Genetics Genetics is the study of genes Genes; sequences of DNA. Genes are packaged together as chromosomes and are passed from parent to offspring. It is our genes that determine who we are and how we function at the most basic cellular level. Sometimes mistakes (mutations) cause significant disability or death, or benefits. Genes; 25,000 genes.

Chromosomes Chromosomes are made up of molecules of DNA, complexed with proteins called histones. Chromosomes together carry the genetic blueprint of an individual. All human somatic (body) cells contain 23 pairs of chromosomes, one pair from each parent, for a total of 46 chromosomes. Each human sex cell, an egg or a sperm, contains 23 unpaired chromosomes.

Gene Activation Although each somatic cell contains the same 23 pairs of chromosomes, only certain genes are activated in any given cell; therefore, only certain proteins or enzymes are produced by that cell. Which genes are activated in which cell is determined during embryologic development and throughout life by circulating growth factors, hormones, and chemical produced by a given cell and its neighboring cells.

Cellular Reproduction All cells reproduce during embryonic development, which allows for growth of the embryo and differentiation (specialization) of the cells making up tissues and organs. After birth and throughout adulthood, many cells continue to reproduce. Cells that reproduce throughout a lifetime include cells of the bone marrow, skin, and digestive tract. Liver and kidney cells reproduce when replacement of lost or destroyed cells is required. Special cells, called stem cells, are capable of reproducing indefinitely. Other cells, including nerve, skeletal muscle, and cardiac muscle cells, do not reproduce significantly after the first few months following birth.

Meiosis Meiosis is the process during which germ cells of the ovary (primary oocytes) or testicle (primary spermatocytes) give rise to mature eggs or sperm . Meiosis involves DNA replication in the germ cell, followed by two cell divisions rather than one, which results in four daughter cells, each with 23 (unpaired) chromosomes. In males, all four daughter cells are viable and continue to differentiate into mature sperm. In females, only one viable daughter cell (egg) is formed; the other three cells become nonfunctional polar bodies. During fertilization, genetic information contained in the 23 chromosomes of the egg joins with genetic information contained in the 23 chromosomes of the sperm. This results in an embryo with 46 total chromosomes (two pairs of 23).

An interesting phenomenon occurs during DNA replication in the first meiotic stage. At this time, pieces of DNA may shift between the matched chromosome pairs, in a process called crossing-over. Crossing-over increases the genetic variability of offspring, and is one reason why siblings within a family may vary considerably in genotype and phenotype.

Genotype and Phenotype Precise genetic information carried in the chromosomes of the offspring is termed the genotype. Physical representation of genetic information (tall or short, dark or light) is called the phenotype. Genetic Testing (cytogenetics) Genetic testing, called cytogenetics, involves looking at the overall structure and number of the chromosomes. Genetic testing can be performed on any cell of the body, but in children and adults it is usually done by withdrawing white blood cells in a venous blood sample. For prenatal testing, fetal cells may be gathered during the processes of amniocentesis, or during chorionic villi sampling.

Amniocentesis Amniocentesis is performed by inserting a needle through the abdominal wall of a pregnant woman into the amniotic sac that surrounds the fetus. Amniotic fluid, into which fetal cells have been shed, is withdrawn. Chromosomes present in the fluid sample are then cultured and fixed, and their number and shape are analyzed for genetic integrity. This test is usually done at approximately 16 weeks' gestation and results are available in approximately 2 weeks.

Chorionic Villi Sampling Chorionic villi sampling involves gathering cells of the chorion , the outer border of the fetal membranes. The cells are gathered by placing a needle through the woman's lower abdomen or cervix between 8 and 12 weeks of pregnancy. The cells do not need to be cultured, so the chromosomal analysis is available in approximately 1 to 2 days..

Pathophysiologic Concepts Mutation: A mutation is an error in the DNA sequence. Mutations can occur spontaneously, or after the exposure of a cell to radiation, certain chemicals, or various viral agents. Most mutations will be identified and repaired by enzymes working in the cell. If a mutation is not identified or repaired, or if the cell does not undergo programmed death, that mutation will be passed on in all subsequent cell divisions. Mutations may result in a cell becoming cancerous. Mutations in the gametes (the egg or sperm) may lead to congenital defects in an offspring

Mutation results Single gene disorder Chromosomal disorder Multifactorial disorders

Single gene disorder Inherited in clearly identifiable patern Mostly caused by autosomal defect Autosomal dominant Autosomal recessive Six linked disorders

Autosomal dominant Male & female equally affected One parent is usually affected If one parent is affected, 50% of offspring is being affected All offspring affected, if both parents are affected

Autosomal recessive inheritance • Male and female are affected equally. • If both parents are unaffected but heterozygous for the trait (carriers), each of their offspring has a one in four chance of being affected. • If both parents are affected, all of their offspring will be affected. • If one parent is affected and the other is not a carrier, all of the parents’ offspring will be unaffected but will carry the altered gene. • If one parent is affected and the other is a carrier, each of the offspring will have a chance 50% of being affected and 50%of being a carrier

Sex-linked inheritance If the two parents are unaffected , each with an altered recessive gene (a) on an autosome. Each offspring will have 25% chance of being affected and 50% chance of being a carrier. Females: homozygous for a disease allele, homozygous for a normal allele, or heterozygous. Males: a single X-linked recessive gene can cause disease

Males are more commonly affected by X- linked recessive diseases than females.

Chromosomal Breaks During mitosis and meiosis, pieces of chromosomes may break off, be added inappropriately to other chromosomes, or be deleted entirely. If deletions or additions occur during meiosis in the egg or sperm, a congenital defect or death of the embryo may result. If deletions or additions of chromosomes occur during mitosis, the affected cell line will usually die out.

