medical genetics

• Signs that suggest a disease is influenced by genes

  • Disorder is more likely to occur in genetic relatives than in the general population
  • Identical twins share the disease more often than fraternal twins
• Identical twins


  Monozygotic twins
• Fraternal twins


  Dizygotic twins
• Concordance


  Percentage of twin pairs in which both twins exhibit the disorder or trait
• Identical twins concordance = 1
• Actual concordance is often less than theoretical values
• Signs that suggest a disease is influenced by genes

  • Disorder does not spread to individuals sharing similar environmental situations
  • Different populations tend to have different frequencies of the disease
  • The disease tends to develop at a characteristic age
  • Human disorder resembles a genetic disorder that has a genetic basis in another mammal
  • Correlation is observed between a disease and a mutant human gene or a chromosomal alteration
• Pedigree analysis


  Used to determine inheritance patterns of human diseases
• Autosomal recessive inheritance


  • Affected offspring has 2 unaffected parents
  • When 2 unaffected heterozygotes have children percentage of affected children is average 25%
  • 2 affected individuals will have 100% affected children
  • Trait occurs with the same frequency in both sexes
• Tay-Sachs Disease (TSD)


  • Patients appear healthy at birth but develop neurodegenerative symptoms at 4-6 months
  • Cerebral degeneration, blindness and loss of motor function
  • TSD patients typically die at 3/4 years of age
• HexA (hexosaminidase A)


  • Enzyme that breaks down a category of lipids called GM2-gangliosides
  • Excessive accumulation of this lipids in cells of the CNS causes neurodegenerative symptoms
• TSD is the result of a mutation in the gene that encodes the HexA enzyme
• TSD is inherited in an autosomal recessive manner
• Heterozygote carrier


  Has 50% of the functional enzyme (this is sufficient for a healthy unaffected phenotype)
• Autosomal Recessive human disorders

  • Albinisim-tyrosinase
  • Cystic fibrosis-CFTR, a chloride transporter
  • Phenykketonuria (PKU)-phenylalanine hydroxylase
  • Sickle cell disease-B globin
• Autosomal Dominant Inheritance


  • Affected offspring has one or both affected parents - can be altered by reduced penetrance
  • Affected individual with only one affected parent is expected to produce 50% affected offspring
  • 2 affected heterozygote individuals will have 25% unaffected offspring
  • Trait occurs with the same frequency in both sexes
  • For dominant disease-causing alleles, homozygote more severely affected with the disorder
• Haploinsufficiency


  Heterozygote has 50% of functional protein, this is not sufficient for a healthy unaffected phenotype
• Gain-of-function mutations


  Mutation changes protein so it gains a new function
• Dominant negative mutations


  Mutant gene product acts antagonistically to the wild-type gene product
• 1. linked Recessive Inheritance


  • Males more likely to exhibit the trait
  • Mothers of affected males have brothers or father are affected with the same trait
  • Daughters of affected males will produce 50% affected sons
• Hemophilia


  • Major symptom is that the blood cannot clot properly when a wound occurs
  • Common accidental injuries pose a threat of severe internal or external bleeding
  • Hemophilia A (classical Hemophilia) caused by a defect in an X-linked gene that encodes a clotting protein called factor VIII
• 1. linked Recessive Inheritance disorders

  • Duchenne muscular dystrophy
  • Hemophilia A
  • Hemophilia B
  • Androgen insensitivity syndrome
• Locus heterogeneity


  Refers to the phenomenon that a disease can be caused by mutations in 2 or more different genes
• Hemophilia A is a defect in (clotting) Factor VIII, Hemophilia B is caused by a defect in Factor IX, both are X-linked recessive disorders, Hemophilia C is caused by a defect in Factor XI (found on chromosome 4, autosomal recessive)
• Allelic variations


  • Single-nucleotide polymorphisms - variation at a single bp in the genome
  • Macrosatellites - variation in the length of short, repetitive sequences
• Haplotype


  Linkage of alleles or molecular markers on a single chromosome
• Founder


  An individual in whom a new mutation producing a disease-causing allele is closely linked to a molecular marker that characterises a haplotype
• Linkage disequilibrium


  A disease-causing allele would likely be transmitted along with one marker but not as likely to be transmitted with another marker
• To detect or identify disease-causing alleles, researchers may try to determine the location of the disease-causing allele due to its proximity to another known gene or to molecular markers along a chromosome
• Linkage to a molecular marker localises a mutation to a chromosomal location that is typically 1 million bp in length, which would contain 5 to 10 genes in a typical human chromosome
• HapMap


  Extensive catalog of common genetic variants that occur in human beings: what the variants are, where these variants are located in the human genome, how they are distributed among the human populations throughout the world
• Genome-Wide Association Studies (GWAS)


  Analyses a genome-wide set of genetic variants to see if any variant is associated with a disease or other trait
• Genetic testing


  Use of tests to discover if an individual carries a genetic abnormality
• Genetic screening


  Population-wide genetic testing
• Genetic testing and screening methods

  • Protein level testing: biochemical, immunological
  • DNA or chromosomal Level: DNA sequencing, In situ hybridisation, Karyotyping, DNA microarrays
• Gene therapy


  Introduction of cloned genes into living cells in an attempt to cure disease
• Gene therapy transfer methods

  • Nonviral approach: liposome technique
  • Viral approach: retroviruses, adenoviruses and parvoviruses
• ADA (Adenosine deaminase)


  • Enzyme involved in purine metabolism
  • If both copies of gene are defective, deoxyadenosine will accumulate and is toxic to B and T cells
  • Destruction of B and T cells leads to disease called SCID (severe combined immunodeficiency)
• Treatments for ADA deficiency

  • Bone marrow transplant from compatible donor
  • Purified ADA coupled to polyethylene glycol (PEG)
  • Gene therapy
• On September 14, 1990 the first human gene therapy was approved for a girl with ADA deficiency