1) Genetic Mutation Types of DNA Mutations and Their Impact Class of Mutation Type of Mutation Description

Point mutation

Substitution

Insertion

Deletion

Chromosomal mutation

Inversion

Deletion

Duplication

Translocation

One base is incorrectly added during replication and replaces the pair in the corresponding position on the complementary strand One or more extra One form of betanucleotides are thalassemia, inserted into Myotonic Dystrophy replicating DNA, often resulting in a frameshift One or more Cystic fibrosis nucleotides is "skipped" during replication or otherwise excised, often resulting in a frameshift One region of a Opitz-Kaveggia chromosome is syndrome flipped and reinserted A region of a Cri du chat syndrome chromosome is lost, resulting in the absence of all the genes in that area A region of a Bardet-Biedl chromosome is syndrome repeated, resulting in an increase in dosage from the genes in that region A region from one Chronic myeloid chromosome is leukaemia aberrantly attached to another chromosome The number of tandem copies of a locus is increased Some breast cancers

Human Disease(s) Linked to This Mutation Sickle-cell anemia

Copy number variation

Gene amplification

Expanding trinucleotide repeat

The normal number of repeated trinucleotide sequences is expanded

Fragile X syndrome, Huntington's disease

A. SUBSTITUTION: Sickle Cell Anemia

Sickle cell anemia is physical condition wherein the blood is deprived or healthy RBCs or Red Blood Cells which carries required amount of oxygen throughout your body. Hence, you body organs does not receive required amount of oxygenated blood. This condition is an inherited form of anemia. Usually RBCs in the blood are round in shape and flexible. They move flawlessly through blood carrying vessels. Under prevalence of sickle cell anemia these red blood cells becomes sticky as well as rigid and coverts into sickle shaped cells or more simply a crescent moon shape. The irregularity in the shape and stickiness may cause obstruction in the blood flow to different parts of the body which may also cause oxygen deprivation. The affected individual may also suffer from pain. However, there are treatments that may help in getting some relieve from the pain as well as prevent further aggravation and problems associate with sickle cell anemia. Causes of sickle cell anemia: Sickle cell anemia results out of gene mutation which causes your body to produce hemoglobin. This is a compound rich in iron and imparts red color to the blood. Hemoglobin enables RBCs to carry oxygen from lungs to other parts of the body. In case of prevalence of this disease the anomalous hemoglobin makes the RBC rigid, abnormal shaped and sticky. This condition can be genetic which can pass on from generations in autosomal recessive inheritance. Autosomal inheritance means that both mother as well as father should pass on defective gene for the child to be affected with the condition.

Treatments for sickle cell anemia:Transplant of bone marrow is the only potential complete cure from sickle cell anemia. However, it is difficult to find a donor; moreover the procedure has serious risk involved in it, even death. Hence, most treatment techniques for sickle cell anemia are focused on curing the symptoms and avoiding serious consequences. People with sickle cell anemia are supposed to visit their doctor regularly in order to keep a check on the RBC count. Some treatment techniques include:

Medications including prescription of antibiotics, pail reliever, hydroxyurea etc Evaluating risk of stroke Developing immunity to infections Transfusion of blood Oxygen supplements Transplant of stem cell Treating complications etc

There are some experimental treatments such as gene therapy, increasing nitric oxide level or medications to increase fetal hemoglobin production. However, it is better deal the condition with experts help.

