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The Bouquots and the Beggs 1973

This course explores genetic and developmental disorders, including their causes, inheritance patterns, and associated phenotypic effects. Topics include single gene disorders, chromosomal aberrations, and multifactorial inheritance.

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The Bouquots and the Beggs 1973

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  1. The Bouquots and the Beggs1973

  2. General Pathology (DENF 2701)Fall, 2005Topic: Genetic and Developmental Disorders Fall, 2005; Mondays & Wednesdays, 11:00-11:50 am; Room 132 Course Director: Dr. Jerry Bouquot Room 3.094B; 713-500-4420; 713-745-2330 (cell)

  3. Genetic Diseases • 30,000 genes in humans – Many capable of affecting multiple characteristics (pleiotropy) – Many characteristics have multiple genes controlling them • Common cause of diseases – 20% of pediatric in-patients have genetically related diseases – 50% of spontaneous abortionshave chromosomal aberrations • Not all inherited genes present in infancy or childhood – e.g. Huntington’s disease(Huntington’s chorea) • Not all birth defects are inherited -- e.g. congenital syphilis

  4. Genetic Terminology • Congenital: present at birth -- Doesn’t have to be inherited, e.g. congenital syphilis • Familial: runs in families (genetics may be unknown) • Hereditary: derived from gametes of one’s own parents • Polygenic (multifactorial) inheritance: multiple genes involved, multiple patterns of inheritance • Polymorphism: multiple allelic forms for one gene • Codominance: both alleles of a gene pair are fully expressed • Pleiotropy: one gene with multiple phenotypic effects • Phenotype: physical or biochemical characteristic controlled by a gene or genes • Genotype: chromosomal/gene characteristics

  5. Genetic Terminology • Autosomal dominant (AD): only one gene is mutated -- Only one is needed for disease • Autosomal recessive (AR): two genes are mutated -- One from each parent, both are needed for disease • Consanguinity: child is a product of sex between close relatives (common in AR disorders) • X-linked (sex-linked): mutation is only X chromosome -- Only one is needed for disease, but only when there is no additional X chromosome to counter it (i.e. girls are unaffected) • Reduced penetrance: gene does not create the clinical/biochemical characteristic it is capable of creating • Variable expressivity: not all clinical/biochemical characteristics of an inherited disorder are expressed in all affected individuals

  6. Genetic Terminology • Heterozygous: the child has only one disease allele of the gene, from only one parent • Homozygous: the child has two disease alleles of the gene, one from each parent Normal Male Karyotype

  7. Genetic Mutations • Permanent DNA change • Only germ cell mutations can be passed on to progeny • Point mutation: single nucleotide base is altered Four basic types: – Missense mutation – Nonsense mutation -- Frameshift mutation – Trinucleotide repeat mutation

  8. Point Mutations: Missense Typee.g. Sickle Cell Anemia/Disease

  9. Point Mutations: Nonsense Typee.g. Sickle Cell Anemia/Disease Stop codon replaces regular nucleotide

  10. Point Mutations: Frameshift Typee.g. Cystic Fibrosis -- Insert or delete 1 or 2 base pairs -- If 3 pairs: protein is created with missing amino acid

  11. Point Mutations: Trinucleotide Repeat Typee.g. Fragile X Syndrome Results in amplification

  12. Basic Types of Genetic Disorders • Single gene mutation • Chromosomal aberration • Single gene mutation with nonclassical inheritance

  13. Single Gene DisordersMedelian Inheritance • 5,000+ disorders; 6-8% of pediatric hospital admissions • Three basic patterns: AD, AR, X-linked • Examples of codominance and polymorphism: – Histocompatibility – Blood group antigens • Pleiotropy occurs -- e.g. Marfan disease (defective fibrillin production) • Mutations at different sites may produce the same phenotypic effect -- Heterogeneity • When less than 50% of the normal gene is controlling: -- Clinical change, -- e.g. retinitis pigmentosa

  14. Cytogenetic (Chromosomal) Disorders • Karyotype (photograph of metaphase spread of chromosomes) – Look for altered number and structure of chromosomes • Chromosomal abnormalities occur in 1/200 newborns -- Higher in stillborns -- ½ of first trimester abortions • Normal: 46 chromosomes, i.e.2n = 46 • Exact multiple = euploid (3n or 4n = polyploid) • Aneuploid (not an exact multiple of the normal set of chromosomes) • Trisomy (2n+1): extra chromosome after meiosis • Monosomy (2n-1); one less chromosome after meiosis -- Not compatible with life • Mosaicism: two or more populations of cells in the same individual (from postzygotic mitotic disjunction)

  15. Multifactorial Inheritance • Risk of expressing the disease is dependent on number of mutations inherited • Risk of new baby with the disease (2-7%) is same for all first-degree relatives (parents, siblings) • Risk of new baby with the disease depends on how many previous babies were affected – 7% risk with one affected sibling; 9% risk with two affected siblings • Concordance with identical twins is 20-40%; less for nonidentical twins • This is probably the inheritance for many common disease, e.g. diabetes mellitus, hypertension, gout, schizophrenia, bipolar disorder, certain congenital heart defects.

