GENETICS and GENETIC DISORDERS GENETICS - the study of heredity, characteristics inherited by children from their parents - science

of potentials and deals with the transfer of biological transformation - study of the function and behavior of genes GREGOR MENDEL - an Austrian monk - Father of Genetics (1822 1884) - Conclusions from his experiments on crossbreeding plants with different characteristics led him to develop explanations for how traits are transmitted from generation to generation. Mendels theories form the foundation of modern genetics (MENDELS LAW) HEREDITY - process by which a particular trait, condition or defect is passed from parents to offspring - refers to the inherited characteristics of an individual, including traits such as height, eye color, and blood type GENES - Genes are bits of biochemical instructions found inside the cells of every organism from bacteria to humans - Fundamental unit of information storage in the cell - Individual units of heredity which are strung along chromosomes, which are threadlike structure in the nucleus of the cells - 2 major types: a. Structural are those DNA sequences that code for the specific amino acid sequences in CHON such as enzymes, hormones or structural protein b. Regulatory are segments of DNA involved in controlling which structural genes are expressed; functions are not clearly understood LOCUS ALLELE specific location occupied by each gene on a chromosome

two members of a gene pair, one inherited from each parent a. Homozygous Allele gene pair that are identical or code the exact same gene product Example: TT, tt

b. Heterozygous Allele gene pair that are different

Example: Tt GENOTYPE - to refer to the combination of genes that code for a trait PHENOTYPE - recognizable trait, physical or biochemical, which is associated with the specific genotype - describes the physical manifestation of that trait - 2 types of traits: a. DOMINANT TRAITS trait exerting its influence over the other; strong genes trait which is often present in parent/grandparent

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a dominant gene will always appear in an individual regardless of whether a gene is paired with another dominant or recessive gene b. RECESSIVE TRAITS hidden/weak genes a recessive gene must be complemented by another recessive gene in order for the character to become apparent in the person

CHROMOSOMES - threadlike structures in the nucleus of the cell that transmits genetic information *The DNA of each cell is packed into chromosomes within the nucleus. Total # of chromosomes: 46 chromosomes or 23 pairs of chromosomes 22 pairs autosomes 1 pair sex chromosomes XX female chromosomes XY male chromosomes **Chances of having a male or a female child in every pregnancy: X X X Y XX XY XX XY 2 XX (2:4) or 50% chance of giving birth to a female child 2 XY (2:4) or 50% chance of giving birth to a male child

**each chromosome contains thousands of genes and each gene occupies a specific position in the chromosomes. Both chromosomes of a given pair contain similar genes so that each gene is paired. If the two genes for a trait are: Identical HOMOZYGOUS (AA, aa) Different HETEROZYGOUS (Aa) INHERITANCE OF TRAITS Dominant Inheritance indicate that trait was present in a parent/grandparent trait transmitted by either sex to a child of either sex if one of the parent possesses the dominant gene, the chance of any child inheriting the gene is 50% a child who receives the gene expresses the trait

1. -

2. Recessive Inheritance - the defect occurs only in an individual whose pair of genes carry the defect - persons who have only one recessive gene for the disease does not exhibit the disease but only act as a carrier 3. Sex-linked Inheritance - carried from one sex and expressed by the other sex VARIATIONS ON DOMINANT RECESSIVE INHERITANCE 1. Incomplete Dominance - absence of the complete dominance and every genotype has a distinguishable phenotype - also called semi-dominance - ex: sickle cell anemia

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Alleles for: Sickle cell affected individual: Sickle Cell Carrier Individual: Normal/Unaffected Individual:

HbSHbS HbSHbA HbAHbA

2. Multi-allele Inheritance - have more than two alternative form - ex.: ABO blood typing Alleles for: Blood Type A: Blood Type B: Blood Type AB: Blood Type O: IA IA or IA Ii I I or IB Ii IA IB Ii Ii
B B

3. Polygenic Inheritance - inherited traits are not controlled by one gene but rather the combined effect of many genes - ex.: skin color Alleles for: Dark Skin Color: Intermediate Skin Color: Fair Skin Color: 4. AABBCC AaBbCc aabbcc

Sex-linked Genes located in either X or Y chromosome trait is affected by the set of offspring 3 types: a. completely sex-linked genes located in the X-chromosome ex.: Hemophilia Alleles for: Normal Female: XH XH Normal Male: XH Y H h Female Carrier of Hemophilia: X X Male with Hemophilia: Female with Hemophilia: Xh Xh

