Modes of inheritance

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<ol><li> 1. Part II. Medical Genetics 2012, Doc I </li><li> 2. Chap 1 Modes of Inheritance </li><li> 3. Modes of Inheritance Inheritance patterns describe how a disease is transmitted in families. These patterns help to predict the recurrence risk for relatives. In general, inheritance patterns for single gene disorders are classified based on whether they are autosomal or X-linked and whether they have a dominant or recessive pattern of inheritance. These disorders are called Mendelian disorders, after the geneticist Gregor Mendel. </li><li> 4. Symbols commonly used in Pedigree </li><li> 5. Autosomal dominant only one copy of a disease allele is necessary for an individual to be susceptible to expressing the phenotype. With each pregnancy, there is a one in two (50%) chance the offspring will inherit the disease allele. Unless a new mutation has occurred, all affected individuals will have at least one parent who carries the disease allele. Autosomal dominant inheritance is often called vertical inheritance because of the transmission from parent to offspring. Across a population, the proportion of affected males should be equal to the proportion of affected females. </li><li> 6. Autosomal dominant Variable expressivity: variations of phenotype in individuals carrying a same genotype !! Complete penetrance: all individuals who have the disease-causing mutation have clinical symptoms of disease Incomplete penetrance or reduced penetrance: Some individuals fail to express the trait, even though they carry the disease allele Incomplete penetrance </li><li> 7. Autosomal dominant Example: Myotonic Muscular Dystrophy can include myotonia, cataracts, arrythmia, MR, etc. However, individuals who carry the myotonic dystrophy gene, even within the same family, will express the condition in a variety of ways. Variable expression </li><li> 8. Autosomal dominant Evidence for autosomal dominant inheritance: The disease is passed from the father (II-3) to the son (III-5), this never happens with X-linked traits. The disease occurs in three consecutive generations, this never happens with recessive traits. Males and females are affected, with roughly the same probability. However, II-1 does not express the disease. He must have inherited the mutant allele because he passed it on to two children, III-1 and III-3. II-1 is a classical example of incomplete penetrance, he has the allele for the disease but he does not express it. </li><li> 9. Autosomal dominant </li><li> 10. Autosomal dominant </li><li> 11. Examples of diseases 1. NEUROFIBROMATOSIS Diagnostic criteria for NF1 Two or more of the following: * Six or more caf-au-lait spots 1.5 cm or larger in post-pubertal individuals, 0.5 cm or larger in pre- pubertal individuals Two or more neurofibromas of any type or one or more plexiform neurofibroma Freckling in the axilla or groin Optic glioma (tumor of the optic pathway) Two or more Lisch nodules (benign iris hamartomas) A distinctive bone lesion: dysplasia </li><li> 12. Examples of diseases 1. NEUROFIBROMATOSIS </li><li> 13. Examples of diseases 1. ACHONDROPLASIA Short stature Rhizomelic (proximal) shortening of the arms and legs Limitation of elbow extension Trident configuration of the hands Genu varum (bow legs) Thoracolumbar gibbus in infancy 1. Exaggerated lumbar lordosis, which develops when walking begins Large head with frontal bossing Midface hypoplasia </li><li> 14. Examples of diseases 2. ACHONDROPLASIA </li><li> 15. Examples of diseases 3. OSTEOGENESIS IMPERFECTA </li><li> 16. Autosomal recessive For rare traits, the pedigree usually involves mating between two unaffected heterozygotes and the production of one or more homozygous offspring. Typically, the parents of an affected individual are not affected but are gene carriers. With each pregnancy of carrier parents: 25% of the offspring will inherit two copies of the disease allele and will therefore have the phenotype. 50% of the offspring will inherit one copy of the disease allele and will be a carrier. 25% of the offspring will inherit no copies of the disease allele As with autosomal dominant inheritance, the proportion of affected males should be equal to the proportion of affected females in a given population. </li><li> 17. Autosomal recessive Risk 1 </li><li> 18. Autosomal recessive Risk 2 </li><li> 19. Autosomal recessive: pedigree </li><li> 20. Autosomal recessive The consanguinity increases the risk Consanguinity: if parents are related (consanguinity) there is an increased risk that both parents carry the same recessive allele </li><li> 21. Autosomal recessive The consanguinity increases the risk </li><li> 22. Examples of diseases 1.Sickle cell disease 2.Cystic fibrosis 3.Metabolic diseases (albinism, etc) </li><li> 23. Examples of diseases </li><li> 24. Albinism </li><li> 25. Haplo-sufficiency in heterozygous Haplosufficiency: The single functional allele provides enough active protein for the cells need </li><li> 26. Complementation Children have normal phenotype when ever the parents carry mutations in different genes e.g. Hearing loss </li><li> 27. X-Linked dominant inheritance Only one copy of a disease allele on the X chromosome is required for an individual to be susceptible to an X-linked dominant disease. Both males and females can be affected, although males may be more severely affected because they only carry one copy of genes found on the X chromosome. When a female is affected, each pregnancy will have a one in two (50%) chance for the offspring to inherit the disease allele. When a male is affected, all his daughters will be affected, but none of his sons will be affected. </li><li> 28. Examples of diseases 1. FRAGILE X SYNDROME Characterized by moderate mental retardation in affected males and mild mental retardation in affected females. Fragile X is the most common form of inherited mental retardation. 