The oxidative phosphorylation (OXPHOS) system: nuclear genes and human genetic diseases

The ubiquitous nature of mitochondria, the dual genetic foundation of the respiratory chain in mitochondrial and nuclear genome, and the peculiar rules of mitochondrial genetics all contribute to the extraordinary heterogeneity of clinical disorders associated with defects of oxidative phosphorylation (mitochondrial encephalomyopathies). Here, we review recent findings about nuclear gene defects in isolated OXPHOS enzyme complex deficiency. This information should help in identifying patients with mitochondrial disease and defining a biochemical and molecular basis of the disorder found in each patient. This knowledge is indispensable for accurate genetic counseling and prenatal diagnosis, and is a prerequisite for the development of rational therapies, which are still, at present, woefully inadequate.     

Genetic screening and genetic counseling: Knowledge,attitudes, and practices in two groups of family planning professionals

Abstract

Genetic counseling has evolved from a eugenic orientation to an orientation concerned with the physical and mental well‐being of counselees. This change in genetic counseling, which has received formal recognition in a new definition of genetic counseling, requires collateral development of the processes and evaluation of the outcomes of counseling. This paper offers a theory of genetic counseling which interrelates genetic information, psychological responses, learning theory, and decision‐making. The theory presented for genetic counseling is based on the more general theories of learning, decision‐making, and adaptation to psychological stress. This theory is extended into a practical model that provides a comprehensive explanation of the relationships between the activities of genetic counseling and informed decision‐making, which is assumed to be a major element of healthy counselee adjustment. Implications of this theory for the genetic counselor, the counselee, and the assessment of clinical and program success are discussed.     

Inheritance of mitochondrial disorders

Over the last decade there have been major advances in our understanding of the genetic basis of mitochondrial disease, enabling genetic counseling for patients with autosomal dominant and autosomal recessive disorders. Genetic counseling for patients with mitochondrial DNA (mtDNA) mutations is less well established. Approximately one-third of adults with a mtDNA disorder are sporadic cases, usually due to a single deletion of mtDNA. About two-thirds of adults with mtDNA disease harbor a maternally transmitted point mutation. The recurrence risks are well documented for homoplasmic mtDNA mutations causing Leber hereditary optic neuropathy, but the situation is less clear for families with heteroplasmic mtDNA disorders. Two large studies have shown that for some heteroplasmic point mutations there appears to be a relationship between the percentage level of mutant mtDNA in a mother's blood and her risk of having clinically affected offspring. The situation is less clear for other point mutations, some of which may cause sporadic disease. Recent evidence has cast light on the general principles behind the transmission of heteroplasmic mtDNA point mutations, which may be important for genetic counseling in the future.     

Heredit?re Fiebersyndrome

Familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD), and tumour necrosis factor (TNF) receptor-1-associated periodic syndrome (TRAPS) are monogenic disorders included under the term??hereditary fever syndromes??. These diseases are characterized by recurrent episodes of fever and inflammation and arise from mutations of genes regulating the innate immune system. The present review describes the clinical and genetic spectrum of hereditary fever syndromes, which are of importance for genetic counseling.     

Mitochondrial ND5 12338T>C variant is associated with maternally inherited hypertrophic cardiomyopathy in a Chinese pedigree

Hypertrophic cardiomyopathy is a primary disorder characterized by asymmetric thickening of the septum and left ventricular wall, which affects 1 in 500 individuals in the general population. Mutations in mitochondrial DNA have been found to be one of the most important causes of hypertrophic cardiomyopathy. Here we report the clinical, genetic and molecular characterization of a Han Chinese family with a likely maternally transmitted hypertrophic cardiomyopathy. Four (2 men/2 women) of 5 matrilineal relatives in this 3-generation family exhibited the variable severity and age at onset of 44 to 79years old. Sequence analysis of the entire mitochondrial DNA in this pedigree identified the known homoplasmic ND5 12338T>C variant. This mitochondrial DNA haplogroup belongs to the Eastern Asian F2a. The 12338T>C variant, highly evolutionarily conserved, resulted in the replacement of the translation initiating methionine with a threonine, shortening the ND5 polypeptide by 2 amino acids. The occurrence of ND5 12338T>C variant exclusively in maternal members of this Chinese family suggested that the 12338T>C variant is associated with maternally inherited hypertrophic cardiomyopathy. Our findings will provide theoretical basis for genetic counseling of maternally inherited hypertrophic cardiomyopathy.     

