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Genetic Conditions That Cause Chronic Cough

Dr. Michelle Frank

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October 11, 2023
CoughPro is not a medical product. It is a wellness app intended only for users to obtain a better understanding of their cough. It is not intended to diagnose, monitor, or treat any illness.

We at Hyfe, Inc., are a company devoted to working on tools to better understand the importance of cough. It is Hyfe’s intention in the future to seek regulatory approval for medical products that analyze cough in order that they may be used to diagnose, monitor, and facilitate better treatment of respiratory illnesses.

Genetics looking at a DNA image

Coughing is a reflex action. This is why it is often dismissed, especially if you have something itchy in your throat. When you notice a lingering chronic cough, the primary suspects are usually infections, gastroesophageal reflux disease, asthma, or a postnasal drip. Rarely would we link a genetic condition to a cough.

However, there are a few genetic conditions that cause chronic cough along with the other primary presenting symptoms. While a few of these, such as cystic fibrosis, are well known and documented in medical literature, others are not routinely considered as possible causes. 

To consider a genetic source of a cough, the cough often has to be chronic (lasting longer than eight weeks), along with symptoms that might direct toward a possible genetic link. A key symptom is when the cough has not subsided with standard methods of management – which may be why you are now seeking medical assistance. If your doctor rules out all the probable sources of a chronic cough, a genetic link is then considered((Kaplan A. G. (2019). Chronic Cough in Adults: Make the Diagnosis and Make a Difference. Pulmonary therapy, 5(1), 11–21. https://doi.org/10.1007/s41030-019-0089-7)).

Throughout this article, we will explore these different genetic conditions that cause a chronic cough as well as signs that can indicate whether you may need to get an evaluation for a potential genetic link to your cough.

1. Cystic Fibrosis 

Cystic fibrosis (CF) is a genetic condition that affects organs such as the lungs, pancreas, reproductive tract, and digestive tract. A recessive gene mutation on chromosome 7 results in a malfunction in a protein that transports salt into and out of the cells lining these organs((Rommens, J. M., et al. (1989). Identification of the Cystic Fibrosis Gene: Chromosome Walking and Jumping. Science. https://doi.org/2772657)). A hallmark of CF is the presence of thick mucus, which inhibits regular organ function.

Typical signs of CF can present at any age depending on how severe the genetic mutation is. Some people may develop symptoms in early childhood, but there are cases that don’t develop until late adolescence and even adulthood((Sagesse, G. J., Yadava, S., & Mandava, A. (2020). Atypical Cystic Fibrosis: Diagnosis at the Age of 57 Years. Cureus, 12(10), e10863. https://doi.org/10.7759/cureus.10863)).

Classically, cystic fibrosis is considered to be a respiratory health condition. Recurrent infections, sinusitis, production of thick sputum, and a persistent cough are hallmark signs. There are also other signs that can indicate a potential CF diagnosis including constipation, foul and greasy stools, inability to gain weight, development of diabetes, and infertility in males((Cystic Fibrosis Foundation. (2023). About Cystic Fibrosis. Cystic Fibrosis Foundation. Retrieved 30th September 2023 from https://www.cff.org/intro-cf/about-cystic-fibrosis)).

Adults with CF cough on average 21 times a day. Coughing in cystic fibrosis has been documented to have two sources. This type of coughing is frequently related to the underlying respiratory disease process((Smith, J. A., et al. (2006). Objective measurement of cough during pulmonary exacerbations in adults with cystic fibrosis. Thorax, 61(5), 425–429. https://doi.org/10.1136/thx.2005.050963)). However, chronic coughing in CF can also be caused due to gastroesophageal reflux (GERD), which can occur due to pancreatic and duodenal dysfunction with CF.

2. Alpha 1-Antitrypsin Deficiency

Genetic mutations in gene SERPINA1 cause a deficiency of the protective enzyme alpha 1-antitrypsin (AAT). The body uses AAT in the lungs, liver, and skin. The lungs and liver are the most common sites affected by AAT deficiency((Fregonese, L., & Stolk, J. (2008). Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. Orphanet Journal of Rare Diseases, 3, 1. https://doi.org/10.1186/1750-1172-3-16)).

AAT limits the activity of infection-fighting neutrophilic enzymes. With a lower amount of or dysfunctional AAT present, healthy lung tissue can be damaged following bouts of infection and chronic cough((Fregonese, L., & Stolk, J. (2008). Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. Orphanet Journal of Rare Diseases, 3, 1. https://doi.org/10.1186/1750-1172-3-16)).

Patients with AAT deficiency classically have a history of recurrent infections, which result in diminishing lung function over time due to uncontrolled lung damage sustained during and following the infection. The symptoms are similar to chronic obstructive lung disease (COPD), such as difficulty in breathing following exertion, fatigue, and a characteristic chronic cough with mucus..