  16. KaryotypeMetaphase Chromosomes Nomenclature and notation of karyotype translocation between long arms of chromosomes 9 and 22p (petit) = short arm of chromosomeq = long arm of chromosomet = translocation Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.

  17. Extra Credit Question Aneuploidy is defined as: • Duplication of chromosomes • Abnormal number of chromosomes in daughter cell • Exact number of chromosomes in daughter cell • Loss of a chromosome in the daughter cell • An extra chromosome in the daughter cell

  18. General Pathology (DENF 2701)Fall, 2005Topic: Genetic and Developmental Disorders Fall, 2005; Mondays & Wednesdays, 11:00-11:50 am; Room 132 Course Director: Dr. Jerry Bouquot Room 3.094B; 713-500-4420; 713-745-2330 (cell)

  19. Structural Changes in ChromosomesChromosomal Breakage; Loss or Rearranged Material • Usually from chromosomal breakage, with loss or rearrangement of material • Each arm is numbered from centromere outward – e.g. 2q34 = region 3, band 4 on long arm of chromosome 2 • Translocations: chromosome fragments are exchanged between chromosomes • Deletion: loss of a portion of a chromosome – If not at terminal of an arm: chromosome is lost • Inversion: two breaks with reunion after pieces turn around • Ring chromosome: after loss of segments from each end of chromosome, the arms unite to form ring – Variant of deletion

  20. Main Structural Changes of Chromosomes Photo:s Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.

  21. Types of Chromosomal Rearrangements

  22. Chromosomal Translocation • t = translocation (transfer of part of one chromosome to another) • Usually reciprocal -- e.g. 46,XX,t(2;5)(q31;p14) = reciprocal translocation between the long arm of chromosome 2 at region 5, band 1 and the short arm of chromosome 5, region 1, band 4 • If balanced: not harmful to the carrier

  23. Centric (Robertsonian) Translocation • Break is close to centromere, short arms affected • Result: one huge and one very small chromosome (which is lost) • Carrier has only 45 chromosomes • Compatible with survival because short arms have many redundant genes

  24. Isochromosome Translocation • Centromere divides horizontally instead of vertically • One arm is lost, remaining arm is duplicated • Most common: long arm of X chromosome: i(Xq)

  25. Trisomy Disorders • Trisomy 21 • Trisomy 13 • Trisomy 18

  26. Down SyndromeTrisomy 21; Mongolism • Extra chromosome 21 (47,XX,+21) – Chromosome 21 has 225 genes • Most common of the chromosomal disorders – 1/700 births – Increased risk with increased mother’s age (1/25 births for mothers over 45 years of age) – Age of father does not affect risk • 4% are from translocation: 46,XX,der(14;21)(q10;q10),+21 – Usually these are familial, with one parent a carrier for robertsonian translocation • 1% are mosaic: 46,XX/47,XX,+21 – From nondisjunction later in embryogenesis – Usually milder case

  27. Trisomy 21Down’s Syndrome, Mongolism • Facies: flat, oblique palpebral fissures, depressed nasal bridge, epicanthal folds, open mouth, macroglossia • Short stature • Short middle phalanx of little finger • Horizontal palmar crease, -- Simian crease • Short, broad hand • Hyperflexibility of joints • Poor muscle tone • Pelvic abnormalities • Congenital heart disease • Mental retardation Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.

  28. Down SyndromeTrisomy 21; Mongolism • Epicanthic folds and antimongolian obliquity • Increased risk of acute leukemia • Cardiac malformations -- Causes most childhood deaths • Live to be about 30 -- Presuming no serious cardiac malformation • Susceptible to infections -- Causes many deaths • If live into middle age: Alzheimer disease or dementia

  29. Trisomy 13Patau Syndrome • Extra chromosome 13 (47,XX,+13) • 1/15,000 births • Mental retardation • Polydactyly • Microcephaly • Rocker-bottom feet • Renal and hear defects • Umbilical hernia • Cleft lip and palate • Microphthalmia