Errors in Chromosome Number Any change from the normal human chromosome number of 46 chromosomes is called aneuploidy. An aneuploidy in which there are only 45 chromosomes is called a monosomy. An aneuploidy in which there are 47 chromosomes is called a trisomy. Having more than 47 chromosomes is possible but rare.

Monosomy If any chromosome other than the X or Y is lost, the embryo will spontaneously abort. However, the loss of one of the sex chromosomes may result in a viable offspring. Usually the Y chromosome is lost, resulting in 44 somatic chromosomes and one sex chromosome, for a total of 45 chromosomes (often expressed 45, X/O, to indicate no Y chromosome). The resulting disorder is called Turner's syndrome. Monosomy of any chromosome is a major cause of spontaneous abortion in the first trimester

Trisomy A trisomy occurs when somatic or sex chromosomes do not separate properly during meiosis. This is called non- disjunction. Most trisomies cause spontaneous abortion of the embryo, but rarely live births may result. Trisomies that may result in live births include trisomies of the sex chromosomes and trisomies of chromosomes 8, 13, 18, and 21. Trisomy 21 is called Down syndrome

Deletions Cri du chat, 5p-

Translocation Robertsonian translocation Reciprocal translocation

Translocation Chromosome break and rejoin in an abnormal arrangement Balanced, reserve genetic material Imbalanced, visible abnormalities (partial monosomies / trisomies)

Multifactorial disorders Genetic & envirpalate, onmental factors (cleftlip/palate, spina bifida) maternal age • use of chemicals • maternal infections during pregnancy or existing diseases in the mother • maternal or paternal exposure to radiation • maternal nutritional factors • general maternal or paternal health • other factors, including high altitude, maternal-fetal blood incompatibility, maternal smoking, and poor-quality prenatal care.

Genetic disorders • multifactorial disorders (cleft lip and cleft palate) • six single-gene disorders (cystic fibrosis, hemophilia, Marfan syndrome, phenylketonuria [PKU], sickle cell anemia) • a chromosomal disorder (Down syndrome).

congenital Defects Also called birth defects, include genotypic and phenotypic errors occurring during embryogenesis and fetal development. Some congenital defects, such as cleft palate and limb abnormalities, may be apparent at birth, whereas other congenital defects, such as an abnormal or absent kidney and certain types of heart disease, may not be recognized immediately. Congenital defects may result from genetic mistakes made during meiosis of the sperm or egg, or from environmental insults experienced by the fetus during gestation.

Terminology hereditary = derived from parents familial = transmitted in the gametes through generations congenital = present at birth (not always genetically determined - e.g. congenital syphilis, toxoplasmosis) ! not all genetical diseases are congenital - e.g. Huntington disease - 3rd to 4th decade of life

Teratogens Alcohol TORCH Radiation

Down syndrome Down syndrome produces mental retardation, characteristic facial features, and distinctive physical abnormalities. It’s also associated with heart defects and other congenital disorders. Life expectancy and quality of life for patients with Down syndrome have increased significantly because of improved treatment of related complications and better developmental education programs.

Clinical Manifestations - Variable levels of mental retardation. - Upward slanting of the eyes. - Short hands that have only one crease on the palm (a simian crease) - low-set ears. - Short stature. - Protruding tongue.

Clinical Features of Down Syndrome Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 18 July 2005 09:03 PM) © 2005 Elsevier

You do not have to see many trisomy-21 patients until you can recognize them very quickly and easily. There is NO way you can learn from a textbook how to recognize these patients quickly. If you KNOW one or are RELATED to one, or loved one, you NEVER fail to recognize the face without having to describe the details, i.e., pattern-recognition. MEMORIZE THIS PIC!

Complications Spontaneously abortion of about 20% between 10 and 16 weeks' gestation. Congenital heart or other organ defects are frequent . Risk of childhood leukemia is increased in children with Down syndrome. Premature senile dementia, similar to Alzheimer’s disease Acute and chronic infections, diabetes mellitus, and thyroid disorders.

Turner syndrome Is a monosomy of the sex chromosomes. Infants born with Turner syndrome have 45 chromosomes: 22 pairs of somatic chromosomes and 1 sex chromosome, usually the X (45, X/O). This disorder is common in spontaneously aborted fetuses. Females with Turner syndrome lack ovaries.

Clinical Manifestations Clinical manifestations may be nonexistent, mild, or moderate and include: Short stature and webbing of the neck. Lack of secondary sex characteristics and amenorrhea . Complications -Congenital heart defects may accompany the sex chromosome monosomy. - Increased risk of childhood bone fractures and adult osteoporosis due to lack of estrogen. -Some individuals may demonstrate signs of learning disability.

  Klinefelter Syndrome Klinefelter syndrome is a polysomic disorder characterized by one or more extra X chromosomes in a genotypic male (47, X/X/Y; 47, X/X/X/Y).. Klinefelter syndrome may result from non-disjunction of the male or female X chromosome during the first meiotic division, at approximately equal rates in males and females. .

Clinical Manifestations Although the infant may appear normal at birth, he may show a decrease in male secondary sex characteristics during puberty. Gynecomastia (breast enlargement) and other female patterns of fat deposit. Infertility and sexual dysfunction. Tall stature in adult life because decreased levels of testosterone do not contribute to epiphyseal bone plate closure. Individuals may demonstrate reduced mental functioning, especially with increasing number of X chromosomes.

“STREAK” ovaries are the rule, neck webbing and cardiac structural abnormalities are also at the top of the list.

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