The Patterns of Genetic Inheritance

By Dr. Joann Boughman, PhD

Mendelian

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Autosomal Dominant Autosomal Recessive X-linked Recessive X-linked Dominant Y-linked

Non-Mendelian

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Imprinting Mitochondrial Multifactorial Sporadic Contiguous gene syndromes

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!

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Non-penetrance New mutation Adult-onset conditions Consanguinity Interaction

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Sex-limited/sex influenced Germline mosaicism Anticipation Heterogeniety Pleiotropy

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

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

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

Autosomal Dominant

New Mutation 3 2 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) Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro

Autosomal Dominant

Late-onset trait

dx 45

3 2 4

dx 60 dx 45

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• An individual who inherits the disease gene but does not develop the condition until adulthood • Examples: Huntington disease, most hereditary cancer syndromes dx 50 Adapted from The Pedigree: A Basic Guide, by Jorgenson, Yoder & Shapiro

Autosomal Dominant

Variable Expressivity

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

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

First cousins

Autosomal Recessive

Consanguinity

• Increased consanguinity (over general population) is often found between parents

2 2

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

X-linked Recessive

2 3 4 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”)

2 3

X-linked Recessive

Other characteristics 2 3 4

• 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

2 3

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)

Y-linked (Holandric)

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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