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The Patterns of Genetic Inheritance By Dr. Joann Boughman, PhD

The Patterns of Genetic Inheritance By Dr. Joann Boughman, PhD. Non-Mendelian. Mendelian. Autosomal Dominant Autosomal Recessive X-linked Recessive X-linked Dominant Y-linked. Imprinting Mitochondrial Multifactorial Sporadic Contiguous gene syndromes.

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The Patterns of Genetic Inheritance By Dr. Joann Boughman, PhD

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  1. The Patterns of Genetic Inheritance By Dr. Joann Boughman, PhD Non-Mendelian Mendelian • Autosomal Dominant • Autosomal Recessive • X-linked Recessive • X-linked Dominant • Y-linked • Imprinting • Mitochondrial • Multifactorial • Sporadic • Contiguous gene syndromes

  2. How to evaluate a pedigree... 1) Transmission: Are there affected family members in every generation (vertical pattern) or in only a single generation (horizontal pattern)? 2) Sex Differences: What is the ratio of affected males to females? 3) Segregation: Is disease/gene being passed through unaffected females? Is there male to male transmission? What % of children are affected (e.g. all of sons but none of daughters)?

  3. …but don’t forget the complicating factors! • Non-penetrance • New mutation • Adult-onset conditions • Consanguinity • Interaction • Sex-limited/sex influenced • Germline mosaicism • Anticipation • Heterogeniety • Pleiotropy

  4. Autosomal Dominant • Vertical pattern: multiple generations affected • Males and females equally likely to be affected • See male to male transmission • Each child of an affected individual has a 50% chance to be affected • Unaffected individuals do pass on the gene • Every affected child has an affected parent Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro

  5. Autosomal Dominant Non-Penetrance • An individual who inherits the disease gene does not develop • the disorder • The disorder appears to “skip” generations Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro

  6. Autosomal Dominant Sex-Limited/Influenced 3 2 3 2 • Gene expression limited to specific sex • Disorder/trait may appear to “skip” generations Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro

  7. Autosomal Dominant New Mutation 3 3 2 • An alteration occurs in the egg or sperm that made the affected individual (may be first family member to be affected) • Recurrence risk for unaffected parents is considered to be low • Risk of new mutation is associated with advanced paternal age in some disorders (e.g. Achondroplasia) Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro

  8. Autosomal Dominant Late-onset trait dx 60 dx 50 dx 45 4 3 4 dx 45 3 2 • An individual who inherits the disease gene but does not develop • the condition until adulthood • Examples: Huntington disease, most hereditary cancer syndromes Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro

  9. Autosomal Dominant Variable Expressivity Lisch nodules café-au-lait spots Neurofibromas café-au-lait spots Lisch nodules café-au-lait spots scoliosis • Variability of severity of • disorder among individuals • with same genotype • Examples: Neurofibromatosis, • Treacher-Collins syndrome Optic glioma learning disability neurofibromas café-au-lait spots

  10. Autosomal Recessive • Horizontal pattern: single generation affected. • Males and females equally likely to be affected • Parents of affected child are unaffected gene carriers and have • a 1 in 4 or 25% recurrence risk • Unaffected siblings have a 2/3 or 67% chance to be carriers. • Children of affected individuals are obligate carriers. Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro

  11. First cousins Autosomal Recessive Consanguinity • Increased consanguinity (over general • population) is often found between parents • of a child with a rare autosomal recessive disorder • Condition may appear to be dominant in a consanguineous family 2 2 Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro

  12. X-linked Recessive 2 3 4 2 3 2 • Males are more often affected than females • Affected males pass the gene to all of their daughters and none of • their sons (NO male-to-male transmission) • Daughters of carrier females have a 50% chance to be unaffected • carriers. Sons of carrier females have 50% chance to be affected. • Affected males in the family are related to each other through carrier • females (“Knight’s move”)

  13. X-linked Recessive Other characteristics 2 3 4 2 3 • For genetically lethal X-linked conditions, 1/3 of isolated cases • (i.e. no family history) are new mutations. • In 2/3 of cases, the mother is an unaffected carrier • Female gene carriers are usually not affected • Exceptions: Turner syndrome, skewed X-inactivation, • X;autosome translocation carriers

  14. X-linked Dominant 2 2 • For rare conditions, females are about 2x as likely to be affected than • males. May be lethal in males and usually milder, but variable, • in females. • Affected males pass the gene to all of their daughters, who will be • affected, and to none of their sons (NO male-to-male transmission) • Sons and daughters of affected females have 50% chance of being • affected (similar to autosomal dominant)

  15. Y-linked (Holandric) 4 4 • Only males are affected • Affected males pass the disease gene to all their sons and to • none of their daughters Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro

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