B. INSERTION: Congenital Myotonic Dystrophy

Background Congenital myotonic dystrophy is a serious form myotonic dystrophy (DM1), which usually affects adults. Congenital means it is present from birth, myotonic means stiffness of the muscles and dystrophy means wasting and weakening. Inheritance patterns DM1 affects and can be passed on by both sexes and each of an affected person's children has a 50 per cent chance of inheriting DM1. However, it is usual for a baby with congenital myotonic dystrophy to inherit it from its mother rather than from its father. By the time a baby with congenital myotonic dystrophy is born in a family, the myotonic dystrophy will often have affected people in at least two of the previous generations. As DM1 is very variable, it might not have been recognised in previous generations. So the baby with congenital myotonic dystrophy might be the first affected person in the family to be diagnosed. What are the causes? It is an inherited (genetic) condition, which is caused by a change (mutation) in the genetic material (DNA) that is passed on from one generation to the next. In DM1 this mutation is not stable and tends to increase in size and severity with each generation. In congenital myotonic dystrophy the mutation can be up to 40 times bigger than the mutation in the most mildly affected adult member of the family. How is it treated? There is no cure but much can be done to help. After intensive support following birth, children with congenital myotonic dystrophy may need extra educational help at playgroup and school. Physiotherapists, occupational and speech and language therapists can also help. Ideally affected children should attend a neuromuscular clinic, which can make sure each child gets the help they need.

C. DELETION: Cystic Fibrosis

Cystic fibrosis facts*

Cystic fibrosis (CF) is an inherited disease that affects the secretory glands, including the mucus and sweat glands. Cystic fibrosis mostly affects the lungs, pancreas, liver, intestines, sinuses, and sex organs. CF is due to a mutation in the CF gene on chromosome 7. The CF gene encodes a protein known as the cystic fibrosis transmembrane regulator (CFTR). The abnormal CFTR protein in patients with CF leads to disruption of chloride channels on the cells. CF is characterized by the production of abnormal mucus that is excessively thick and sticky. The abnormal mucus leads to blockages within the lungs and airways. This leads to repeated, serious lung infections that can damage the lungs. Lung function often starts to decline in early childhood in people who have cystic fibrosis. Over time, permanent damage to the lungs can cause severe breathing problems. The thick, sticky mucus also can block tubes, or ducts, in the pancreas. As a result, the digestive enzymes from the pancreas can't reach the small intestine, causing impaired absorption of fats and proteins. This can cause vitamin deficiency and malnutrition. Due to the defect in chloride channels, CF fibrosis also causes the sweat to become very salty. Every person inherits two CFTR genes -- one from each parent. CF is inherited in an autosomal recessive manner; children who inherit a faulty gene from each parent will have cystic fibrosis. Children who inherit one faulty gene and one normal gene will be "CF carriers." Cystic fibrosis carriers usually have no symptoms of cystic fibrosis, but they can pass the faulty gene on to their children

Who is at risk for cystic fibrosis?

Cystic fibrosis (CF) affects both males and females and people from all racial and ethnic groups. However, the disease is most common among Caucasians of Northern European descent. CF also is common among Latinos and American Indians, especially the Pueblo and Zuni. The disease is less common among African Americans and Asian Americans. More than 10 million Americans are carriers of a faulty CF gene. Many of them don't know that they're CF carriers.

How is cystic fibrosis treated? Cystic fibrosis (CF) has no cure. However, treatments have greatly improved in recent years. The goals of CF treatment include:

Preventing and controlling lung infections Loosening and removing thick, sticky mucus from the lungs Preventing or treating blockages in the intestines Providing enough nutrition

Preventing dehydration (a lack of fluid in the body)

D. INVERSION: Opitz Kaveggia Syndrome

Background FG syndrome was first described by Professor Opitz and Dr Kaveggia in 1974. It became known as FG syndrome according to the system used at that time by Dr Opitz, who preferred to name conditions with the initials of the names of the first presenting families, rather than eponymously, after the name of the doctors who wrote the first medical reports. Nevertheless, the Opitz-Kaveggia name is now preferred by some doctors and the name Keller syndrome is a name that is seldom used. Inheritance patterns X-chromosome linked but it is likely that there is more than one FG syndrome gene on the Xchromosome. What are the causes? Opitz-Kaveggia/ FG syndrome is sometimes due to a mutation in a gene called MED12 that is located on the X chromosome. Female carriers are generally unaffected but a few carriers may have some symptoms or signs. Because MED12 gene mutations have been identified recently, DNA-based postnatal and prenatal diagnosis may be possible in the future in some but not all families.