XhY

b. holandric genes - trait is located in the Y chromosome

ex.: hypertricosis

c. incompletely sex-linked genes located in either X or Y chromosome

ex.: enamel hypoplasia Example of Problem Solving: Problem: Mr. ABC, who is a carrier of sickle cell, is married Ms. XYZ who is also a carrier. On their scheduled genetic counseling session, they asked you the possibility of having children who are also affected with the said disorder. As a knowledgeable nurse, what would be your answer? Solution: HbS HbA HbS HbS HbS HbS HbA HbA HbS HbA HbA HbA
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Answer: Their children will have a 25% (1:4) chance of being affected with sickle cell (HbS HbS), 50% (2:4) chance of becoming carriers (HbS HbA) and 25% (1:4) chance that they will be unaffected or normal (HbA HbA). CLASSIFICATION OF GENETIC DISORDERS *GENETIC DISORDERS these are discrete events that affects gene expression in a group of cells related to each other by gene linkage; that are caused by an alteration in DNA sequences altering the synthesis of single gene product

A. SINGLE GENE DISORDER

disorder caused by a single defective or mutant gene which maybe present on an autosome or the X-chromosome and it may affect only one member on an autosomal gene pair or both members of the pair it follows the Mendelian Pattern of Inheritance, therefore, they are usually transmitted from one generation to another a. Autosomal Dominant Disorders A single mutant allele from an affected parent is transmitted to an offspring regardless of sex Points to Remember: the affected parent has 50% chance to transmit disorder to each offspring unaffected relatives of the parent or siblings of the offspring do not transmit the disorder in many conditions, the age of onset is delayed, signs and symptoms of the disorder do not appear until later in life Example Disease: Marfans Syndrome connective tissue disorder with abnormalities in skeletal, ocular, or cardiovascular system average age of death is 30 40 years old manifestations: i. Skeletal deformities long, thin body with exceptionally long extremities and long, tapering fingers (arachnodactyly or spider fingers) hyperextensible joints variety of spinal deformities just like kyphoscoliosis chest deformities like pectus excavatum (deeply depressed sternum) or pectus carinatum or pigeon chest (sternum project outward) ii. Ocular or Eye disorder bilateral dislocation of the lens myopia or nearsightedness predisposition to retinal detachment

iii.

Cardiovascular defect (This is the most threatening effect of MARFANS Syndrome) - Mitral valve prolapse - Progressive dilatation of the aortic valve ring - Weakness of the wall of the aorta and other arteries

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Dissection and rupture of aorta lead to premature death

b. Autosomal Recessive Disorders Manifested only when both members of the genes are affected Points to Remember: - both parents maybe unaffected but are carriers of the defective gene - affect both males and females - occurrence risk in each pregnancy: affected child: 1 in 4 or 25% carrier child: 2 in 4 or 50% normal or unaffected homozygous child: 1 in 4 or 25 % - age of onset is frequently early in life - results in disorders due to deficiencies in enzymes rather than abnormalities in structural proteins Example Disease: Phenylketonuria (PKU) rare metabolic disorder caused by a deficiency of the liver enzyme phenylalanine hydroxylase results into accumulation of toxic levels of the amino acid phenylalanine in the blood and other tissues inherited as recessive trait and is manifested only in the homozygote if not treated, it results to mental retardation, microcephaly, delayed speech, and other signs of impaired neurologic development c. X-linked Disorders - sex-linked disorders almost always associated with the X chromosome or the female chromosome and the inheritance pattern is predominantly recessive Points to Remember: - Carrier mother (one with a normal and one with defective/mutant allele on X-chromosome) has 50% chance of transmitting to her sons, and her daughters have a 50% chance of being carriers of the mutant gene - When the affected son procreates, he transmit the mutant gene to all of his daughter, who become carriers Example Disease: Hemophilia A

Recessive disorder that primarily affect males

a. Mild Hemophilia 6 30% of normal factor VIII activity in the

circulation b. Moderate Hemophilia 2 5% of normal factor VIII activity in the circulation c. Severe Hemophilia 1% or less of normal factor VIII activity in the circulation Manifestations: - bleeding in soft tissues, GIT, hips, knees, elbows and ankle joints - joint bleeding begins when the affected child begins to walk - muscle hematoma - intracranial hemorrhage (it is the most common cause of death) - joint fibrosis (result of chronic bleeding and inflammation)

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B. -

MULTIFACTORIAL INHERITANCE DISORDER caused by multiple genes and in many cases, environmental factors

