Inheritance patterns

The following inheritance patterns are seen:

1. Autosomal dominant (AD): A disease or trait is typically seen in every generation of a family because only one mutated allele is needed to express the trait (dominant). Males and females (sons and daughters) are equally affected. If the disease arises from a new mutation, or if the disease shows incomplete penetrance, an AD condition may not appear in every generation. Examples include Marfan syndrome, Huntington disease, achondroplasia, some inherited cancers, familial hypercholesterolemia, and neurofibromatosis type 1.

Following is the risk when one parent carries the faulty gene, for each pregnancy:

• 1 in 2 or 50% chance that the child will be affected, assuming complete penetrance

• 1 in 2 or 50% chance that the child will not be affected, assuming complete penetrance

Following is the risk when both parents carry the faulty gene, for each pregnancy:

• 1 in 4 or 25% chance that the child will be normal

• 3 in 4 or 75% chance that the child will be affected, assuming complete penetrance. Of these 3, 1 will be homozygous for the defective gene and will have more severe disease, while 2 will be heterozygous and have less severe disease.

2. Autosomal recessive (AR): This pattern is seen when an individual is homozygous for a mutated gene/allele. It may also be seen in compound heterozygotes, because they lack a normally functioning copy of the gene. The disease may not be present in every generation. Males and females are often equally affected, and consanguinity may be present. Parents are typically asymptomatic carriers. Risk to every child born to two parents who are both carriers of an AR disease is as follows:

• 1 in 4 or 25% chance that the child is born with two normal genes (normal)

• 1 in 2 or 50% chance that the child is born with one normal and one abnormal gene (carrier, without disease)

• 1 in 4 or 25% chance that the child is born with two abnormal genes (homozygous, has disease)

Most enzyme deficiencies are inherited as AR, such as phenylketonuria, galactosemia, and Gaucher disease. Cystic fibrosis, sickle cell disease, and Friedrich ataxia are also AR.

3. X linked dominant: In an X-linked dominant disorder, the inheritance pattern depends on which parent is affected.

• If the father carries the abnormal X gene, all of his daughters will inherit the disease and none of his sons will have the disease. This is because daughters always inherit their father’s X chromosome.
• If the mother carries the abnormal X gene, half of all children (daughters and sons) will inherit the disease tendency.

Some X-linked dominant disorders are so severe that males with the genetic disorder may die before birth. As a result, females may appear to be affected in disproportionately higher numbers.

Common X linked dominant diseases

• X linked hypophosphatemic rickets, Vit D resistant rickets
• Rett syndrome
• Alport syndrome
• Fragile X syndrome

Following is the risk when the mother is affected by X linked dominant, for each pregnancy:

• 1 in 2 or 50% of the daughters will be affected

• 1 in 2 or 50% of the sons will be affected

There is no carrier state because it is a dominant condition/trait.

Following is the risk when the father is affected, for each pregnancy:

• All daughters will be affected

• No sons will be affected

4. X linked recessive: This pattern is caused by mutations on the X chromosome. Because the trait is recessive, males (who have only one X chromosome) are more likely to be affected. Heterozygous females are carriers for X linked recessive diseases. A key feature of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission). However, fathers can pass the diseased X to their daughters, and through daughters to their grandsons, who may become affected. Examples include red-green color blindness, hemophilia, Fabry disease, G6PD deficiency, Hunter syndrome, Lesch-Nyhan syndrome, Duchenne muscular dystrophy, Bruton agammaglobulinemia, and Wiskott-Aldrich syndrome.

Following is the risk when the mother is a carrier and the father is unaffected, for each pregnancy:

• 1 in 4 or 25% chance of having an affected son

• 1 in 4 or 25% chance of having an unaffected son

• 1 in 4 or 25% chance of having a totally normal daughter

• 1 in 4 or 25% chance of having a carrier daughter

In other words, if pregnant with a son, there is a 50% chance he will be affected by the condition. If pregnant with a daughter, there is a 50% chance she will be a genetic carrier of the condition.

Following is the risk distribution for each pregnancy when the father is affected:

• All sons will be normal

• All daughters will be carriers

5. Codominant inheritance: In codominant inheritance, two different alleles of a gene are expressed, and each version makes a slightly different protein. For example, both maternal and paternal alleles of the HLA gene are expressed in each nucleated cell. Other examples include alpha 1 antitrypsin deficiency and ABO blood group antigens.

6. Mitochondrial or maternal inheritance: Mitochondrial DNA is inherited only from the mother to all children. Mutations affect the electron transport chain and ATP production, so organs that depend on a constant ATP supply (muscle, liver, brain, heart, and kidneys) are affected the most. Conditions caused by mitochondrial DNA mutations can appear in every generation and can affect both males and females, but fathers do not pass these disorders to their daughters or sons. Examples include mitochondrial myopathies, MELAS, and Leber hereditary optic neuropathy.

Heteroplasmy: The presence of two or more mitochondrial DNA variants in the mitochondria of an individual. This may lead to phenotypic differences in individuals affected by the same mitochondrial diseases Threshold effect: An individual who has inherited a mitochondrial disease would only develop symptoms if the proportion of mitochondria with the faulty gene, or the total number of copies of the faulty mitochondrial genes, reaches and exceeds a critical threshold level that interferes with mitochondrial function

7. Y linked inheritance: A condition is considered Y-linked if the mutated gene that causes the disorder is located on the Y chromosome. Because only males have a Y chromosome, a mutation can only be passed from father to son. It is transmitted as a dominant trait and is seen in all generations of the family. Seen in Y chromosome infertility and Swyer syndrome.