The Patterns of Genetic Inheritance
By Dr. Joann Boughman, PhD
Mendelian
• Autosomal Dominant
• Autosomal Recessive
• X-linked Recessive
• X-linked Dominant
• Y-linked
Non-Mendelian
• 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!
• Non-penetrance
• New mutation
• Adult-onset conditions
• Consanguinity
• Interaction
• 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
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
2
Autosomal Dominant
New Mutation
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
3
Autosomal Dominant
dx 60
Late-onset trait
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
Autosomal Dominant
Lisch nodules
café-au-lait spots
Variable Expressivity
Neurofibromas
café-au-lait spots
Lisch nodules
• Variability of severity of
disorder among individuals
with same genotype
• Examples: Neurofibromatosis,
Treacher-Collins syndrome
café-au-lait spots
scoliosis
Optic glioma
learning disability
neurofibromas
café-au-lait spots
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
Autosomal Recessive
First cousins
Consanguinity
• Increased consanguinity (over general
2
2
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
X-linked Recessive
2
3
4
2
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”)
3
X-linked Recessive
Other characteristics
2
3
4
2
• 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
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
4