E2

2 Pedigree analysis

2.1 Autosomal dominant (AD) AA, Aa —affected. A — mutant gene on autosome.

A pedigree demonstrating the pattern of the autosomal dominant inheritance.

Characteristics of autosomal dominant inheritance: ·Usually, males and females are equally likely to be affected. ·There is no skipping of generations: if an individual has the disease, one parent must also have it.

·Father-son transmission of the disease gene is observed. ·Affected family members usually have unaffected partners and produce a 1:1 ratio of normal and affected children.

Figure illustrating the mating of an unaffected individual (aa) with an individual who is heterozygous for an autosomal dominant disease gene (Aa). The genotypes of affected offspring are shaded.

A diagram of autosomal dominant inheritance Parents

× Aa

Gametes

Offspring

1 : 1

aa

Autosomal dominant inheritance is characterized by vertical transmission of the disease phenotype, a lack of skipped generations, and roughly equal numbers of affected males and females. Father-son transmission may be observed.

For example: Postaxial polydactyly.

Postaxial polydactyly, the presence of an extra digit next to the fifth digit.

2.2 Autosomal recessive (AR) aa —affected. Aa —carrier. a — mutant gene on autosome. Carrier: an individual who has a copy of a disease-causing gene but does not express the disease. The term is usually used to denote heterozygotes for a recessive disease gene.

A pedigree demonstrating the pattern of the autosomal recessive inheritance.

Characteristics of autosomal recessive inheritance: ·As in autosomal dominant inheritance, usually males and females are equally likely to be affected.

·Unlike autosomal dominant diseases, in which the disease phenotype is seen in one generation after another, autosomal recessive diseases are usually seen in one or more siblings but not in earlier generations. ·On average, one fourth of the offspring of two heterozygous carriers will be affected with the disorder.

Figure illustrating the mating of two heterozygous carriers of an autosomal recessive gene. The genotype of affected offspring is shaded.

·Consanguinity is present more often in pedigrees involving autosomal recessive diseases than in those involving other types of inheritance.

A diagram of autosomal recessive inheritance ×

Parents

×

Gametes

Offspring

1 : 1 : 1 : 1

1 : 1

Autosomal recessive inheritance is characterized by observation of the disease phenotype in one or more siblings, but the disease is not usually seen among parents or other ancestors. Equal numbers of affected males and females are usually seen, and consanguinity may be present.

For example: Phenylketonuria (PKU).

A child with phenylketonuria. Mental retardation.

2.3 X-linked recessive (XR) XaXa, XaY—affected. XAXa —carrier. Xa — mutant gene on X chromosome.

A pedigree demonstrating the pattern of the Xlinked recessive inheritance.

Characteristics of X-linked recessive inheritance: ·More males than females show the recessive phenotype. ·The disease allele can be transmitted through a series of phenotypically normal heterozygous females, causing the appearance of “skipped” generations.

·No sons of the affected male will inherit the gene (i.e. there is no male-tomale transmission). ·If a mother is a carrier her sons have a 50% chance of being affected and her daughters a 50% chance of being carriers.

·Affected males may have unaffected parents but will often have an affected maternal uncle or cousin.

A diagram of X-linked recessive inheritance Parents

×

×

×

Gametes

Offspring

1:1:1:1

1:1

1:1:1:1

X-linked recessive inheritance is characterized by an absence of father-son transmission, skipped generations when genes are passed through female carriers, and a preponderance of affected males.

For example: Hemophilia A.

The enlarged knee joints of a patient with hemophilia A, demonstrating the effects of hemarthrosis.

2.4 X-linked dominant (XD) XAXA, XAXa, XAY—affected. XA — mutant gene on X chromosome.

A pedigree demonstrating the pattern of X-linked dominant inheritance.

Characteristics of X-linked dominant inheritance: ·Disease phenotype can be seen in generation after generation. ·Affected females are about twice as common as affected males.

·Affected females are usually heterozygotes and thus have a 50% chance of passing the disease allele to their daughters and sons. ·Male-male transmission cannot be seen. Affected males with normal mates have no affected sons and no normal daughters.

A diagram of X-linked dominant inheritance Parents

×

×

Gametes

Offspring

1:1:1:1

1:1

X-linked dominant diseases display characteristic patterns of inheritance. They are about twice as common in females as males, skipped generations are uncommon, and fatherson transmission is not seen.

For example: Hypophosphataemic rickets.

Mother and her son who have X-linked dominant hypophosphataemic rickets. Growth retardation and rickets, reduced serum phosphate.

2.5 Y-linked Holandric inheritance.

A pedigree demonstrating the pattern of Y-linked inheritance. Transmission is exclusively male-male.

Transmission of Y-linked traits is strictly father-son.

For example: Hairy ears.

Hairy ears.