Pedigree

Pedigree Symbols

Unaffected Male

Unaffected Female

Affected Male

Affected Female

Heterozygote, Male

Female Carrier for an x-linked trait

Deceased male

Sex unspecified

Pedigree Symbols

3

Marriage of unrelated individuals

Divorced or severed relationship

Consanguineous mating

Illegitimate or non-paternal offspring

Three children, unspecified sex

No offspring

Pedigree Definitions

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

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

Pedigree Symbols

C19 17

18dx @ 15

22

4346

20

d @ 24

6670

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 “knight’s 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

aa aa aa

aa aa aaaa aa

aa

Dominant PedigreeA a

A a

Recessive Pedigree

A a A a

A a A a

aaaa

AA AA

AA

Factors Influencing Inheritance

• Non-penetrance• New mutation• Adult-onset

conditions• Consanguinity• Interaction

• Sex-limited/Sex influenced•Germline mosaicism•Anticipation•Heterogeneity•Pleiotropy

• 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

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

Autosomal Dominant

Non-Penetrance

3

3

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

Autosomal Dominant

Sex-Limited/Influenced

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

Autosomal Dominant

New Mutation

4

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 45dx 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

• 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

Autosomal Recessive

Consanguinity

First cousins

• 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

• 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

• 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

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

Y-linked (Holandric)

I

II

III

I

II

III

I

II

III

I

II

III