Monogenic disorders are genetic diseases caused by an alteration or mutation in a single gene within a person’s DNA sequence. This single-gene defect disrupts the normal function of the protein the gene codes for, leading directly to the disorder. These conditions contrast sharply with polygenic disorders, such as heart disease or type 2 diabetes, which are influenced by the combined effects of multiple genes. They are also distinct from complex disorders, where both multiple genes and environmental factors contribute to the disease’s development.
How Single Gene Disorders Are Inherited
Monogenic disorders follow one of three fundamental Mendelian inheritance patterns, determined by the gene’s location (autosome or sex chromosome) and the number of altered copies required for the disease to manifest.
In the autosomal dominant pattern, a person needs to inherit only one copy of the altered gene from either parent to be affected. An affected parent has a 50% chance of passing the condition to each child, and the disorder rarely skips generations.
Autosomal recessive inheritance requires an individual to inherit two copies of the altered gene, one from each parent, to have the condition. Parents who carry one copy are usually healthy carriers. If both parents are carriers, there is a 25% chance their child will inherit two copies and be affected.
The third primary pattern is X-linked inheritance, involving genes located on the X chromosome. Because males have only one X chromosome, X-linked recessive disorders affect them if they inherit the altered gene. Females, having two X chromosomes, are typically carriers and are often unaffected or only mildly affected.
Well Known Examples of Monogenic Disorders
Cystic Fibrosis (CF) is an autosomal recessive condition caused by mutations in the CFTR gene. This disorder primarily affects the respiratory and digestive systems by disrupting chloride ion flow, leading to thick, sticky mucus that clogs airways and ducts.
Sickle Cell Disease (SCD) is another autosomal recessive disorder, involving a single point mutation in the HBB gene that codes for hemoglobin. This defect causes red blood cells to deform into a rigid, sickle shape, leading to chronic anemia and blockage of blood flow.
Huntington’s Disease (HD) is inherited in an autosomal dominant manner, requiring only a single copy of the altered HTT gene. HD is a progressive neurodegenerative disorder resulting in the breakdown of nerve cells in the brain. It leads to uncontrolled movements, cognitive decline, and psychiatric problems, caused by an abnormally expanded trinucleotide repeat within the HTT gene.
Identifying Monogenic Disorders
Identifying monogenic disorders begins with genetic testing to analyze an individual’s DNA for a pathogenic gene variant. Testing may involve sequencing a specific gene, such as the CFTR gene, to pinpoint the exact mutation.
For couples planning a family, carrier screening determines if either partner carries a gene variant for a recessive or X-linked disorder without showing symptoms. If both partners are carriers of the same autosomal recessive condition, genetic counseling is recommended.
High-risk couples have options like prenatal diagnosis, which analyzes fetal cells, and preimplantation genetic testing (PGT-M), which screens embryos created through in vitro fertilization. Newborn screening programs also mandate testing for a panel of monogenic disorders shortly after birth, allowing for early detection and intervention.
Current and Emerging Treatments
Management of monogenic disorders involves symptomatic treatments and targeted molecular therapies. Symptomatic treatment focuses on managing disease manifestations, including medications, physical therapy, and lifestyle adjustments to alleviate complications. For Sickle Cell Disease, this includes pain management, infection prevention, and blood transfusions to mitigate anemia.
Targeted molecular therapies, such as CFTR modulators for Cystic Fibrosis, directly address the underlying protein defect. These drugs help the faulty protein function more effectively, moving beyond symptom management. Gene therapy also aims to introduce a correct, functional copy of the affected gene into the patient’s cells to replace the defective one.
The most promising emerging approach is gene editing, utilizing tools like CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology. Gene editing allows scientists to make precise corrections to the patient’s own DNA, fixing the mutation at its source. This technology has shown promise for blood disorders like Sickle Cell Disease, with the first CRISPR-based therapies recently gaining approval, offering a potential one-time cure for some patients. Hematopoietic stem cell transplantation also offers a curative option for some blood disorders, but requires finding a suitable donor.