How is it treated? Multidisciplinary treatments and support are required for the child who has complex or severe learning disabilities and surgical treatment is required to correct an imperforate or narrowed anus.

E. CHROMOSOMAL DELETION: Cri Du Chat Syndrome

Cri du Chat syndrome is a caused by a deletion of a small piece of chromosome 5 and is estimated to occur in around 1 in 15,000 to 50,000 babies born. Infants with this condition often have a high-pitched cry that sounds like a cat. The condition is characterised by intellectual disability and delayed development, small head size, low birth weight and low muscle tone in infancy. Affected individuals also have distinctive facial features and some children with Cri du Chat syndrome are born with a heart defect Inheritance patterns Most cases of Cri du Chat syndrome are not inherited. The deletion occurs sporadically in these individuals. About 10 percent of people with Cri du Chat syndrome inherit the chromosome abnormality from an unaffected parent. In these cases, the parent carries a chromosomal rearrangement called a balanced translocation, in which no genetic material is gained or lost. However, this can result in the birth of a baby with an unbalanced chromosome pattern, including the chromosome change responsible for Cri du chat syndrome. Families affected by the condition should seek genetic advice.

What are the causes? Cri du Chat syndrome is caused by a deletion of the end of the short (p) arm of chromosome 5. The signs and symptoms of the syndrome are probably related to the loss of multiple genes.

How is it treated? There is no cure for Cri du Chat syndrome. Growth, nutrition and developmental progress should be monitored. The routine schedule of childhood immunisation is advised to reduce likelihood of infections. Early physiotherapy, speech and language therapy and occupational therapy are recommended to improve learning, coordination and movement. Corrective surgery may be required for heart defects.

F. DUPLICATION: Bardet-Biedl Syndrome Also known as: Laurence-Moon-Bardet-Biedl syndrome, Laurence-Moon-Biedl syndrome

Background Bardet-Biedl syndrome (BBS) is a rare inherited condition. It is characterised by visual difficulties, obesity, additional fingers and/or toes, undeveloped genitals, learning difficulty (see entry Learning Disability) and renal (kidney) problems. BBS occurs more frequently in populations where there is marriage between family members and children born as a result of that (consanguineous marriage). It is also more common in historically isolated communities, such as Newfoundland. Inheritance patterns For the majority of cases, inheritance is autosomal recessive (two mutations required to manifest the

disease). Although in a few cases, more than two mutations in two BBS genes may be required to display symptoms of the condition (this is known as 'triallelic inheritance'). What are the causes? Mutations in at least 16 genes are known to be associated with BBS. Not all people with BBS have mutations in these known genes, so more remain to be discovered. It is now known that these mutations result in abnormal cilia function. These are finger-like projections that are important for cells to sense their surrounding environment and communicate with one another.

How is it treated? There is no cure for BBS. Treatment aims to reduce the symptoms experienced by a person with BBS. Regular eye check-ups by an ophthalmologist will highlight any existing problems. Visual aids and educational programmes can assist with visual difficulties. Obesity is managed with diet, exercise and behavioural therapies. Hypercholesterolemia (high cholesterol) and diabetes mellitus may be treated with the appropriate medications and changes to diet. Early intervention, special education provision and speech and language therapy can help with learning. In cases of severe renal abnormality, renal transplantation may be required. Genital abnormalities, for example hypospadias, may be surgically corrected. Hormone replacement therapy can be initiated for hypogonadism (where sex glands produce little or no sex hormones). Cardiac abnormalities need to be monitored and may be corrected surgically. Surgery to remove extra digits prevents difficulties walking and balancing and poor fitting of footwear.