A case report also documented that patients with AAT deficiency have a greater likelihood of developing increased airway hyperresponsiveness, which can result in asthmatic symptoms((Sanduzzi, A., Ciasullo, E., Capitelli, L., Sanduzzi Zamparelli, S., & Bocchino, M. (2020). Alpha-1-Antitrypsin Deficiency and Bronchiectasis: A Concomitance or a Real Association? International journal of environmental research and public health, 17(7), 2294. https://doi.org/10.3390/ijerph17072294)). This can further contribute to a decline in respiratory function.

3. Cerebellar Ataxia With Neuropathy and Vestibular Areflexia Syndrome (CANVAS) and Other Neurological Disorders

CANVAS is a slow and progressive neurological disorder, and approximately 60% of patients present with a chronic cough as a clinical sign((Doi, H., & Tanaka, F. (2022). Brain and nerve = Shinkei kenkyu no shinpo, 74(11), 1267–1271. https://doi.org/10.11477/mf.1416202226)).

Some of the characteristic indications of possible CANVAS are its late onset in life, ataxia (negatively affected balance and coordination), disturbances in balance due to vestibular (inner ear) dysfunction, and a loss or alteration of sensation of touch, temperature, body position, and pain((Szmulewicz, D. J., Roberts, L., McLean, C. A., MacDougall, H. G., Halmagyi, G. M., & Storey, E. (2016). Proposed diagnostic criteria for cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). Neurology. Clinical practice, 6(1), 61–68. https://doi.org/10.1212/CPJ.0000000000000215)).

The exact mechanism of the cough in CANVAS is unknown but we hypothesize it to be either due to hypersensitivity syndrome or cerebellar circulatory impairment (damage to the cerebellum in the brain)((Dominik, N., Galassi Deforie, V., Cortese, A., & Houlden, H. (2021). CANVAS: a late onset ataxia due to biallelic intronic AAGGG expansions. Journal of Neurology, 268(3), 1119–1126. https://doi.org/10.1007/s00415-020-10183-0)). In many cases, chronic cough precedes the neurological hallmarks of CANVAS, in some cases, up to 30 years before((Cortese, A., Tozza, S., Yau, W. Y., Rossi, S., Beecroft, S. J., Jaunmuktane, Z., Dyer, Z., Ravenscroft, G., Lamont, P. J., Mossman, S., Chancellor, A., Maisonobe, T., Pereon, Y., Cauquil, C., Colnaghi, S., Mallucci, G., Curro, R., Tomaselli, P. J., Thomas-Black, G., Sullivan, R., … Reilly, M. M. (2020). Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion. Brain: A Journal of Neurology, 143(2), 480–490. https://doi.org/10.1093/brain/awz418)).

4. Hereditary Hemorrhagic Telangiectasia (HHT)

Hereditary hemorrhagic telangiectasia (HHT) is a genetic condition affecting the formation of blood vessels. Due to this pulmonary arteriovenous malformations (PAVM), abnormal connections between pulmonary arteries and veins form. Approximately 80-90% of PAVMs are associated with HHT((Circo, S., & Gossage, J. R. (2014). Pulmonary vascular complications of hereditary haemorrhagic telangiectasia. Current Opinion in Pulmonary Medicine, 20(5), 421–428. https://doi.org/10.1097/MCP.0000000000000076)).

The problem with PAVMs is that there is a direct connection between the arteries and veins in the lungs, bypassing the capillary network surrounding the alveoli. The severity of the symptoms that one can develop is based on the number of these malformations and where exactly they form. Having a PAVM reduces the gas exchange frequency in the lungs. This is why one of the primary symptoms is difficulty breathing and signs of low blood oxygen((Meier, N. M., Foster, M. L., & Battaile, J. T. (2018). Hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations: clinical aspects. Cardiovascular diagnosis and therapy, 8(3), 316–324. https://doi.org/10.21037/cdt.2017.12.07)).

Coughing can result from a decline in lung function over time. In addition, a case report documented the specific location of a PAVM in the left upper lobe of the lung as causing chronic cough((Jutant, E. M., Puyo, P., El Hajjam, M., Blivet, S., Houdart, E., Aubier, M., Lacombe, P., & Chinet, T. (2015). Severe, chronic cough caused by pulmonary arteriovenous malformations in a patient with hereditary hemorrhagic telangiectasia: case report. BMC Pulmonary Medicine, 15, 28. https://doi.org/10.1186/s12890-015-0024-0)). This suggests that routine screening for PAVMs in patients with hereditary hemorrhagic telangiectasia is crucial, especially with the appearance and persistence of new symptoms.

