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4.4 Single Gene Disorders

Single-Gene Disorders

Single gene disorders are among the most well-understood genetic disorders, given their straightforward inheritance patterns (recessive or dominant) and relatively simple genetic etiology. Although the majority of these diseases are rare, in total, they affect millions of Americans. Some of the more common single-gene disorders include cystic fibrosis, hemochromatosis, Tay-Sachs, and sickle cell disease.

Even though a single gene primarily causes these diseases, several different mutations can result in the same disease but with varying degrees of severity and phenotype. However, even the same mutation can result in slightly different phenotypes. This may be caused by differences in the patient’s environment and other genetic variations that may influence the disease phenotype or outcome. For example, other genes have been shown to modify the cystic fibrosis phenotype in children who carry the same CFTR mutation. In addition, mutations in different genes can result in similar phenotypes for some disorders, such as galactosemia.

Genetic testing is available for many single-gene disorders. However, the clinical examination is extremely important in the differential diagnosis, particularly in patients with no family history. For some genetic conditions, patients can often be treated for their symptoms or modify their diets to prevent the onset of symptoms if diagnosed at an early age (newborn screening). However, despite advancements in the understanding of genetic etiology and improved diagnostic capabilities, no treatments are available to prevent disease onset or slow disease progression for a number of these disorders.

Some useful resources to bookmark include GeneTests and OMIM. GeneTests is an online genetic testing laboratory database providing information about conditions and laboratory testing services. The Online Mendelian Inheritance in Man database is a comprehensive resource that includes information about the genetic etiology, clinical symptoms, and a bibliography. Of over 5,000 known genetic conditions, the molecular basis is known in almost 2,000.

Table 1: Conditions, Genes & Inheritance Patterns
Condition Gene (Chr. Location) Inheritance Pattern
Congenital Deafness
(nonsyndromic)		 Connexin 26 (13q11) Recessive
Tay-Sachs hexosaminidase A (15q23) Recessive
Familial hypercholesterolemia LDL receptor (19p13) Dominant
Sickle cell anemia Beta-globin (11p15) Recessive
Duchenne muscular dystrophy Dystrophin (Xq21) X-linked Recessive
Cystic Fibrosis CFTR (7q31) Recessive
Hemochromatosis HFE (6p21) Recessive
Huntington disease Huntington (4p16) Dominant

Cystic Fibrosis (CF) — Autosomal Recessive

Cystic fibrosis (CF) is one of many diseases that geneticists have shown to be primarily caused by mutation in a single, well-characterized gene. Cystic fibrosis is the most common ([latex]\frac{1}{2,500}[/latex]) life-limiting autosomal recessive disease among people of European heritage, with ~ 1 in 25 people being carriers. The frequency varies in different populations. Most of the deaths caused by CF are the result of lung disease, but many CF patients also suffer from other disorders, including infertility and gastrointestinal disease. The disease is due to a mutation in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, first identified by Lap-chee Tsui’s group at the University of Toronto (Tsui, 1995). Lap-Chee Tsui was inducted into the Canadian Medical Hall of Fame in March 2012 and is still a leader in CF research (Canadian Medical Association, n.d.).

 

This illustration shows a wild-type cell membrane on the left and the mutant form of CFTR in the cell membrane on the right. Across each cell membrane is an ion channel in blue. In wild-type, the CFTR ion channel is gated. When activated by ATP, the channel opens and allows ions to move across the membrane. The image shows the gate open, and ions within the channel. In some CFTR mutations, the channel does not open. This prevents ions and water movement, allowing mucus to build up on the lung epithelium. In the image the gate opening in blocked and there is nothing in the channel.
Figure 4.14 Wild-Type and Mutant Forms of CFTR in the Cell Membrane. In wild-type, the CFTR ion channel is gated. When activated by ATP, the channel opens and allows ions to move across the membrane. In some CFTR mutants, the channel does not open. This prevents ions and water movement, allowing mucus to build up on the lung epithelium. Source: CFTR Protein by Lbudd14, CC BY-SA 3.0.

Epithelial tissues in some organs rely on the CFTR protein to transport ions (especially Cl-) across their cell membranes. The passage of ions through a six-sided channel is gated by another part of the CFTR protein, which binds to ATP.  If there is insufficient activity of CFTR, an imbalance in ion concentration results, which disrupts the properties of the liquid layer that normally forms on the epithelial surface. In the lungs, this causes mucus to accumulate and can lead to infection.  Defects in CFTR also affect the pancreas, liver, intestines, and sweat glands — all of which need this ion transport. CFTR is also expressed at high levels in the salivary gland and bladder. Still, defects in CFTR function do not cause problems in these organs, probably because other ion transporters can compensate.

