined, including the reproductive organs. In an effort to increase the hematopoietic cell transduction to clinically relevant levels, we repeated our initial studies with 1,000-fold higher titer vectors. This led to only a modest (two- to fourfold) increase in the transduction levels, suggesting that factors other than absolute vector dosage were responsible for the low levels of gene transfer. For this reason, we have more recently begun evaluating the effect of recipient gestational age on the efficiency of gene transfer to both hematopoietic and nonhematopoietic tissues. Thus far, we have observed an inverse relation between the gestational age at the time of vector administration and the level of transduction and expression of the transgene within the hematopoietic system, such that fetuses injected earlier in gestation have higher levels of hematopoietic cell transduction. These elevated levels have persisted for at least 1 year after injection, suggesting that the enhancement is at the level of primitive stem/progenitor cells. When analyzing the liver sections from animals that had received the vector at different gestational ages, we also observed an inverse correlation between recipient age and efficiency of gene transfer to the hepatocytes, such that a high efficiency of gene transfer occurred at early ages, while very little occurred at later stages of gestation. In contrast to the findings in the hematopoietic system and in the liver, analysis of the lungs of these same animals revealed that the efficiency of transduction of nonhematopoietic lung tissue increased with increasing gestational age. These results demonstrate that both hematopoietic cells and nonhematopoietic cells within liver and lung are transduced following direct injection of murine retroviral vector supernatants into the peritoneal cavity of preimmune fetal sheep and suggest that the developmental stage of each organ at the time of injection may determine its etermine its susceptibility to in utero gene transfer.

Animals↗
PubMed2004

Human disorders of ubiquitination and proteasomal degradation.

PURPOSE OF REVIEW: The goal of this review is to provide an overview of rapidly evolving information on a new group of genetic inborn errors affecting ubiquitination and proteasomal degradation of proteins and to suggest a classification scheme for these disorders. The relevant genes encode ubiquitin, ubiquitin enzymes (E1 and many E2s and E3s), deubiquitinating enzymes, proteasomal subunits, and substrates undergoing ubiquitination. RECENT FINDINGS: Since the initial recognition that Angelman syndrome is caused by maternal deficiency of the E6-AP ubiquitin E3 ligase (gene symbol UBE3A), several. other disorders of E3 ligases have been identified, including autosomal recessive juvenile Parkinson disease, the APECED form of autoimmune polyendocrinopathy syndrome, von Hippel-Lindau syndrome, and congenital polycythemia. Disorders that disturb ubiquitin regulatory signaling include at least two subtypes of Fanconi anemia, the BRCA1 and BRCA2 forms of breast and ovarian cancer susceptibility, incontinentia pigmenti, and cylindromatosis. Many disorders affect ubiquitin pathways secondarily. SUMMARY: The authors propose both a genetic and a functional classification for disorders of ubiquitination and proteasomal degradation, as follows. Genetic classes include mutations in (1) the UBB ubiquitin gene; (2) enzymes of ubiquitination including E1, E2, E3, and related proteins; (3) deubiquitinases; (4) proteasomal subunits; and (5) substrates of ubiquitination. Functional classes include defects in (1) proteolytic degradation, (2) ubiquitin signaling, and (3) subcellular localization of substrates. Additional functional classes are likely to be defined, and individual disorders may involve multiple functional defects.

Alzheimer Disease↗
PubMed2004

Integration of genetics into medical practice.

It has been a century since the first human genetic disorders were recognized, but only recently have there been any prospects that the genetic approach would become integral to medical practice. Throughout most of the 20th century, medical genetics has focused on rare monogenic and chromosomal disorders. There were major successes, including chromosomal analysis, prenatal diagnosis and newborn screening for inborn errors of metabolism, but the impact was confined to a relatively narrow corner of medicine. The situation has changed, however, with advances in genetics and especially with the sequencing of the human genome. The tools are now at hand to begin to understand the genetic basis of common as well as rare disorders. It is expected that this will lead to major advances in both diagnosis and treatment, so that physicians in all areas of medicine will be using the tools of genetics in their daily practice.

Genetic Diseases, Inborn↗
PubMed2004

The "duty to warn" a patient's family members about hereditary disease risks.

Genetic tests for adult-onset disorders, including common forms of cancer, are now commercially available, and tests for genetic polymorphisms that predict drug effects or toxicity after treatment are under development. For each of these circumstances, testing of 1 individual may imply an increased risk to his/her relative. The obligation, if any, to warn family members of the identification of a genetic mutation has generated concerns regarding the conflict between the physician's ethical obligations to respect the privacy of genetic information vs the potential liabilities resulting from the physician's failure to notify at-risk relatives. A duty to warn relatives about risks due to some infectious agents has been assumed by state and local health agencies, and the duty to breach confidentiality to warn of imminent harm has been the subject of case law. In general, the special nature of genetic tests has been viewed as a barrier to physicians' breaching the confidentiality of personal genetic information. However, the failure to warn family members about hereditary disease risks has already resulted in 3 lawsuits against physicians in the United States. While the findings of case law and the state and federal statutes that bear on the issue of "duty to warn" of inherited health risk are still being defined, we believe that health care professionals have a responsibility to encourage but not to coerce the sharing of genetic information in families, while respecting the boundaries imposed by the law and by the ethical practice of medicine.

Duty to Warn↗