G. TRANSLOCATION: Chronic myeloid leukaemia CML is sometimes called chronic myelogenous leukaemia, chronic granulocytic leukaemia, or chronic myelocytic leukaemia. CML develops due to a problem with a stem cell in the bone marrow, which becomes abnormal. The abnormal stem cell multiplies and the cells that are made from the abnormal stem cells mature and develop into near-normal white cells - mainly neutrophils, basophils and eosinophils (collectively called granulocytes). Large numbers of these cells are made in the bone marrow and spill into the bloodstream. (In contrast, in acute myeloid leukaemia (AML) the abnormal cells that are made in large quantities are immature abnormal 'blast cells'. This is quite a different disease to CML. (The separate Acute myeloid leukaemia leaflet provides further details.) Typically, CML develops and progresses slowly - over months or years, even without treatment. Who gets chronic myeloid leukaemia?

CML is the rarest of the four main types of leukaemia. There are around 750 cases in the UK each year. It occurs mainly in adults and becomes more common with increasing age. The average age at diagnosis is 50 years. It is very rare in children. It is more common in men than in women. What causes chronic myeloid leukaemia? A leukaemia is thought to start first from one abnormal cell. What seems to happen is that certain vital genes which control how the cell divides, multiplies and dies, are damaged or altered. This makes the cell abnormal. If the abnormal cell survives it may multiply, produce many abnormal cells and develop into a leukaemia. In the case of CML, it is a blood stem cell which is first damaged and affected. In most cases of CML, the reason why a stem cell becomes abnormal is not known. Research has shown that exposure to electromagnetic fields and living near high-voltage electricity cables do not increase your risk of developing chronic myeloid leukaemia. There are certain 'risk factors' which increase the chance that leukaemia will develop, but these only account for a small number of cases. Risk factors known for CML are high-dose radiation (for example, previous radiotherapy for another condition) and exposure to the chemical benzene. CML is not an inherited condition and does not run in families. What is the treatment for chronic myeloid leukaemia? Treatment for the initial chronic phase The aim of treatment is to control the disease process, to ease any symptoms, and to prevent (or delay) the progression into the further two stages.

Imatinib (Glivec) tablets. This medicine is known as a 'tyrosine kinase inhibitor'. The chemical tyrosine kinase is made by the abnormal gene BCR-ABL on the 'Philadelphia' chromosome described above. This is thought to be responsible for the abnormal growth and behaviour of the abnormal cells. Imatinib works by blocking the effect of tyrosine kinase. Interferon alfa. This medicine has been shown to help the immune system to combat leukaemia cells. Interferon alfa is sometimes given, although now imatinib is given much more often. Chemotherapy tablets. Chemotherapy is a treatment which uses anti-cancer medicines to kill cancer cells, or to stop them from multiplying. (See separate leaflet called Chemotherapy with cytotoxic medicines for more detail.) Another medicine called arabinoside is also sometimes used to treat CML. A stem cell transplant (SCT) - sometimes called a bone marrow transplant - is sometimes an option in younger patients with CML. This may be curative. (See separate leaflet called Stem cell transplant for further detail.)

Treatment for transformation and blast phases Treatment is usually with more intensive chemotherapy than is given for the chronic phase. This usually means a combination of chemotherapy medicines given directly into a vein (intravenous chemotherapy). Imatinib (Glivec) tablets may also be used.

Supportive treatment Other treatments include antibiotics or antifungal medicines if infection occurs and blood and platelet transfusions to improve low levels of red blood cells and/or platelets.

H. GENE AMPLIFICATION: Breast Cancer

Breast cancer is one of the most common cancers. Around one in nine women develop breast cancer at some stage in their lifeMost develop in women over the age of 50 but younger women are sometimes affected. Breast cancer can also develop in men, although this is rare. Breast cancer develops from a cancerous cell which develops in the lining of a duct or lobule in one of the breasts. There are some subtypes of breast cancer which are important to know, as the treatment and outlook (prognosis) vary depending on the exact type of the cancer. The following gives a rough idea of the main subtypes. Your specialist will be able to give you more details as to the exact subtype of breast cancer that you have. What causes breast cancer?

