Genetic Inheritance of Single
Gene Disorders

The genetic mode of inheritance can be useful in predicting the clinical status of individuals possessing mutations and is critical for assessing risk to the family members of a patient affected with a genetic disorder. The mode of inheritance can also be used to rule out certain genetic disorders in a differential diagnosis when there is a family history of disease.

The inheritance mode of single gene disorders may be dominant, recessive or mitochondrial (genetic transmission may also impacted by anticipation, mosaicism, genomic imprinting and uniparental disomy - topics beyond the scope of this basic introduction). In dominant inheritance, a single copy of a mutation will result in disease (a variation on this principle is dominant disorders with reduced penetrance). Alternatively, in recessive inheritance, an individual will not be affected if he/she has at least one normal allele. Individuals with one normal allele and one mutated allele are called carriers. If a patient possesses no normal allele, only genes with recessive mutations, they will be affected with the disorder. In mitochondrial inheritance, the clinical status of a patient is correlated to the proportion of mitochondria with mutations versus mitochondria with normal gene copies.

Autosomal Dominant Inheritance

Characteristics of Autosomal Dominant Inheritance:

• The child of an affected parent has a 50% chance of inheriting the parent's mutated allele and thus being affected with the disorder.
• A mutation can be transmitted by either the mother or the father. All children, regardless of gender, have an equal chance of inheriting the mutation.

Addendum to principle of Autosomal Dominant Inheritance:

• Some autosomal dominant disorders may be characterized by reduced penetrance, i.e., an individual may inherit a mutation and not manifest clinical symptoms. However, these individuals may transmit the mutation and have affected offspring.

Example of an Autosomal Dominant Pedigree: (Darkened circles and squares indicate affected individuals.)

Autosomal Recessive Inheritance

Characteristics of Autosomal Recessive Inheritance:

• An individual will be a "carrier" if they posses one mutated allele and one normal gene copy.
• There is a 50% chance that a carrier will transmit a mutated gene to a child.
• If two carrier parents have a child there is a:
  • 25% chance that both will transmit the mutated gene; in this case, the child will inherit only mutated copies of the gene from both the mother and the father and thus will be affected with the disorder.
  • 50% chance that one carrier parent will transmit the mutated gene and the other will transmit the normal gene; in this case, the child will have one mutated gene and one normal gene and will be a carrier of the disorder.
  • 25% chance that both carrier parents will transmit the normal gene; in this case the child will have only normal genes and will not be affected and will not be a carrier.

This punnet square illustrates the possible genetic combinations for the child of two carrier parents. A capital "A" indicates a normal gene copy. A lower case "a" indicates the mutated gene. The carrier parents (Aa) are indicated outside the square. The possible offspring combinations are denoted within the 4 squares: 1 in 4 (25%) possibility that the child will be affected (aa); 2 in 4 (50%) that the child will be a carrier (Aa); 1 in 4 (25%) that the child will have only normal genes (AA).

• All children of an affected individual will be carriers of the disorder.
• A mutation can be transmitted by either the mother or the father. All children, regardless of gender, have an equal chance of inheriting mutations.

Example of an Autosomal Recessive Pedigree: (The half-filled circles and squares represent carriers of an autosomal recessive genetic disease. The fully blackened square represents an affected individual.)

X-Linked Dominant Inheritance

Characteristics of X-Linked Dominant Inheritance:

• A male or female child of an affected mother has a 50% chance of inheriting the mutation and thus being affected with the disorder.
• All female children of an affected father will be affected (daughters possess their fathers' X-chromosome).
• No male children of an affected father will be affected (sons do not inherit their fathers' X-chromosome).

Example of an X-Linked Dominant Pedigree: (Darkened circles and squares indicate affected individuals.)

X-Linked Recessive Inheritance

Characteristics of X-Linked Recessive Inheritance:

• Females possessing one X-linked recessive mutation are considered carriers and will generally not manifest clinical symptoms of the disorder.
• All males possessing an X-linked recessive mutation will be affected (males have a single X-chromosome and therefore have only one copy of X-linked genes).
• All offspring of a carrier female have a 50% chance of inheriting the mutation.
• All female children of an affected father will be carriers (daughters posses their fathers' X-chromosome).
• No male children of an affected father will be affected (sons do not inherit their fathers' X-chromosome).

Example of an X-Linked Recessive Pedigree: (Darkened squares indicate affected males; dark circles within clear circles indicate carrier females.)

Mitochondrial Inheritance

Characteristics of Mitochondrial Recessive Inheritance:

• Mitochondrial DNA is inherited from the mother only (maternal inheritance). Fathers do not contribute mtDNA to their offspring.
• All children of a mother with a mtDNA mutation are at risk to be either affected with the disorder or asymptomatic carriers of the disorder.
• An individual will be affected with a mitochondrial disorder if the percentage of mitochondria possessing mutated mtDNA reaches a threshold value beyond which the normal mtDNA does not compensate for the mutated mtDNA.
• The mixture of mitochondria possessing mutated mtDNA and mitochondria with normal DNA is referred to as heteroplasmy.

Example of an Mitochondrial Inheritance Pedigree: (Darkened circles and squares indicate clinically affected individuals. Squares and circles with gray shading indicate presence of familial mitochondrial mutation in varying proportions.)