5. Other Potential Genetic Conditions That Cause Chronic Cough

In medical literature, chronic cough has also been documented with other hereditary neurological conditions. Some of these include: 

  • Hereditary sensory neuropathy((Spring, P. J., Kok, C., Nicholson, G. A., Ing, A. J., Spies, J. M., Bassett, M. L., Cameron, J., Kerlin, P., Bowler, S., Tuck, R., & Pollard, J. D. (2005). Autosomal dominant hereditary sensory neuropathy with chronic cough and gastro-oesophageal reflux: clinical features in two families linked to chromosome 3p22-p24. Brain: A Journal of Neurology, 128(Pt 12), 2797–2810. https://doi.org/10.1093/brain/awh653)) 
  • Charcot-Marie-Tooth disease type 2((Gonzalez, M. A., Feely, S. M., Speziani, F., Strickland, A. V., Danzi, M., Bacon, C., Lee, Y., Chou, T. F., Blanton, S. H., Weihl, C. C., Zuchner, S., & Shy, M. E. (2014). A novel mutation in VCP causes Charcot-Marie-Tooth Type 2 disease. Brain: A Journal of Neurology, 137(Pt 11), 2897–2902. https://doi.org/10.1093/brain/awu224)) 
  • Dominant ataxia((Coutinho, P., Cruz, V. T., Tuna, A., Silva, S. E., & Guimarães, J. (2006). Cerebellar ataxia with spasmodic cough: a new form of dominant ataxia. Archives of Neurology, 63(4), 553–555. https://doi.org/10.1001/archneur.63.4.553)) 
  • Holmes-Adie syndrome((Kimber, J., Mitchell, D., & Mathias, C. J. (1998). Chronic cough in the Holmes-Adie syndrome: association in five cases with autonomic dysfunction. Journal of Neurology, Neurosurgery, and Psychiatry, 65(4), 583–586. https://doi.org/10.1136/jnnp.65.4.583)).

Cough in these conditions is frequently dry and persistent. Sometimes patients may document triggers such as eating, smoking, talking, or consuming dry and spicy food((Tatineni, S., Jarrouj, G., Gomez, C. M., & Baird, B. J. (2023). Characterization of a chronic cough in cerebellar ataxia, neuropathy, vestibular areflexia syndrome. Laryngoscope investigative otolaryngology, 8(3), 730–738. https://doi.org/10.1002/lio2.1067)).

A 2020 study called the Rotterdam study estimated the prevalence of chronic cough in adults over 45 to be about 10.9%((Arinze, J. T., de Roos, E. W., Karimi, L., Verhamme, K. M. C., Stricker, B. H., & Brusselle, G. G. (2020). Prevalence and incidence of, and risk factors for chronic cough in the adult population: the Rotterdam Study. ERJ open research, 6(2), 00300-2019. https://doi.org/10.1183/23120541.00300-2019)). Even with its wide prevalence, cough as a symptom has only recently been studied and used as a diagnostic tool for guiding the treatment of underlying health conditions.

Having a chronic cough has been observed as a leading symptom that causes a decline in the quality of life.

While the immunological and neurological basis of cough has been vastly studied, there have been fewer studies done to investigate a possible genetic link to chronic cough. Some studies have highlighted mutations in the genes TRPV1((Liviero, F., Campisi, M., Scarpa, M. C., Mason, P., Guarnieri, G., Maestrelli, P., & Pavanello, S. (2020). Multiple single nucleotide polymorphisms of the transient receptor potential vanilloid 1 (TRPV1) genes associated with cough sensitivity to capsaicin in healthy subjects. Pulmonary pharmacology & therapeutics, 61, 101889. https://doi.org/10.1016/j.pupt.2020.101889)) and MUC5AC1 with an increased likelihood of developing cough following infections. These genes are associated with eliciting a cough reflex and mucus production respectively.

For a chronic cough to be considered as having a genetic cause, frequently hereditary patterns and a combination of symptoms are often considered. Since all these factors are not always present during the initial clinical presentation, it can take years to link a chronic cough to a possible genetic cause.

Conclusion

A chronic cough can be a troublesome symptom, more so if an underlying cause is not sourced out. It frequently worsens and interrupts one’s quality of life, with all the medications required, as well as doctor visits to find out a cause. Using a cough tracking application on your smartphone to understand how your symptoms evolve can be a way to have more insightful conversations with your healthcare provider and help narrow down likely diagnoses. Ideally, if your cough doesn’t subside in a week or two, checking in with your healthcare provider is advised.

Because coughing will still be associated with common conditions likely to cause it, there is still a long way to go in understanding how genes play a role in chronic cough. More research can help enable earlier diagnosis and targeted treatment strategies, especially for those who suffer from a chronic cough with no known cause((Millqvist E. (2016). TRPV1 and TRPM8 in Treatment of Chronic Cough. Pharmaceuticals (Basel, Switzerland), 9(3), 45. https://doi.org/10.3390/ph9030045)).

  1. Li, Y., & Tang, X. X. (2021). Abnormal Airway Mucus Secretion Induced by Virus Infection. Frontiers in immunology, 12, 701443. https://doi.org/10.3389/fimmu.2021.701443 []

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