Inheritance patterns

The following inheritance patterns are seen:

1. Autosomal dominant (AD): Disease or character is seen in all generations of a family, even though only one allele is mutated (dominant trait). Males and females, sons and daughters, are equally affected. If disease arises from a new mutation or the disease has incomplete penetrance, then the AD disease would not be seen in all generations of a family. Examples are Marfan’s syndrome, Huntington’s disease, achondroplasia, some inherited cancers, familial hypercholesterolemia and neurofibromatosis type 1.

Following is the risk of when one of the 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 of 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): It is seen in individuals who are homozygous for the mutated gene/allele. It may be seen in compound heterozygotes also, as they lack a normally functioning copy of the gene. Disease may not be present in all generations of the family. 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, both of whom are carriers of an AR disease are 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, like phenylketonuria, galactosemia or Gaucher’s disease. Cystic fibrosis, sickle cell disease and Friedrich ataxia are also AR.

3. X linked dominant: For an X-linked dominant disorder, 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. That is because daughters always inherit their father’s X chromosome. If the mother carries the abnormal X gene, half of all their 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. Therefore, it may appear that females are 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 of 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 as it is a dominant condition/trait.

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

• All daughters will be affected

• No sons will be affected

4. X linked recessive: It is caused by mutations in the X chromosome, but as the trait is recessive, males , since they have only one X chromosome, are more likely to suffer from X linked recessive disorders. Heterozygous females are carriers for X linked recessive diseases. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission), but they can transfer the diseased X to their daughters, and through daughters to their grandsons who may become affected by the disease. 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 of 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 they will be affected by the condition and if pregnant with a daughter, a 50% chance they 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 are alpha 1 antitrypsin deficiency and ABO blood group antigens.

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

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, in Y-linked inheritance, 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.