Pedigree Symbols

Unaffected Male Unaffected Female Heterozygote, Male Female Carrier for an x-linked trait Affected Male Affected Female Deceased male Sex unspecified

Pedigree Symbols
Marriage of unrelated individuals Three children, unspecified sex

Divorced or severed relationship

Consanguineous mating

No offspring

Illegitimate or nonpaternal offspring

Pedigree Definitions
Proband--individual through whom the family came to your attention (arrow)

Consultand--individual seeking you advice (C double bar)

Pedigree Symbols

70

66

d @ 24

46

43

20

19

17

22

18 dx @ 15

Modes of Inheritance
Autosomal dominant:
Vertical pedigree pattern, with multiple generations affected Each affected person normally has one affected parent Each child of an affected person has a 1 in 2 chances of being affected Males and females are equally affected and equally likely to pass the condition on

 Autosomal recessive:
A horizontal pedigree pattern, with one or more sibs affected; often only a single affected case Parents and children of affected people are normally unaffected Each subsequent sib of an affected child has a 1 in 4 chance of being affected Males and females are equally affected Affected children are sometimes the product of consanguineous marriages. In families with multiple consanguineous marriages, affected individuals may be seen in several generations

 X-linked recessive:
A knights move pedigree pattern affected boys may have affected maternal uncles Parents and children of affected people are normally unaffected. Never transmitted from father to son Affects mainly males: females can be carriers, and affected males in a pedigree are linked through females, not through unaffected males Subsequent brothers of affected boys have 1 in 2 risk of being affected; sisters are not affected but have a 1 in 2 risk of being carriers

 X-linked dominant:
Features very similar to autosomal dominant pedigrees, except that all daughters and no sons of an affected father are affected Condition is often milder and more variable in females than in males

 Y-linked
A vertical pedigree pattern All sons of an affected father are affected Affects only males

 Mitochondrial:
A vertical pedigree pattern Children of affected men are never affected All children of an affected woman may be affected, but mitochondrial conditions are typically extremely variable even within a family

Dominant Pedigree
aa
Aa

aa

aa

aa

aa

Aa

aa

aa

aa

aa

Recessive Pedigree
Aa AA AA Aa

Aa

Aa

aa

aa

AA

Factors Influencing Inheritance

Non-penetrance New mutation Adult-onset conditions Consanguinity Interaction Sex-limited/Sex influenced Germline mosaicism Anticipation Heterogeneity 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

Autosomal Dominant
Non-Penetrance

An individual who inherits the disease gene does not develop the disorder The disorder appears to skip generations

Autosomal Dominant
Sex-Limited/Influenced

3 3

Gene expression limited to specific sex Disorder/trait may appear to skip generations

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 maternal and paternal age in some disorders (e.g. Achondroplasia)

Autosomal Dominant
dx 60

Late-onset trait
dx 45 dx 45

dx 50

4 3 2

An individual who inherits the disease gene but does not develop
the condition until adulthood Examples: Huntington disease, most hereditary cancer syndromes

Autosomal Dominant
Variable Expressivity
Lisch nodules caf-au-lait spots

Neurofibromas caf-au-lait spots Lisch nodules

caf-au-lait spots scoliosis

Variability of severity of disorder among individuals with same genotype Examples: Neurofibromatosis, Treacher-Collins syndrome

Optic glioma learning disability neurofibromas caf-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.

Autosomal Recessive
Consanguinity

First cousins

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

X-linked Recessive

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 (Knights move)

X-linked Recessive
Other characteristics

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 Dominant

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)

Only males are affected Affected males pass the disease gene to all their sons and to none of their daughters

II

III

II

III

II

III

II

III