Inheritance patterns describe how genetic variants are distributed in families. Understanding these patterns is crucial to predicting disease risk in family members of an affected individual.
Monogenic or Mendelian conditions refer to conditions caused by pathogenic variants in a single gene. One or both alleles of a gene may be affected depending on the type of inheritance.
An autosomal dominant condition is one where only one copy of a gene with a pathogenic variant is necessary for an individual to be affected. This means that a person will be affected even if they are heterozygous.
Males and females are usually affected equally by autosomal conditions. However, this distribution can be skewed for conditions with variable penetrance or when only a small number of people are included in the family history.
If one parent is heterozygous for an autosomal dominant condition, then each of their children has a 50% chance of inheriting the genetic variant. However, reduced penetrance and/or variable expressivity may also influence the phenotype of the affected child. There are generally affected family members in every generation.
Examples: Huntington disease, Marfan syndrome, familial hypercholesterolaemia.
A person must have a pathogenic variant in both copies of a disease gene to be affected by an autosomal recessive condition. Individuals with only one copy of the pathogenic variant are referred to as carriers, and are generally asymptomatic.
If both parents are carriers, then each child will have a 1 in 4 (25%) chance of being affected, 1 in 2 (50%) chance of being an unaffected carrier, and 1 in 4 (25%) chance of being neither affected or a carrier. The phenotype of the affected child may also depend on variable expressivity.
Examples: cystic fibrosis, Tay-Sachs disease, haemoglobinopathies
Compound heterozygosity refers to a scenario where a person inherits two different alleles of a gene (one from each parent), each with a different pathogenic variant. In contrast, recessive conditions where a person has inherited two alleles of a gene with identical pathogenic variants are known as homozygous variants . The latter scenario is more likely for common pathogenic variants or if parents are consanguineous.
Hereditary hemochromatosis is an iron overload disorder that follows an autosomal recessive pattern of inheritance. It is most commonly caused by two copies of C282Y variant in the HFE gene, also known as homozygous C282Y. More rarely, hereditary hemochromatosis is the result of compound heterozygosity. These patients will have one copy of C282Y and one copy of H63D. Both C282Y and H63D are SNVs within the HFE gene, their numbers signify the position of amino acid substitution. HFE gene encodes for a protein involved in iron metabolism.
This refers to conditions where the associated pathogenic variant is carried on a gene on the X chromosome.
X-linked disease is generally more common in males than females because males only having one copy of the X-chromosome while females have two copies. The wide variability in penetrance and expressivity in females can be attributed to many factors including variability and randomness of X-inactivation, where one copy of the X chromosome is silenced in the developing embryo. Consequently, females heterozygous for an X-linked condition are often asymptomatic carriers, and have a chance of passing the condition on to their children despite not being affected themselves.
Father to son inheritance rules out X-linked conditions because only the Y chromosome is being passed on in this instance.
Examples: red-green colour blindness, haemophilia A and B, Fragile X Syndrome.
As only males have a Y chromosome, Y-linked variants can only be passed from fathers to sons and all sons will carry the pathogenic variant.
Due to the small number of genes on the Y chromosome, Y-linked disease is less common. Variants on the Y chromosome have been known to cause male infertility, as well as rare disorders of sexual development.
Example: Swyer syndrome.
Mitochondrial inheritance involves genes found only in mitochondrial DNA (mtDNA). During early development, it is a mother’s egg cells that contribute mitochondria to the embryo. Variants in mitochondrial DNA are therefore only passed from mothers to their children, although both males and females can be affected by mitochondrial conditions.
Each cell contains many copies of mitochondrial DNA. It is possible to have both pathogenic and benign mtDNA variants within one cell (including egg cells), this is known as heteroplasmy. The ratio of pathogenic to benign mtDNA variants can vary greatly between cells and between different tissues in the body.
As a consequence, a mother with very few copies of pathogenic mtDNA variant may be asymptomatic, because she has adequate numbers of functioning mitochondria. However, it is possible for this unaffected mother to pass on this pathogenic mtDNA variant onto her future children, who may have different hetroplasmy ratios, sufficient to develop disease.
Example: mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndromes.
De novo variants are a type of variant present for the first time in a child, and not inherited from either parent. De novo variants can occur spontaneously during the formation of the egg or sperm cell, or shortly after fertilisation. This can explain scenarios where a child has a variant in every cell in the body that is not present in either parent’s genome, or has a genetic condition that is not present in their family.
If a variant is de novo, it is unlikely that the parents will have another child with the same condition.
The way in which the condition is passed on to subsequent generations will depend on the pattern of inheritance (ex. autosomal dominant).
A recessive disease may also be caused by the combination of a single inherited pathogenic variant and a de novo variant in the same gene.
Multifactorial or complex inheritance
Multifactorial or complex conditions are the product between multiple gene interactions and external factors such as environment and lifestyle choices.
The pattern of inheritance is difficult to define for complex conditions, however they often cluster in families.
Examples: type 2 diabetes, coronary artery disease.