  30. Trisomy 18Edwards Syndrome • Extra chromosome 18 (47,XX,+18) • 1/8,000 births • Mental retardation • Renal and heart malformations • Rocker-bottom feet • Overlapping fingers • Short neck, low-set ears • Micrognathia

  31. Sex Chromosome Disorders • Usually compatible with life • There is little genetic information on the Y chromosome • -- Genes for male attributes are on short arm • Phenotypically normal males have had 2 or 4 Y chromosomes • Klinefelter syndrome (47,XXY) • Turner syndrome (45,XO) • XYY syndrome (47,XYY)

  32. Lyonization of X Chromosome • Lyonization of X chromosomes: females are actually mosaics • Barr body = genetically inactive X chromosome, stuck to nuclear membrane • Inactivation occurs about 16 days after conception • Once inactivated, all daughter cells have same kind of X chromosome • Only 1 X chromosome is ever active in a cell

  33. Photos: N. Vigneswaran, University of Texas at Houston, Houston, Texas

  34. Klinefelter’s SyndromeXXY Male • 15% are mosaic >> mild cases • ↑ maternal age >> ↑ risk • ↑ maternal age >> ↑ risk • Low serum testosterone • Tall stature • Long arms and legs • Hypogonadism (small testes) • Sterile (testicular atrophy) • Small penis • Mental retardation More Xs >> More MR • Gynecomastia * • Female pubic hair profile * • High pitched voice * • Reduced facial & body hair * • *feminization feature Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.

  35. Turner’s SyndromeNon-dysfunction in meiotic division of gamete formation = 45,XO • 50% = mosaic • Infantile genitalia (even when adult) • No secondary sex features • Widely spaced nipples • Micrognathia • Prominent ears • Short stature • Neck webbing (distended lymphatics) • Primary amenorrhea • Cubitus valgus (wide carrying angle) • Short fourth metacarpal bone • Congenital renal anomalies • Congenital aortic anomalies Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.

  36. Autosomal Dominant InheritanceRules of Inheritance • Gender of child is not a factor • Gender of parent is not a factor; usually inherit from one parent • Each child has 50% risk of inheriting disease gene • Only affected children can pass on the disease gene • Usually anatomic/physical anomalies • Homozygous inheritance may be lethal Osteogenesis Imperfecta AD Inheritance

  37. Autosomal Dominant InheritancePunnett (Genetic) Square A = disease gene a = normal gene Therefore, 50% of children will be affected.

  38. Autosomal Dominant Disorders

  39. Autosomal Dominant DisordersMendelian Inheritance with Organ Systems Involved

  40. Extra Credit Question 47, XXY refers to what genetic disease? • Down syndrome • Turner syndrome • Klinefelter syndrome • Marfan syndrome • Trisomy 13

  41. Autosomal Recessive DisordersMendelian Inheritance • Largest group of mendelian disorders • Both alleles are mutated -- One defective gene from each parent • Most persons with mutation are unaffected -- Because they are heterozygous • Parents of AR child are normal in appearance -- But have the disease gene • Disease is not manifested unless child has both genes -- Homozygous • With only one gene: child is a carrier -- Can pass on the gene -- Does not have the disease

  42. Autosomal Recessive DisordersMendelian Inheritance • Each child has a 25% chance of being affected -- Regardless of gender • Consanguinity is common -- Similar genes in both parents • New mutations are rare (or are rarely discovered) • Usually a biochemical problem -- e.g. missing enzyme Results: -- Less end product -- Accumulation of garbage

  43. Autosomal Recessive InheritanceFamily pedigree (expression is in homozygotes) • Rules of inheritance: • Gender of child is not a factor • Gender of parent is not a factor; must inherit from both parents to be affected • Risk of inheriting disease gene varies (50-100%) • Affected children are homozygotes • Usually enzymatic/chemical anomalies • Unaffected children can pass on the disease gene Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.

  44. Autosomal Recessive InheritancePunnett (Genetic) Square – Single Parent with Gene Therefore, 50% of children will be carriers. A = disease gene a = normal gene

  45. Autosomal Recessive InheritancePunnett (Genetic) Square – Both Parents with Gene Therefore, 50% of children will be carriers and 25% will have the disease. A = disease gene a = normal gene

  46. Autosomal Recessive InheritancePunnett (Genetic) Square – Single Parent with Disease Therefore, all children are carriers A = disease gene a = normal gene

  47. Autosomal Recessive InheritancePunnett (Genetic) Square – Both Parent with Disease Therefore, all children are affected A = disease gene a = normal gene

  48. Autosomal Recessive Disorders

  49. Autosomal Recessive DisordersMendelian Inheritance with Organ Systems

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