Telephone genetic counseling for high-risk women undergoing BRCA1 and BRCA2 testing: rationale and development of a randomized controlled trial

Genetic counseling and testing, particularly for adult onset conditions, has become increasingly available over the last decade, and it is expected that this trend will continue as additional genes are identified and as such testing diffuses into mainstream clinical care. To meet the increased demand for services, it will become necessary to explore alternative avenues to traditional face-to-face genetic counseling. One such modality is the use of telephone genetic counseling (TGC), which is easy to implement and still allows for comprehensive service delivery. Although TGC has been used with increased frequency, there is a paucity of data about its effectiveness and impact on important patient outcomes. This paper provides an overview of the evolution of telephone counseling in nongenetics and genetics settings. The rationale and aims of the largest randomized clinical trial to be performed with this mode of counseling in the context of cancer susceptibility testing for mutations in the BRCA1 and BRCA2 genes are also explained. In addition, procedural aspects of the genetic counseling intervention and the novel tools developed to facilitate this process and to ensure adequate counselor training and quality assurance are described.     

Humangenetische Beratung

With the increasing possibilities of genetic testing in clinical practice, genetic counseling becomes more and more important. Such counseling involves an attempt to answer questions and solve problems in connection with a possible genetic disorder. Reasons for genetic counseling are, among others, a possible genetic disorder in a child, a parent or a relative, advanced parental age, consanguinity, multiple pregnancy loss, stillbirths, infertility, and possible mutagenic or teratogenic exposure. Prenatal diagnosis, predictive and heterozygosity testing may have implications which differ from those of conventional diagnoses in medicine. The decision for testing should be made informed after genetic counseling. An overview of the aims, practical aspects and possible reasons for genetic counseling is provided.     

Rett syndrome molecular diagnosis and implications in genetic counseling

Rett syndrome is a rare genetic X-linked dominant disorder. This syndrome is the most frequent cause of mental retardation in girls. In the classical form of the disease, the presenting signs and the course of development are characteristic. However clinical diagnosis can be very difficult when the expression is not in the classical form. Mutations in MeCP2 are responsible for 80% of cases. When MeCP2 mutation is found in an index case, genetic counseling is similar to that in other X-linked dominant genetic diseases. However, mutations in this gene can cause a spectrum of atypical forms. On the other hand, other genetic conditions like translocations, sex chromosome numerical anomalies, and mutations in other genes can complicate genetic counseling in this syndrome. We present the first case of molecular diagnosis of Rett syndrome in Iran and discuss the recent developments in its genetic counseling.     

Population genetic structure and historical demography of Oratosquilla oratoria revealed by mitochondrial DNA sequences

Genetic diversity, population genetic structure and molecular phylogeographic pattern of mantis shrimp Oratosquilla oratoria in Bohai Sea and South China Sea were analyzed by mitochondrial DNA sequences. Nucleotide and haplotype diversities were 0.00409?C0.00669 and 0.894?C0.953 respectively. Neighbor-Joining phylogenetic tree clustered two distinct lineages. Both phylogenetic tree and median-joining network showed the consistent genetic structure corresponding to geographical distribution. Mismatch distributions, negative neutral test and ??star-like?? network supported a sudden population expansion event. And the time was estimated about 44000 and 50000 years ago.     