A cancerous tumour starts from one abnormal cell. The exact reason why a cell becomes cancerous is unclear. It is thought that something damages or alters certain genes in the cell. This makes the cell abnormal and multiply out of control. Risk factors Although breast cancer can develop for no apparent reason, there are certain risk factors which increase the chance that breast cancer will develop. These include:

Age. The risk of developing breast cancer roughly doubles for every 10 years of age. Most cases develop in women over the age of 50. Where you live. The rate of breast cancer varies between countries. This may reflect genetic or environmental factors. Family history. This means if you have close relatives who have or have had breast cancer. In particular, if they were aged under 50 when diagnosed. If you have had a previous breast cancer. Being childless, or if you had your first child after the age of thirty. Not having breast-fed your children. Early age of starting periods. Chest being exposed to radiation. Having a menopause over the age of 55. Taking continuous combined hormone replacement therapy (HRT) for several years (in women over 50 years), leading to a slightly increased risk. Excess alcohol.

What is the treatment for breast cancer? Treatment options which may be considered include surgery, chemotherapy, radiotherapy and hormone treatment. Often a combination of two or more of these treatments is used. The treatments used depend on:

The cancer itself - its size and stage (whether it has spread), the grade of the cancer cells, and whether it is hormone responsive or contains HER2 receptors; AND The woman with the cancer - your age, whether or not you have had your menopause, your general health and personal preferences for treatment.

Surgery The types of operation which may be considered are:

Breast-conserving surgery. This is often an option if the tumour is not too big. A lumpectomy (or wide local excision) is one type of operation where just the tumour and some surrounding breast

tissue are removed. It is usual to have radiotherapy following this operation. This aims to kill any cancer cells which may have been left in the breast tissue. Removal of the affected breast (mastectomy). This may be necessary if there is a large tumour or a tumour in the middle of the breast. It is often possible to have breast reconstructive surgery to create a new breast following a mastectomy. This can often be done at the same time as the mastectomy, although it can also be done months or years later. There now are many different types of reconstruction operations available. A sentinel lymph node biopsy may be performed. This is a way of assessing if the main lymph nodes draining the breast contain cancer. If they are clear then the remaining lymph nodes in the armpit will not need to be removed. If it is not possible to do this, one or more of the lymph nodes in the armpit may be removed. This helps to stage the disease accurately and to guide the specialist as to what treatment to advise following surgery.

Radiotherapy Radiotherapy is a treatment which uses high-energy beams of radiation which are focused on cancerous tissue. This kills cancer cells, or stops cancer cells from multiplying. See separate leaflet called Radiotherapy for more details. For breast cancer, radiotherapy is mainly used in addition to surgery. For example, if you have breastconserving surgery it is usual to have radiotherapy to the affected breast after the operation. This aims to prevent breast cancer returning in the same breast. When radiotherapy is used in addition to surgery it is called adjuvant radiotherapy. Hormone treatments Some types of breast cancer are affected by the female hormones oestrogen and progesterone. These hormones stimulate the cancer cells to divide and multiply. Most oestrogen and progesterone are made by the ovaries. Treatments which reduce the level of these hormones, or prevent them from working, are commonly used in people with breast cancer.

Chemotherapy Chemotherapy is a treatment of cancer by using anti-cancer medicines which kill cancer cells, or stop them from multiplying. This aims to kill any cancer cells which may have spread from the main tumour site. Chemotherapy is sometimes given before surgery to shrink a tumour so that surgery may have a better chance of success and also a smaller operation may be performed. This is known as neoadjuvant chemotherapy. The type of chemotherapy given may depend on the type of cancer. New gene tests are being developed to help doctors decide which women will benefit the most from chemotherapy. Chemotherapy may also be used for some women to treat breast cancer which has spread to other areas of the body.

