Benefits of genetic testing Reveal the cause of diseases High quality testing and good medical understanding is the most important criteria for a successful collaboration with physicians and medical specialists around the world. We deliver sophisticated and clinical analyses including differential diagnostic and a detailed interpretation of the data. 2 Table of contents Chapter 1: Introduction 4 Chapter 2: What is a gene? / How do genes work? 5-7 Chapter 3: How are genes linked to a disease? 8 Chapter 4: How does a mutation in a gene trigger a disease? 9-10 Chapter 5: How do we get mutations and how do we inherit them? 11-14 Chapter 6: What is genetic testing? 15 Chapter 7: What are the uses of genetic testing? 16 Chapter 8: How are mutations associated with diseases identified? 17 Chapter 9: What types of diseases can be diagnosed with genetic tests? 18 Chapter 10: What is the relationship between genes and cancer? 19 Chapter 11: What are the benefits of genetic testing? 20 Chapter 12: What are the limitations and risks of genetic testing? 21 Chapter 13: What is genetic counseling? 22 Chapter 14: Who is a candidate for genetic testing? 23 Chapter 15: How can someone decide whether to have a genetic test or not? 24 Chapter 16: Additional information 25 Chapter 17: The advantages of choosing genetic testing at CENTOGENE 26-27 Chapter 18: Glossary 28-34 3 Chapter 1: Introduction Genetic testing is a type of medical testing that identifies changes in genes. We inherit genes from our parents and we pass them to our children. Genetic tests may be used to confirm a suspected disease, or to test for an increased risk of developing a disorder that runs in a family. These tests also help us choose additional diagnostic tests (like radiological imaging), the best treatment or monitor responses to treatment. More than 2,000 genetic tests are currently in use, with more being developed all the time. CENTOGENE has created this brochure in order to inform you about genetic diseases and possibilities to diagnose them by using genetic testing, as well as to inform you about the benefits and potential risks of genetic testing. Examples for methods that can be used for genetic testing: › Molecular genetic tests (or gene tests): Study single genes or short lengths of DNA to identify variations or mutations that may lead to a genetic disorder. › Chromosomal genetic tests: Analyze all chromosomes of an individual at once. › Biochemical genetic tests: Study the amount or activity level of proteins (encoded by specific genes) which may indicate a genetic disorder. Genetic testing is voluntary. It has benefits as well as risks and limitations, thus the decision about whether to be tested or not is a personal and complex one. A geneticist or genetic counselor can help by providing information about the pros and cons of the test and by discussing the social and emotional aspects of testing. There are several reasons for considering a genetic test: › A patient or his/her child(ren) have symptoms of a disorder and you want to facilitate a diagnosis or find a biological cause responsible for the disease. › A patient is at risk of developing this condition during lifetime. › A genetic condition runs in the family or the patient belongs to a group or population in which there is an increased risk of a specific genetic condition and he/she want to know whether they are at risk or might pass this condition on to their child(ren). 4 Chapter 2: What is a gene? / How do genes work? Each person has the same set of genes – more than 20,000 in total. These genes contain the information needed to make us who we are, using a kind of writing that describes how things should function. The vast majority of genetic information is identical in all humans, and the differences between people come from slight variations in the genes. Our bodies contain more than 50 trillion cells, and nearly every type of cell has a nucleus with our genes inside. Genes are made of DNA, and DNA is ’packaged’ in the so-called chromosomes, which we can see inside the nucleus with a microscope. Cell Chromosome DNA Fig. 1*: The genetic code of each person is inside the nucleus and organized into ‘blobs’ of DNA called chromosomes. Humans inherit 23 chromosomes from the mother and 23 from the father – so we have 23 pairs of chromosomes (or 46 chromosomes in total). One of these pairs decides what sex we are – male or female – so these are called the sex chromosomes: X and Y. Females inherit one X from each parent, while males get one X from the mother and one Y from the father. The other 22 pairs of chromosomes are exactly the same in males and females and are called the autosomal chromosomes. 