Genetic Counseling: An Evaluation of Public Health Genetic Clinics

The geographic distribution of County Health Department clinic facilities in the state of California has made it readily possible to establish a regionalized program for genetic counseling services, using public health nurses as a major source of case-finding. From both consumer and health professional standpoints, regionalized satellite genetic counseling clinics have been successful, and in particular, the effectiveness of public health nurses in identifying clinical genetic problems is readily apparent.Long-term follow-up reinforcement of genetic counseling appears to be an important conclusion from these studies. It is our suggestion that reinforcement of counseling would best be accomplished through the health team member (physician, nurse and so forth) following the patient or family rather than through the consulting geneticist.     

中国遗传咨询网——我国首个在线遗传咨询与遗传教育网站的开发

随着互联网的普及, 网络用户已习惯从网上获取相关资讯, 包括求医问药。由于我国的临床遗传学体系尚未完全建立, 许多遗传病患者或遗传咨询者无法得到较为专业的知识和咨询服务。为此, 建立了中国首个提供常见遗传病科普和网上遗传咨询服务的公益性网站—中国遗传咨询网(http://www.gcnet.org.cn)。该网站主要介绍遗传病的基本知识以及常见遗传病的一般情况、临床表现、诊断与防治方法、遗传方式与遗传咨询要点等。通过组织国内外50多名遗传咨询医师或医学遗传学专家, 就咨询者关心的问题, 进行一般性咨询答复, 或指导咨询者就诊。在线遗传咨询是网络时代的一种新型的方式。该网站的运行在一定程度上弥补了我国现有遗传咨询工作的不足, 有助于推动我国临床遗传学、遗传教育和人口与健康事业的发展。     

Molecular base of biochemical complex I deficiency

The oxidative phosphorylation (OXPHOS) system, consisting of five enzyme complexes (I-V) together with 2 electron carriers, has an important role in the energy metabolism of the cell. With 45 subunits, complex I is the first and largest complex of the respiratory chain. It is under bigenomic control and a proper interaction between the mitochondrial and the nuclear genome is important for a good biogenesis and functioning of the complex. Isolated complex I deficiency is the most frequently diagnosed form of mitochondrial disorders caused by the disturbance of the OXPHOS system. It has a wide clinical variety and, at present, in many patients the underlying genetic cause of the complex I deficiency is still not known. In this review, the role of complex I in the oxidative phosphorylation and the localization and function of the different complex I subunits will be described. Furthermore, a brief overview of the assembly process and biochemical studies, performed when a patient is suspected of a mitochondrial disorder is given. Finally, the present knowledge for molecular base of complex I deficiency is described and the findings in a research cohort of patients with complex I deficiency are reported. Identifying new genes encoding proteins involved in complex I biogenesis is challenging and in the near future new powerful techniques will make high throughput screening possible. Progress in elucidating the genetic defect causing complex I deficiencies is important for a better genetic counseling, prenatal diagnostic possibilities and further development of new treatment strategies to cure the complex I deficiencies in the future.     

Parental attitudes toward genetic testing for pediatric deafness

Recent molecular genetic advances have resulted in genetic testing becoming an option for deaf individuals and their families. However, there is little information about the interest in such testing. To investigate this issue, parents with normal hearing who have one or more deaf children were surveyed about their attitudes toward diagnostic, carrier, and prenatal genetic testing for deafness. This population was chosen because it represents the majority of individuals who are encountered in clinical practice, given that 90%-95% of deaf individuals are born to persons with normal hearing. Of 328 surveys distributed, 96 were completed and returned. Of the respondents, 96% recorded a positive attitude toward genetic testing for deafness, including prenatal testing, although none would use this information to terminate an affected pregnancy. All respondents had a poor understanding of genetics, with 98% both incorrectly estimating the recurrence risk of deafness and misunderstanding the concept of inheritance. Notably, these findings were similar in the group who had had genetic testing for their children and in the group who had not, suggesting either that the parents who received genetic testing did not receive genetic counseling or that the counseling was not effective. On the basis of these results, it was concluded that this population is interested in the use of genetic testing and that testing should not be done without first providing formal genetic counseling. Appropriate counseling can help parents to understand the risks, benefits, and limitations of genetic testing.     

