Human genetics and gender Markus Hengstschla¨ger Abstract Human genetics is the study of genetics and biological variation in Homo sapiens and medical genetics is the science of such variation as it relates to health and disease. The scope of medical genetics includes teaching, basic research, genetic counseling, as well as genetic testing services. These services offer genetic testing for confirmation of clinical diagnoses, predictive genetic testing and prenatal genetic testing. There are clear gender-specific differences in the importance and consequences of the specific application of such genetic tests (e.g. genetic aspects of infertility, hereditary cancer syndromes). Accordingly, gender-specific genetic counseling must be part of the management of every prenatal, postnatal or predictive genetic testing. ß 2004 WPMH GmbH. Published by Elsevier Ireland Ltd.
Markus Hengstschla¨ger, PhD Department of Obstetrics and Gynecology, Prenatal Diagnosis and Therapy, Medical University of Vienna, Wa¨hringer Gu¨rtel 18-20, 1090 Vienna, Austria E-mail: markus.hengstschlaeger@ akh-wien.ac.at
Online 12 May 2004
Human genetics is the study of genetics and biological variation in Homo sapiens. Its various branches are population genetics, cytogenetics, biochemical genetics, and genome studies including biodiversity and human evolution . Clinical genetics or medical genetics is the science of human biological variation as it relates to health and disease. Although we have long been aware that individual people differ, that children tend to resemble their parents, and that certain diseases tend to run in families, the scientific basis for these observations was only discovered during the past 125 years. The terms clinical genetics or medical genetics are also applied to the clinical speciality which is concerned with the delivery of medical genetics services. These services include clinicians, genetic counselors, nurses, scientists, and support staff and provide genetic testing and genetic assessment and counseling . Disease causing mutations may take place in the DNA itself or at chromosome level. Monogenic diseases are determined by mutations in a single gene, whereas several different genes are responsible for one so-called
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polygenic disease. Currently, it is becoming increasingly apparent that ‘‘real’’ monogenic diseases probably do not exist because most (if not all) of them depend on the regulating influences of several other genes. The majority of diseases are thought to be caused multifactorially arising from the interaction between environment and heredity. Population screening of unselected newborns has yielded an incidence of about 5% inherited disorders. About 0.6% have chromosome aberrations (including balanced rearrangements, but excluding variants) and about 1% have a monogenic inherited disorder. Genetic predisposition to diseases differs between men and women, but this is not only due to the different sex chromosomes [3–5].
Genetic testing for confirmation of clinical diagnoses Genetic testing for confirming clinical diagnoses is important because diagnoses based on clinical evidence are often uncertain. More and more genetic tests are becoming available to enable final clarification in such cases (e.g. cystic fibrosis ). An interesting
ß 2004 WPMH GmbH. Published by Elsevier Ireland Ltd.
Practicing medicine example of the role of genetic testing to optimize therapeutic management is delayed puberty in males or females. Normal puberty is a time of life and a process of development that results in full adult maturity of growth, sexual development, and psychosocial achievement. Delayed puberty describes the clinical condition in which the pubertal events start late or are attenuated in progression. The differential diagnosis includes constitutional delay of growth and maturation associated with chronic diseases, monogenic and polygenic disorders, and the well-known chromosome abnormalities, Turner syndrome in women and Klinefelter syndrome in men (including all types of mosaic forms). The application of androgen, estrogen or growth hormone therapies depends on the results of the genetic testing [7,8]. Another example of the importance of genetic testing for confirmation of clinical diagnosis is the management of infertility. From the genetic point of view, male and female infertility patients seeking assisted reproduction have to be classified as a highrisk group. The prevalence of numerical chromosomal abnormalities is around 10% in these patients compared with 0.85% in the general population. The prevalence of structural chromosomal abnormalities is around 0.1% in the general population and is increased up to 1% in patients seeking assisted reproduction. Up to about 9% of azoospermic or severely oligozoospermic men carry a deletion in the azoospermia factor gene region (AZF) on the Y chromosome. Around 60-85% of men with bilateral absence of the vasa deferentia carry mutations in the cystic fibrosis transmembraneconductance regulator (CFTR) gene. In addition, a broad range of other gene mutations and genetic syndromes are associated with male and female infertility. For counseling of patients (parental genetic factors can be transferred to offspring that probably would not have been conceived by natural means), for optimizing the therapeutic concept as well as to basically understand how genetic factors affect fertility, it is important to include cytogenetic (and/or in the case of molecular genetic) laboratory testing to screen for genetic alterations in both partners before assisted reproduction [9–12].