Points to Remember: - multifactorial inheritance is described as a threshold phenomenon in which the factors contributing to the trait may be compared with water filling a glass, in which, when the glass overflows, the disorder is expressed - the disorder can be expressed during fetal life, may be present at birth or may be expressed later in life - Examples: 1. Congenital Disorders or birth defects - any abnormalities of structure or function that are present at birth. The process of fetal development can be disrupted by a variety of external factors such as exposure to radiation, heat, chemicals, infectious agents, or maternal disease. An external agent that alters fetal development is called a teratogen (Greek teratos, monster; genes, born). Developmental malformations can also be the result of abnormalities in the genetic makeup of the fetus, or they can be caused by a combination of genetic and environmental influences. - Examples include the following: Cleft Lip or palate Club foot Congenital Heart Disease 2. Environmental Related Disorders - disorders that develop later in adult life in which environmental factors play a significant role - Examples include the following: Coronary Artery Disease (CAD) Diabetes Mellitus (DM) Hypertension Cancer Psychiatric Disorders like Bipolar Disorders, schizophrenia C. CHROMOSOMAL DISORDER - due to chromosomal defects that usually develop because of defective movement during meiosis or because of breakage of a chromosome with loss or translocation of genetic material - accounts for a large proportion of reproductive wastage (early gestational abortions), congenital malformations, and mental retardation - it can be linked to more than 60 identifiable syndromes that are present in 0.7% of all live births, 2% of all pregnancies in women older than 35 years of age, and 50% of all first term abortions Mechanisms in the Development of Chromosomal Disorders a. Alteration in Chromosome Structure - occurs when there is a break in one or more of the chromosomes followed by a rearrangement or deletion of the chromosome parts - related factors include the following: exposure to radiation sources ex. X-rays influence of chemicals ex. Teratogenic drugs/medicines extreme changes in cellular environment viral infections

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1. Inversion disorder in which the genetic material crosses over in a single

chromosome, as a result, the genes are arranged in abnormal order

2. Deletion a piece of the chromosome is broken off and lost 3. Translocation Parts of dissimilar chromosome are broken off and relocate.
In some cases where there is a balanced reciprocal translocation, no genetic information is lost; therefore, persons with translocation are usually normal chromosomes b. Alterations in Chromosome Duplication Mosaicism is the presence in one individual of two or more cell lines characterized by distinctive karyotypes which resulted from an accident during chromosomal duplication. Sometimes, mosaicism consists of an abnormal karyotype and a normal one, in which case the physical deformities caused by the abnormal cell line usually are less severe.

4. Crossing over exchange of genetic material between two homologous

c. Alterations in Chromosome Number (Aneuploidy) - among the causes of aneuploidy is failure of the chromosomes to separate
during oogenesis or spermatogenesis which is termed as Non-disjunction

Examples of Chromosomal Disorders DOWNS SYNDROME (Trisomy 21) - was first described in 1866 by John Langdon Down - causes a combination of birth defects, including characteristic facial featuresthat are apparent at birth, some degree of mental retardation (IQ ranges from 20 70) and other health problems - it is the most common chromosomal disorder, occurring approximately in every 800 to 1000 births - approximately 95% of all cases are caused by disjunction during the first meiotic division, resulting in a trisomy of chromosome 21 - the risk of having a child with Down syndrome increases with maternal age: it is 1/1300 at 25 years of age, 1/365 at 35 years, and 1/30 at 45 years of age. Physical Features of a Child with Downs syndrome: small, square head upward slanting of the eyes small, low-set and malformed ears a fat pad at the back of the neck an open mouth large protruding tongue shot, stubby hands, with fingers that curl inward single palmar crease (Simean Crease) hypotonia and joint laxity Common Health Problems of a Child with Downs syndrome: Congenital Heart Disorder Gastrointestinal Malformations Acute Leukemia Risk of development of Alzheimer disease in later life (approximately at the age of 40)

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 TURNER SYNDROME (Monosomy X)

describes an absence of all (45, X/0) or part of the X chromosome affects approximately 1 of every 2500 live births almost all fetuses with the 45, X/0 karyotype are spontaneously aborted during the first trimester commonly affects women associated to a meiotic error in the father with normal intelligence but have problems with spatial perception, visualmotor coordination, mathematics and learning activities

Physical Features of Child with Turner syndrome: short stature with normal body proportions no menstruation and show no signs of secondary sex characteristics due to the absence of ovaries webbing of the neck with redundant skin folds nonpitting lymphedema of the hands and feet Common Health Problems of a Child with Turner syndrome: Congenital Heart Defect specifically Coarctation of the Aorta Abnormal Kidney Development (abnormal location, abnormal blood supply or double collecting system) Changes in nail growth, high-arched palate, short fourth metacarpal and strabismus

KLINEFELTER SYNDROME (Polysomy X) a condition of testicular dysgenesis accompanied by the

presence of one or more extra X-chromosomes in excess of the normal XY complement commonly affects men 50% of cases are caused by the nondisjunction of Xchromosome from mother with rising frequency with increased maternal age with normal intellect but with some degree of language impairment Physical Features of Child with Klinefelter syndrome: Half-developed female-like breasts (gynecomastia) Sparse facial and body hairs Tall stature with abnormal body proportions in which the lower part of the body is longer than the upper part small penis, and small, firm testicles with the inability to produce sperm Deficient secondary male characteristics (ex: voice remains feminine in pitch) Common Health Problems of a Child with Klinefelter syndrome: Sterility - permanent inability to produce offspring

Eden Pearl Chan Castillo, R.N. Instructor