Impact of Genetic Counseling and Connexin-26 and Connexin-30 Testing on Deaf Identity and Comprehension of Genetic Test Results in a Sample of Deaf Adults: A Prospective,Longitudinal Study

Using a prospective, longitudinal study design, this paper addresses the impact of genetic counseling and testing for deafness on deaf adults and the Deaf community. This study specifically evaluated the effect of genetic counseling and Connexin-26 and Connexin-30 genetic test results on participants'' deaf identity and understanding of their genetic test results. Connexin-26 and Connexin-30 genetic testing was offered to participants in the context of linguistically and culturally appropriate genetic counseling. Questionnaire data collected from 209 deaf adults at four time points (baseline, immediately following pre-test genetic counseling, 1-month following genetic test result disclosure, and 6-months after result disclosure) were analyzed. Four deaf identity orientations (hearing, marginal, immersion, bicultural) were evaluated using subscales of the Deaf Identity Development Scale-Revised. We found evidence that participants understood their specific genetic test results following genetic counseling, but found no evidence of change in deaf identity based on genetic counseling or their genetic test results. This study demonstrated that culturally and linguistically appropriate genetic counseling can improve deaf clients'' understanding of genetic test results, and the formation of deaf identity was not directly related to genetic counseling or Connexin-26 and Connexin-30 genetic test results.     

Application of deafness diagnostic screening panel based on deafness mutation/gene database using invader assay

Despite progress in identification of deafness genes, clinical application has lagged due to the genetic heterogeneity of deafness. We designed and tested a comprehensive and simple diagnostic strategy to simultaneously detect deafness gene mutations based on a mutation/gene database followed by Invader assay screening of 41 known mutations of nine known deafness genes. Three hundred thirty-eight Japanese patients with congenital or childhood-onset (up to age 10) bilateral sensorineural hearing loss participated in this study. A total of 100 (29.6%) subjects had at least one mutation in GJB2, SLC26A4, and/or the mitochondrial 12S rRNA, indicating that these are the three major causative genes in Japanese deafness patients. The present study demonstrated that the Invader assay has excellent sensitivity and accuracy, and its application to deafness mutation screening will greatly improve medical management and facilitate extensive genetic counseling for hearing impairment.     

A human pathology-related mutation prevents import of an aminoacyl-tRNA synthetase into mitochondria

Mutations in the nuclear gene coding for the mitochondrial aspartyl-tRNA synthetase, a key enzyme for mitochondrial translation, are correlated with leukoencephalopathy. A Ser?? to Gly?? mutation is located in the predicted targeting signal of the protein. We demonstrate in the present study, by in vivo and in vitro approaches, that this pathology-related mutation impairs the import process across mitochondrial membranes.     

Genetic testing and genetic counseling among medicaid-enrolled children with autism spectrum disorder in 2001 and 2007

The rise in the prevalence of autism spectrum disorder (ASD) has resulted in increased efforts to understand the causes of this complex set of disorders that emerge early in childhood. Although research in this area is underway and yielding useful, but complex information about ASD, guidelines for the use of genetic testing and counseling among children with ASD conflict. The purpose of this study was to determine the frequency of use of genetic testing and counseling before the widespread implementation of clinical chromosomal microarray (CMA) to establish a baseline for the use of both services and to investigate potential disparities in the use of both services among children with ASD. We found that about two-thirds of children with ASD received genetic testing or counseling and the use of both services is increasing with time, even in the pre-CMA era. Being female and having a comorbid intellectual disability diagnosis both increased the likelihood of receiving genetic testing and genetic counseling. Initial discrepancies in the use of both services based on race/ethnicity suggest that troubling disparities observed in other services delivered to children with ASD and other mental health disorders persist in genetic testing and counseling as well. These results should incentivize further investigation of the impact of genetic testing and counseling on children with ASD and their families, and should drive efforts to explore and confront disparities in the delivery of these services, particularly with the advancing scientific research on this topic.     