1. Fragile X syndrome is associated with increased CGG repeats in the FMR1 gene, which is on the X chromosome. Males with fragile X syndrome often have abnormal facies, including a long face, large ears, prominent jaw and macroorchidism (abnormally large testes). Affected females tend to have milder features than the males. </li><li> 29. Examples of diseases 1. FRAGILE X SYNDROME </li><li> 30. Examples of diseases 1. FRAGILE X SYNDROME Fragile X syndrome is associated with increased CGG repeats in the FMR1 gene, which is on the X chromosome. </li><li> 31. Examples of diseases 2. INCONTINENTIA PIGMENTI Disorder of skin pigmentation with neurologic, ophthalmologic, and dental involvement. Lethal alleles in males Skin, hair, nails, dental abnormalities, seizures, developmental delay, mental retardation, ataxia, spastic abnormalities, microcephaly, cerebral atrophy, hypoplasia of the corpus callosum Ocular defects, atrophic patchy alopecia, dwarfism, clubfoot, spina bifida, hemiatrophy, and congenital hip dislocation </li><li> 32. X-Linked recessive inheritance Two copies of a disease allele on the X chromosome are required for an individual with two X chromosomes (a female) to be affected with an X-linked recessive disease. Since males are hemizygous (they have only one X chromosome), one copy of an X-linked recessive disease allele is affected. Females are usually carriers because they only have one copy of the disease allele. For a carrier female, with each pregnancy there is a one in two (50%) chance her sons will inherit the disease allele and a one in two (50%) chance her daughters will be carriers. Affected males transmit the disease allele to all of their daughters, who are then carriers, but to none of their sons. Women are affected when they have two copies of the disease allele. All of their sons will be affected, and all of their daughters will be unaffected carriers </li><li> 33. X-Linked recessive inheritance </li><li> 34. Examples of diseases 1.Duchenne Muscular Dystrophy 2.Hemophilia A 3.Daltonism 4. Anhydrotic Ectodermal Dysplasia </li><li> 35. Examples of diseases 1.Duchenne Muscular Dystrophy progressive muscle disease, with diagnosis made usually around 4 years. Boys typically require the use of a wheelchair by the age of 12. Respiratory infections and cardiomyopathy are the most common causes of death, typically in the third decade. 1. Approximately 70% of males with DMD have deletions or duplications in the DMD gene on chromosome X. </li><li> 36. Examples of diseases 2. Hemophilia A </li><li> 37. Examples of diseases 3. Hypohydrotic Ectodermal Dysplasia X-linked recessive disease characterized by failure to form ectodermal derivatives. Sweat glands and teeth may be missing (anhidrosis and anodontia, respectively), and there may be scant hair, and malformation of the iris. </li><li> 38. X-chromosome inactivation (Lyonization) Process by which one of the 2 X chromosomes in female mammals is inactivated The inactive X is condensed into transcriptionally inactive heterochromatin This inactivated X chromosome is called Barr body Lyon hypothesis (1961) states that in cells with multiple X chromosomes, all but one are inactivated during mammalian embryogenesis. This happens early in embryonic development at random in mammals </li><li> 39. X-chromosome inactivation (Lyonization) In men and women with more than one X chromosome, the number of Barr bodies visible at interphase is always one less than the total number (n) of X chromosomes (Barr body= n-1) In some cases, females who carry X-linked genetic diseases can be affected by those diseases, if X- inactivation is not random. </li><li> 40. Co-dominance AB are codominant A and B have antigenes O no antigene e.g.: ABO blood group Means that both alleles are expressed in the phenotype of individuals that have heterozygous alleles </li><li> 41. Co-dominance However, there are other markers that affect blood groups. One of these is known as the Rhesus factor and is either positive or negative. Positive is dominant and negative is recessive. This means that we have two types of gene for the same thing. It is possible to work out the possible outcomes of offspring </li><li> 42. Co-dominance (exercise) In CHUB hospital, four newborns were accidentally mixed up. The doctors know that the blood groups of the babies are O, A, B and AB, respectively. The blood groups of the four putative parents pairs were determined. Indicate the baby corresponding probably to each parent couple: (a) ABxO, (b) AxO, (c) AxAB, (d) OxO </li><li> 43. Co-dominance (exercise) In CHUB hospital, four newborns were accidentally mixed up. The doctors know that the blood groups of the babies are O, A, B and AB, respectively. The blood groups of the four putative parents pairs were determined. Indicate the baby corresponding probably to each parent couple: (a) ABxO, baby with blood group B (b) AxO, baby with blood group A (c) AxAB, baby with blood group AB (d) OxO baby with blood group O </li></ol>

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