Concept in Action

Watch The video Cystic Fibrosis | Molecular Mechanism & Genetics (4 mins) by Hussain Biology (2018) on YouTube which discusses the genetic basis and mechanism by which cystic fibrosis occurs.

Video source: Hussain Biology. (2018, January 17). Cystic fibrosis | Molecular mechanism & genetics [Video]. YouTube. https://www.youtube.com/watch?v=QfjIGXNey3g

Over one thousand different mutant alleles of CFTR have been described. Any mutation that prevents CFTR from sufficiently transporting ions can lead to cystic fibrosis (CF). Worldwide, the most common CFTR allele among CF patients is called ΔF508 (delta-F508; or PHE508DEL), which is a deletion of three nucleotides that eliminates phenylalanine from position 508 of the 1480 aa wild-type protein. Mutation ΔF508 causes CFTR to be folded improperly in the endoplasmic reticulum (ER), preventing CFTR from reaching the cell membrane. ΔF508 accounts for approximately 70% of CF cases in North America, with ~1/25 people of European descent being carriers. The high frequency of the ΔF508 allele has led to speculation that it may confer some selective advantage to heterozygotes, perhaps by reducing dehydration during cholera epidemics or by reducing susceptibility to certain pathogens that bind to epithelial membranes.

CFTR is also notable because it is one of the well-characterized genetic diseases for which a drug has been developed that compensates for the effects of a specific mutation. The drug, Kalydeco (Ivacaftor), was approved by the FDA and Health Canada in 2012, decades after the CFTR gene was first mapped to DNA markers (in 1985) and cloned (in 1989). Kalydeco is effective on only some CFTR mutations, most notably G551D (i.e., where glycine is substituted by aspartic acid at position 551 of the protein GLY551ASP). This mutation is found in less than 5% of CF patients. The G551D mutation affects the ability of ATP to bind to CFTR and open the channel for transport. Kalydeco compensates for this mutation by binding to CFTR and holding it in an open conformation. Kalydeco is expected to cost approximately $250,000 per patient per year.

Exercises

Explore the National Human Genome Research Institute website or the Genomics Education Programme website for the following genetic disorders:

  • Beta-thalassemia
  • Down syndrome
  • Duchenne muscular dystrophy
  • Familial adenomatous polyposis
  • Familial hypercholesterolemia
  • Fragile X syndrome
  • Hemophilia
  • Huntington’s disease
  • Klinefelter syndrome
  • Lynch syndrome
  • Marfan syndrome
  • Parkinson’s disease
  • Phenylketonuria
  • Sickle cell disease

Consider the following:

    1. Are these disorders caused by a single gene? If so, what is the pattern of inheritance?
    2. Is it a chromosomal or mitochondrial condition?
    3. Is it a multifactorial condition?
    4. What is the gene and chromosome that is affected?
    5. How do penetrance and expressivity affect the phenotype in these disorders?
    6. What is anticipation, and which disorders does it apply to?

Assignment tip: the Scholarly Poster Presentation assignment asks you to select an actionable gene variant. Reviewing these disorders may lead you to choose a variant that can cause a disorder you would be interested in doing the project on.

 

Attribution & References

Except where otherwise noted, this page is adapted from:

References

Canadian Medical Association. (n.d.). 2012 Inductee: Lap-Chee Tsui, PhD. Canadian Medical Hall of Fame. https://cdnmedhall.ca/laureates/lapcheetsui

Cystic Fibrosis Canada. (n.d.). What is Kalydeco? https://www.cysticfibrosis.ca/our-programs/advocacy/access-to-medicines/kalydeco

Hussain Biology. (2018, January 17). Cystic fibrosis | Molecular mechanism & genetics (video file). YouTube. https://www.youtube.com/watch?v=QfjIGXNey3g

Tsui L. C. (1995). The cystic fibrosis transmembrane conductance regulator gene. American Journal of Respiratory and Critical Care Medicine, 151(3 Pt 2), S47–S53. https://doi.org/10.1164/ajrccm/151.3_Pt_2.S47

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Precision Healthcare: Genomics-Informed Nursing Copyright © 2025 by Andrea Gretchev, RN, MN, CCNE is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, except where otherwise noted.

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