Genetic risks for children of women with myotonic dystrophy

In genetic counseling, the recommended risk estimate that any heterozygous woman with myotonic dystrophy (DM) will have a congenitally affected child is 3%-9%. However, after already having had such an offspring, a DM mother's risk increases to 20%-37%. The risks of 10% and 41%, respectively, calculated in this study are similar to the estimates in the literature. However, our data on clinical status of the mothers demonstrate that only women with multisystem effects of the disorder at the time of pregnancy and delivery are likely to have congenitally affected offspring. No heterozygous woman with polychromatic lens changes but no other clinically detectable multisystem involvement had a congenitally affected child. In addition, our data suggest that the chance of having a more severely affected child increases with greater severity of maternal disease. The findings of this study are relevant for genetic counseling, as the risk of having a congenitally affected child for women with classical manifestations of the disease is shown to be higher than predicted by the overall risk estimate for any heterozygous woman. We consider it appropriate to give these classically affected women risk figures which approach the recurrence risk given to mothers with congenitally affected children. However, the risk of having a congenitally affected child for heterozygous women with no multisystem involvement appears to be minimal. Our findings support the earlier proposed hypothesis of maternal metabolites acting on a heterozygous offspring. Neither genomic imprinting nor mitochondrial inheritance is able to explain the correlation between the clinical status of heterozygous mothers and that of their children.     

Does genetic counseling have any impact on management of breast cancer risk?

Despite there being an increasing literature on the impact of cancer genetic counseling on risk perception and mental health, there is a lack of data describing impact on risk management. Genetic counseling and testing for cancer predisposition genes aims to improve the future health of those at high risk through appropriate surveillance and screening. However, management of breast cancer risk in women with a family history of this disease is an area of controversy. Counseling services may recommend specific risk management options to women, who then rely on their local screening service to make provision. This study investigated the impact of genetic counseling on management of breast cancer risk in women attending Cancer Family Clinics. A total of 293 women attending four genetic clinics were enrolled. Rates of breast self-examination, clinical breast examination, mammography, biopsy, detected cancers, and other screenings were documented. Participants' perceived benefits and barriers to mammography were assessed along with cancer worry. Results show that rates of mammography, clinical breast examination, and breast self-examination were increased following clinic attendance (p < 0.001). Women in the under 35 age-group had limited access to screening. Rates for biopsy and detected cancers were low. Women reported positive attitudes to mammography, with few reported barriers. Contrary to previous studies, there was no evidence that anxiety about breast cancer impedes uptake of health surveillance methods. Genetic counseling had a positive impact on management of breast cancer risk. Whether this translates into future health gains remains to be established.     

The delivery of genetic counseling services in Europe

Summary Oranizational forms and the current status of genetic counseling within the health care system of 15 European countries were evaluated by questionnaire and at a symposium, with individuals present from Austria, Belgium, Czechoslovakia, Denmark, the Federal Republic of Germany, the German Democratic Republic, Finland, France, Hungary, Italy, the Netherlands, Norway, Switzerland, the United Kingdom, and the Soviet Union. In spite of wide differences between these countries, certain similarities with respect to the delivery of genetic counseling services could be observed: (i) most genetic counseling is done within university institutions or closely linked to it; (ii) governmental support of genetic counseling is developing slowly, and genetic counseling is usually not yet fully integrated into the health care system; (iii) there is lack of qualified personnel; (iv) no guide lines for formal education have been developed, but a postgraduate training period of no less than four years is considered a minimum; (v) without appropriate support, genetic counseling is a burden for research in human genetics; yet, a strict separation of genetic counseling and research activities is not recommended; (vi) on the average, a team providing genetic counseling for about 1–2 million people should consist of 3–4 physicians, 5–10 technicians, 2–3 secretaries, and other supportive personnel.This study was supported in part by the Deutsche Forschungsgeneinschaft