Trastuzumab (Herceptin) Trastuzumab (also known as Herceptin) is a treatment that may be given to women who have a large number of HER2 receptors in their cancer. It is a type of medicine called a monoclonal antibody. It works by attaching to HER2 receptors on the surface of breast cancer cells, thereby stopping the cancer cells from dividing and growing.

I.

EXPANDING: Huntington's Disease Facts

Is Huntington's disease genetic? Huntington's disease (HD) is an inherited disease that causes certain nerve cells in the brain to waste away. People are born with the defective gene, but symptoms usually don't appear until middle age. Early symptoms of HD may include uncontrolled movements, clumsiness or balance problems. Later, HD can take away the ability to walk, talk or swallow. Some people stop recognizing family members. Others are aware of their environment and are able to express emotions. There is no cure. Medicines can help manage some of the symptoms, but cannot slow down or stop the disease. What causes Huntington's disease? HD results from genetically programmed degeneration of nerve cells, called neurons,* in certain areas of the brain. This degeneration causes uncontrolled movements, loss of intellectual faculties, and emotional disturbance. Specifically affected are cells of the basal ganglia, structures deep within the brain that have many important functions, including coordinating movement. Within the basal ganglia, HD especially targets neurons of the striatum, particularly those in the caudate nuclei and the pallidum. Also affected is the brain's outer surface, or cortex, which controls thought, perception, and memory. How is Huntington's disease inherited?

HD is found in every country of the world. It is a familial disease, passed from parent to child through a mutation or misspelling in the normal gene. A single abnormal gene, the basic biological unit of heredity, produces HD. Genes are composed of deoxyribonucleic acid (DNA), a molecule shaped like a spiral ladder. Each rung of this ladder is composed of two paired chemicals called bases. There are four types of bases--adenine, thymine, cytosine, and guanine--each abbreviated by the first letter of its name: A, T, C, and G. Certain bases always "pair" together, and different combinations of base pairs join to form coded messages. A gene is a long string of this DNA in various combinations of A, T, C, and G. These unique combinations determine the gene's function, much like letters join together to form words. Each person has about 30,000 genes--a billion base pairs of DNA or bits of information repeated in the nuclei of human cells-which determine individual characteristics or traits. Genes are arranged in precise locations along 23 rod-like pairs of chromosomes. One chromosome from each pair comes from an individual's mother, the other from the father. Each half of a chromosome pair is similar to the other, except for one pair, which determines the sex of the individual. This pair has two X chromosomes in females and one X and one Y chromosome in males. The gene that produces HD lies on chromosome 4, one of the 22 non-sex-linked, or "autosomal," pairs of chromosomes, placing men and women at equal risk of acquiring the disease. Treatment Physicians may prescribe a number of medications to help control emotional and movement problems associated with HD. It is important to remember however, that while medicines may help keep these clinical symptoms under control, there is no treatment to stop or reverse the course of the disease. In August 2008 the U.S. Food and Drug Administration approved tetrabenazine to treat Huntington's chorea, making it the first drug approved for use in the United States to treat the disease. Antipsychotic drugs, such as haloperidol, or other drugs, such as clonazepam, may help to alleviate choreic movements and may also be used to help control hallucinations, delusions, and violent outbursts. Antipsychotic drugs, however, are not prescribed for another form of muscle contraction associated with HD, called dystonia, and may in fact worsen the condition, causing stiffness and rigidity. These medications may also have severe side effects, including sedation, and for that reason should be used in the lowest possible doses. For depression, physicians may prescribe fluoxetine, sertraline, nortriptyline, or other compounds. Tranquilizers can help control anxiety and lithium may be prescribed to combat pathological excitement and severe mood swings. Medications may also be needed to treat the severe obsessive-compulsive rituals of some individuals with HD.