Predictive genetic testing Predictive genetic tests are a new and growing class of medical tests, which differ in fundamental ways from conventional medical diagnostic tests. Predictive genetic testing is the use of a genetic test in an asymptomatic person to predict future risk of disease. The hope is that early identification of people at risk of a specific condition will lead to reduced morbidity and mortality through targeted screening, surveillance, and prevention [13,14]. In inherited tumor syndromes germline mutations are associated with a specific risk for tumor formation . For example tuberous sclerosis is an autosomal dominantly inherited tumor syndrome occurring in about 1 in 6000 live births. It is characterized by mental retardation, epilepsy, and by the development of different growths, including cortical tubers, affecting, e.g. kidneys, heart, lung, and skin. Male or female patients carry a mutant TSC1 gene on chromosome 9q34 or a mutant TSC2 gene on chromosome 16p13.3 in each of their somatic cells. Tumor development is assumed to be the result of somatic ‘‘second hit’’ mutations according to Knudson‘s tumor suppressor model [16,17]. Mutations of the breast cancer susceptibility gene BRCA1, located on chromosome 17q21, predispose to breast and ovarian cancer (and possibly also to prostate cancer). Approximately 5-10% of all breast cancer cases are heritable and a distinct percentage of them are caused by mutations in BRCA1. Female BRCA1 mutation carriers have a 50-80% risk of developing breast cancer by the age of 70 years. Patients and investigators alike hope to identify women at risk before breast cancer develops [18,19]. Whereas for tuberous sclerosis inherited mutations in TSC1 or TSC2 have very similar consequences for both sexes, BRCA1 mutations predominantly predispose women to cancer development.
Prenatal genetic testing Prenatal diagnosis is based on non-invasive techniques, such as ultrasound or maternal serum screening. Indications for genetic prenatal diagnosis, such as advanced maternal
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Practicing medicine age or signs from ultrasound examination, were the driving force for the establishment of invasive techniques to isolate cells of fetal origin. Nowadays, amniocentesis, chorionic villus sampling or fetal cord blood sampling are routinely used to enable genetic and biochemical prenatal diagnosis of human genetic diseases. Due to recent research developments the importance of the genetical aspects in prenatal medicine has dramatically increased. After years of focus on standard chromosome analyses the new area of prenatal genetic diagnosis is represented by new molecular cytogenetic techniques, by new mutation detection techniques for single gene disorders, or by microarray analyses including polymorphism studies. All current methods for invasive tissue sampling in prenatal medicine carry procedure-related risks which has been the motivation for many years for developing less invasive techniques, originally by studying fetal cells in the maternal circulation [20,21]. Preimplantation genetic diagnosis is an alternative to prenatal diagnosis, in which genetic testing is done on in vitro fertilization embryos before clinical pregnancy is established. Preimplantation genetic diagnosis is applied to increase implantation rates, reduce the incidence of spontaneous abortions and prevent trisomic offspring in women of advanced maternal age undergoing fertility treatment. Preimplantation genetic diagnosis applied to patients carrying specific chromosomal rearrangements has been proven to reduce the number of spontaneous abortions and to prevent the birth of children affected with chromosome imbalance. Another major
group of patients receiving this diagnosis are those at high risk of transmitting a monogenic disorder to their children. Preimplantation genetic diagnosis now in its thirteenth anniversary has been conducted in many cycles yielding about 1000 children born. In some countries, e.g. Austria and Germany, preimplantation genetic diagnosis is prohibited by law [22–25].
Genetic counseling Genetic counseling seeks to assist patients affected or at-risk individuals and families to understand the nature of the genetic disorder, its transmission and the options open to them in management and family planning. The five major components of genetic counseling are: 1) to take a family history, 2) making a diagnosis, 3) estimating risk, 4) empathic communication of facts to the client, 5) follow-up and support [26,27]. Obviously, genetic counseling is not necessarily connected to any genetic test. But it is most important that a gender-specific genetic counseling is part of the management of every prenatal, postnatal or predictive genetic testing.
Acknowledgement I wish to thank all colleagues of the laboratory and the department for helpful discussion. I would like to apologize that data have been cited indirectly because of space limitations.
This article introduces a series of articles on Genetics in relation to gender medicine. Further articles in the series will take up specific areas of the subject in detail and will be published in future issues of the journal.
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