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RareShare Guide on Genetic Inheritance

Publication date: 3 Jun 2023

How do genes cause rare diseases?


Genetic Inheritance Tutorial

A human gene is made of a substance called DNA, which carries the blueprint for our body structure and instructions for our various organs to function properly. It is estimated that every person has around 25,000 genes. Each gene codes for a protein that is essential for a specific bodily function. These genes are located on structures called chromosomes, which consist of tightly condensed sequences of DNA. Every person has 23 pairs of chromosomes and therefore two copies of each gene, one inherited from each parent. The first 22 pairs of chromosomes are called autosomes and are numbered from one onwards, from smallest to largest. The remaining pair of chromosomes are the sex chromosomes. People who are assigned female at birth have two X chromosomes, whereas people assigned male at birth have one X and one Y chromosome. Thus, the Y chromosome can only be inherited from the father. Every single cell in our body  contains all 23 pairs of chromosomes. Different cell types (such as a lung cell vs. a heart cell) express different genes as they have different functions. Genetic diseases are caused by mutations (changes) in a specific gene that alter its blueprint or instructions. Mutations in different genes can cause different genetic conditions.

Autosomal Dominant Inheritance

Autosomal dominant inheritance means that a mutation in one copy of the gene (on one chromosome) is enough to cause the disease. These mutations are located in one of the autosomes (the first 22 chromosomes). Autosomal dominant conditions are typically inherited from one parent with the mutated gene and disorder,  but can also occur randomly in a person. A person with an autosomal dominant genetic condition has a 50% or 1 in 2 chance of passing on the mutated gene and the condition to each of their children. Examples of genetic conditions that show dominant inheritance: Huntington’s Disease and Marfan Syndrome.

Autosomal Recessive Inheritance

Autosomal recessive inheritance means that a mutation must be present on both pairs of chromosomes in order to cause the disease. These mutations are typically located in one of the autosomes (the first 22 chromosomes). Autosomal recessive conditions are inherited from both parents. The parents do not have the disorder and are called carriers since they only have one mutated gene on one of their chromosomes.  Many ultra-rare genetic conditions are caused by recessive inheritance. Examples of genetic conditions that show recessive inheritance: Cystic Fibrosis, Sickle Cell Anemia, and Phenylketonuria (PKU).

X-Linked Recessive Inheritance

X-linked recessive inheritance is caused by mutations in genes on the X chromosome. Females have two X chromosomes while males have one X and one Y chromosome. Because of this, X-linked conditions more commonly affect males. Males with an X-linked condition inherit the mutated gene and disease from their mothers who are typically unaffected. These unaffected mothers are called carrier females as they have one mutated gene on one of their X-chromosomes. Carrier females are less commonly affected by X-linked conditions as they have two X chromosomes and both need to be mutated to cause disease. Notably, affected males pass the mutated gene to all their daughters (making them carriers) but cannot pass on the mutated gene to their sons. Examples of genetic conditions that show X-linked inheritance: Color Blindness and Hemophilia.

Codominant Inheritance

An allele refers to the version of the gene on one chromosome. Since our chromosomes come in pairs, we have two alleles of each gene. Codominance means that one allele is not dominant over the other. Rather, both alleles (on both chromosomes) are expressed. Human blood types are a good example of co-dominance. If a mother has blood type A and the father has blood type B, the child will have blood type AB because the A and B alleles are codominant. 

Polygenic Inheritance

A trait (e.g. height) or a condition (e.g. hypertension) is considered polygenic when the appearance of the trait/condition is influenced by many different genes. Because of this, polygenic inheritance can result in a very wide range of traits that are on a continuum. Many polygenic traits/conditions are also influenced by environmental factors and are sometimes called multifactorial. Many conditions that are common in the general population such as coronary heart disease and diabetes follow polygenic inheritance.

Epigenetic Inheritance

Chemical modification of DNA or of DNA  associated proteins can persist through cell divisions and affect gene expression. These modifications, which include the methylation of DNA or acetylation of DNA binding proteins called histones, are not strictly dependent upon the DNA sequence. They can either suppress or enhance the expression of specific genes. The inheritance and expression pattern does not follow the typical one gene from each parent model.

Mitochondrial Genetics

Mitochondria, also known as the “powerhouses” of the cell are small structures within the cell that convert energy from food into a usable form. While most of the cell’s DNA is packaged within chromosomes in the nucleus, the mitochondria carry a small portion of genetic material in a closed circular DNA molecule (mtDNA). The mitochondrial genome encodes 37 genes that are essential for normal mitochondrial function. 24 of these genes encode tRNA and rRNA molecules, and the other 13 genes encode enzymes involved in oxidative phosphorylation.

Mutations occurring in mtDNA cause several disease syndromes with overlapping symptoms. Some examples are mitochondrial encephalomyopathy; lactic acidosis and stroke-like episodes (MELAS);  myoclonus epilepsy with ragged-red fibers (MERFF); neuropathy, ataxia, retinitis pigmentosa syndrome (NARP); Leber hereditary optic neuropathy (LHON);  and Leigh Syndrome. While in most cases, mutations in mtDNA are inherited, a few cases of de-novo mutations in affected individuals have been documented. Mitochondrial DNA mutation syndromes are maternally inherited through egg cells, meaning affected males do not transmit the mutations to their offspring. The number of mtDNA molecules in a cell can vary greatly. In addition, mutated mtDNA molecules can co-exist with wild type DNA in each cell, a phenomenon known as heteroplasmy. Due to these two factors, the severity varies greatly from case to case.

Gene Therapy

Gene therapy is a new technique using genetic material such as DNA or RNA to treat, prevent, or even potentially cure a disease. There are many types of gene therapy that utilize different methods. Some therapies involve simply delivering a working copy of the gene into the body (gene addition), while others involve modifying/correcting the faulty gene (gene editing). Other techniques include suppressing a disease-causing mutation (gene silencing) and switching on genes that may decrease disease symptoms. Gene therapy can also be done in vivo or ex vivo. For in vivo treatment, the gene therapy is delivered directly into the body. Ex vivo therapy on the other hand, requires cells to be removed from the affected individual and treated with the modified genetic material in the lab before being reintroduced back into the body to grow and replace diseased cells. 

Gene therapy is difficult to master because every cell in the body carries the same genetic material, but the gene and therefore, protein, associated with disease is only expressed in some cell types. For example, muscle proteins that enable the heart to pump blood may not be produced in the stomach to digest food because these are different organs. Scientists are working very hard to target gene therapies to the organs that are most affected by the genetic condition in question. 

Most forms of gene therapy are still experimental and have a long way to go. There are currently only a handful of gene therapies that have been FDA-approved. Some examples include Luxturna for inherited retinal disorder and Spiranza for spinal muscular atrophy.  



1.  How Genetic Disorders are Inherited:'s%20disease%20and%20Marfan%20syndrome,are%20transmitted%20in%20this%20pattern.

2.  Codominance:,different%20traits%20in%20an%20individual.

3.  Codominance:,a%20mutant%20hemoglobin%20%CE%B2%2Dchain.

4.  Difference Between Incomplete Dominance and Codominance:,effects%20of%20a%20recessive%20allele.

5.  Complex Inheritance:,production%20of%20a%20nonfunctional%20enzyme.

6.  Gene Therapy Basics:,Gene%20therapy%20is%20the%20use%20of%20genetic%20material%20to%20treat,is%20produced%20by%20the%20cell.