1. The Patterns of Genetic Inheritance By 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

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. 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

5. 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

6. Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro 3 32 2 Gene expression limited to specific sex Disorder/trait may appear to “skip” generations Autosomal Dominant Sex-Limited/Influenced

7. Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro 2 3 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

8. 4 Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro 32 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 50

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

12. 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

13. 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

14. 234 23 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

15. 234 23 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

16. 22 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

17. Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro 44 Only males are affected Affected males pass the disease gene to all their sons and to none of their daughters Y-linked (Holandric)