The Patterns of Genetic Inheritance By Dr. Joann Boughman, PhD Autosomal Dominant Autosomal...
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Transcript of The Patterns of Genetic Inheritance By Dr. Joann Boughman, PhD Autosomal Dominant Autosomal...
The Patterns of Genetic InheritanceBy Dr. Joann Boughman, PhD
• Autosomal Dominant• Autosomal Recessive• X-linked Recessive• X-linked Dominant• Y-linked
• Imprinting• Mitochondrial• Multifactorial• Sporadic• Contiguous gene syndromes
Mendelian Non-Mendelian
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)?
…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
Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro
• 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
Autosomal Dominant
Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro
• An individual who inherits the disease gene does not develop the disorder• The disorder appears to “skip” generations
Autosomal Dominant
Non-Penetrance
Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro
3
3 2
2
• Gene expression limited to specific sex• Disorder/trait may appear to “skip” generations
Autosomal Dominant
Sex-Limited/Influenced
Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro
23 3
• 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)
Autosomal Dominant
New Mutation
4
Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro
3 2
43
• An individual who inherits the disease gene but does not develop the condition until adulthood • Examples: Huntington disease, most hereditary cancer syndromes
Autosomal Dominant
Late-onset trait
dx 60
dx 45
dx 45
dx 50
Lisch nodulescafé-au-lait spots
Neurofibromascafé-au-lait spotsLisch nodules
café-au-lait spotsscoliosis
Optic gliomalearning disabilityneurofibromascafé-au-lait spots
• Variability of severity of disorder among individuals with same genotype• Examples: Neurofibromatosis, Treacher-Collins syndrome
Autosomal Dominant
Variable Expressivity
Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro
• 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.
Autosomal Recessive
22
• 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
Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro
Autosomal Recessive
Consanguinity
First cousins
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”)
X-linked Recessive
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
X-linked Recessive
Other characteristics
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)
X-linked Dominant
Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro
4 4
• Only males are affected• Affected males pass the disease gene to all their sons and to none of their daughters
Y-linked (Holandric)