5 DNA are very large molecules composed of four types of units - the deoxyribonucleotides. These four types of nucleotides, called Adenine, Thymine, Cytosine, and Guanine, are represented by the four letters in the DNA alphabet - A, T, C and G. The deoxyribonucleotides are attached to each other to form a strand. This strand is unstable and thus, to make DNA stable, the strands pair together and twist a bit, forming the familiar spiral of a DNA helix. When strands pair together, ‘A’ always pairs with ‘T’, and ‘G’ always pairs with ‘C’. Fig. 2.1*: Selected parts of DNA Fig. 2.2*: Nucleotides in detail: molecules are designated Adenine (A), Thymine (T), as genes Cytosine (C) and Guanine (G) DNA alphabet We can picture our genome, meaning the collection of all our genes, as a library with several books that represent the chromosomes. Each book (chromosome) has a certain number of pages (genes) filled with letters (nucleotides) that are arranged in sentences (exons and introns). We can only interpret a certain part of the sentences, the exons. Other parts, the introns, cannot yet be interpreted at this time. Every page, provides instructions for the synthesis of a specific protein in our body. 6 Genes make proteins Cells use genes to make proteins - Proteins have many different Once the mRNA reaches the roles, they build muscles, skin, bones, and all organs, they organize ribosome, it is ‘translated’ into cells’ shape and structure, digest nutrients, transport information, and other functions. The sum of our genetic information with proteins. the resulting proteins interact with the environment and all this together makes up all our characteristics, including color, height, The ribosome reads the mRNA, personality, weight and also predisposition to diseases. whereas the genetic ‘words’ are Proteins are composed of amino acids and they are made inside always made up of 3 letters. our cells in small ‘factories’ called ribosomes. Ribosomes receive information about the protein from genes through a messenger Each group of 3 letters/nucleo- called RNA. This messenger RNA (or mRNA for short) is like a tides in a row is called a codon. copy of the gene, which can travel outside the nucleus to reach the ribosome (genes can never leave the safety of the nucleus). Just like DNA, RNA is composed of nucleotides, but RNA is single Each codon codes for a specific stranded. It reflects most but not all of the information of the amino acid, which is added to gene. This mRNA includes only exons of the genes, and not the build the protein step by step. introns. Fig. 3*: Molecules of messenger RNA (mRNA) are transcribed from genes (DNA molecules) and then they are transported from the nucleus to ribosomes and present the template for synthesis of a protein. Proteins are made by incorporation of amino acids, one by one, according to the codons in the mRNA molecule. 77 Chapter 3: How are genes linked to a disease? Some genetic diseases are Many diseases are called genetic diseases. They are caused by passed on from a patient‘s abnormalities in genes or chromosomes. Most genetic disorders are quite rare, and many conditions are present from before parents. Some develop over birth. Also, a genetic disease may or may not be a heritable time. disorder. At the moment, about 6,000 Some genetic diseases are passed down from the parents’ genes, but others are frequently or always caused by new single-gene disorders are changes to the DNA. In other instances, the same disease, e.g. known of. some forms of cancer, may arise due to an inherited genetic condition, in new mutations or entirely due to enviromental or At CENTOGENE it is possible other non genetic causes. to test for all of them. So far, about 6,000 known single-gene (or monogenic) disorders are known, and we test for all of them. As their name ‘monogenic’ suggests, these diseases are caused by events in one gene, which radically changes its function, thus leading to a disorder. Such unfavorable changes in the genetic material are called pathogenic variants and more colloquial ‘mutations’. In contrast, many common diseases such as heart attack or diabetes are polygenic disorders and are caused by variants in several genes, frequently in combination with environmental factors. In these cases we do not use the term ‘mutation’. The changes in genes that can lead to such common disorders may have, in an other setting, advantages. Only specific combinations of genes and environment lead to the disease. 8 Chapter 4: How does a mutation in a gene trigger a disease? If we use our ‘book and pages’ example where genes are pages, then it’s easy to imagine how ‘DNA letters’ could be accidentally switched with another letter.