1 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Chapter 21 CONGENITAL AND GENETIC DISORDERS

2 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Genetic Control  Genetic information stored in chromosomes  23 pairs in humans  22 pairs—autosomes  One pair of sex chromosomes—XX or XY  Karyotype  Visual representation of chromosomes arranged in order of size  Used in diagnosis of chromosomal disorders

3 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Examples of Karyotypes

4 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Genetic Control (Cont.)  Genotype  Actual genetic information carried by the individual  All cells except the gametes of an individual have the same genotype.  Not all genes are expressed in all cells.  Phenotype  Expression of genes  Appearance of the individual’s characteristics

5 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Congenital Disorders  Disorders present at birth  Include inherited or developmental disorders  Inherited disorders may be caused by  Single-gene expression  Chromosomal defect  Polygenic expression  Single-gene disorders  Trait controlled by one set of alleles  Transmitted to subsequent generations

6 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Congenital Disorders (Cont.)  Chromosomal anomalies  Usually caused by an error during meiosis  Nondisjunction  Translocation

7 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Congenital Disorders (Cont.)  Teratogenic agents  Agents that cause damage during embryonic or fetal development  Multifactorial disorders  Large number of disorders are of this type  Often have pattern of familial inheritance  Environmental component

8 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Congenital Disorders (Cont.)  Other congenital or developmental disorders  Result from premature birth  Difficult labor and delivery  Cerebral palsy is an example.

9 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Single-Gene Disorders  Classified by inheritance patterns  Recessive  Dominant  X-linked recessive  Single gene controls a specific function  Example: color blindness  May have systemic effects  Examples: cystic fibrosis, Tay-Sachs disease, phenylketonuria (PKU)

10 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Single-Gene Disorders  Autosomal dominant disorders  Adult polycystic kidney disease  Huntington’s chorea  Familial hypercholesterolemia  Marfan’s syndrome

11 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Autosomal Recessive Disorders  Both parents must pass on the allele for disorder.  Parents may be heterozygous and unaffected; they are termed carriers.  Parents may be homozygous and affected.  Male and female children are affected equally.  Homozygous recessive child has the disorder.  Heterozygous child  No clinical signs of disease  Child is a carrier

12 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Autosomal Recessive Disorders (Punnett Square) (Cont.)

13 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Autosomal Recessive Disorders (Cont.)  Cystic fibrosis  PKU  Tay-Sachs disease

14 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Autosomal Dominant Disorders  Inheritance of one allele causes disorder; only one parent needs to carry allele  No carriers  Unaffected persons do not transmit the disorder.  Some conditions become evident later in life.  Allele for disorder may have been passed on to next generation before diagnosis of disease in parent.  Termed delayed lethal genotype

15 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Autosomal Dominant Disorders (Punnett Square) (Cont.)

16 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Autosomal Dominant Disorders (Cont.)  Adult polycystic kidney disease  Huntington’s disease  Familial hypercholesterolemia  Marfan’s syndrome

17 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. X-Linked Disorders  Recessive  Allele carried on the X chromosome but not the Y chromosome  Manifested in heterozygous males lacking the matching unaffected gene on the Y chromosome  Heterozygous females are carriers.  Homozygous recessive females may be affected.  Inheritance may appear to skip generations.  Examples:  Duchenne muscular dystrophy  Classic hemophilia

18 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. X-Linked Recessive Disorder (Punnett Square)

19 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. X-Linked Disorders (Cont.)  Dominant disorder  Heterozygous males and females affected  Reduced penetrance in females  Fragile X syndrome is an example.  Most common genetic cause of cognitive deficits  Effects are variable and related to the extent of mutation of the allele.

20 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Single-Gene Disorders  Autosomal recessive disorders  Cystic fibrosis  Phenylketonuria  Sickle cell anemia  Tay-Sachs disease  X-linked dominant disorders  Fragile X syndrome  X-linked recessive disorders  Color blindness  Duchenne muscular dystrophy  Hemophilia A

21 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Chromosomal Disorders  Down syndrome  Trisomy 21  May be caused by nondisjunction or translocation  Turner syndrome XO  Affects females  Short stature  Infertility  Klinefelter syndrome XXY  Extra X chromosome is present  Infertility

22 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Down Syndrome  Trisomy 21  Common chromosomal disorder  Affects physical and mental development  Risk increases with maternal age  Triple or quad screening test and/or first-trimester screening test (ultrasound + maternal blood screening)  May be used to screen for risk of Down syndrome  Amniocentesis or chorionic villi sampling used to confirm the disorder prior to birth

23 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Characteristics of Down Syndrome  Small head, round face, flat facial profile  Slanted eyes and epicanthic fold  Large tongue, high-arched palate  Small hands, single palmar crease  Short stature  Muscles tend to be hypotonic; loose joints  Delayed developmental stages  Cognitive impairment ranges from mild to major  Delayed or incomplete sexual development  Males infertile  Females have lower rate of conception

24 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Down Syndrome (Cont.)

25 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Down Syndrome (Cont.)

26 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Multifactorial Disorders  Genetic influences combined with environmental factors  Examples:  Cleft palate  Congenital hip dislocation  Congenital heart disease  Type 2 diabetes mellitus

27 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Developmental Disorders  Exposure to drugs, chemicals, or radiation during childbearing years  TORCH—acronym for maternal infections that can result in anomalies  Routine prenatal screening tests  Exposure to known teratogens in the first 2 months of development  Impairs organogenesis

28 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Effects of Teratogens During Pregnancy

29 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Diagnostic Tools  Testing may be available.  Prior to conception  During first trimester of pregnancy  In newborn  Testing recommended for:  Family history of a specific disease  Previous birth to child with abnormality  Ethnic groups with high risk for specific disease  Pregnant women > 35 years of age

30 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Diagnostic Tools (Cont.)  Blood tests of pregnant woman  Alpha-fetoprotein testing  In utero testing  Amniocentesis  Chorionic villi assay  Neonatal testing  Excreted metabolites (e.g., PKU)  Blood testing

31 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Genetic Engineering  Isolating, copying, and transplanting genes  In microorganisms, plants, animals, humans  Used in agriculture to produce transgenic or genetically modified foods  Ultimate goal  Insert normally functioning allele to prevent disease  Technically possible but clinical trials have not been uniformly successful

32 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Gene Therapy  Identifies gene and protein responsible for condition  Determines how gene expression is controlled  Produces drug that will inhibit gene expression  Research focus on cancer growth promoters has resulted in these types of drugs.

33 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Genetic Screening and DNA Testing  Screening at-risk populations for a specific allele  Costly  Concerns regarding privacy and access to information  DNA testing to identify individuals for paternity or forensic purposes  Legislation has been drafted in the United States to protect the genetic rights of individuals.  Health care  Employment  Insurance

34 Copyright © 2014, 2011, 2006 by Saunders, an imprint of Elsevier, Inc. Designer Drugs  Proteomics research  Gene expression  Characterization of proteins significant in the metabolic pathway for expression of a particular allele  Some designer drugs act differently in genetically different individuals.  This research will help develop drugs tailored to an individual’s genotype.  Reduce unwanted side effects of commonly used medications