Inherited Pulmonary Disorders


Hereditary lung diseases can affect the airways (asthma, COPD, cystic fibrosis and primary ciliary dyskinesia), parenchyma (pulmonary fibrosis, Birt–Hogg–Dubé syndrome and, tuberous sclerosis) and vasculature (hereditary haemorrhagic telangiectasia) of the lung. Such conditions include simple monogenic disorders such as Kartagener syndrome and α1‐antitrypsin, wherein mutations of critical genes are sufficient to induce well‐defined disease phenotypes. However, many are complex genetic traits in which inheritance subtly affects pathogenesis, for example asthma and idiopathic pulmonary fibrosis. A greater understanding of the genetic basis of pulmonary conditions has provided new insights into their underlying pathophysiology and helped in some cases to shed light on more common sporadic forms. Importantly, the identification of causative genes has also enabled prenatal diagnosis and genetic counselling to be introduced for many diseases.

Key Concepts

  • Common diseases frequently have a genetic component which with the advent of genome‐wide association studies can now be elucidated.
  • The study of rare monogenic disorders can provide important mechanistic clues to the pathogenesis of more common sporadic disease.
  • Pulmonary manifestations can be the presenting feature of several important inherited diseases.
  • Making a definitive genetic diagnosis permits the practicing of personised medicine.
  • Molecular testing using gene panels and whole genome sequencing is revolutionising respiratory medicine.

Keywords: idiopathic pulmonary fibrosis; fibrosing alveolitis; bronchiectasis; primary ciliary dyskinesia; hyaline membrane disease; serpinopathies; pneumothorax; Birt–Hogg–Dubé syndrome; tuberous sclerosis; hereditary haemorrhagic telangiectasia; Marfan syndrome

Figure 1. Histological appearance of normal alveoli (a) and alveoli affected by disease. (b) Lung biopsy from a baby with neonatal respiratory distress syndrome from insufficient surfactant. The formation of hyaline membranes grossly distorts the delicate alveolar architecture. (c) The airway from an individual with bronchiectasis. The airway wall is grossly thickened with fibrosis and there is inflammatory exudate within the lumen. (d) A patient with the usual interstitial pneumonitis variant of cryptogenic fibrosing alveolitis. The alveolar walls are thickened with collagen which impairs gaseous exchange. Kindly provided by Dr Martin Goddard, Papworth NHS Trust, Cambridge.
Figure 2. Diagram (a) and electron micrograph (b) of the cross section of normal cilia. The central part of the spermatozoan flagellum has an identical ultrastructure. Nine microtubular doublets surround two central microtubules. The dynein arms are responsible for causing the nine microtubules to slide relative to each other. The nexin links restrict the sliding with the result that the cilium bends. Kindly provided by Dr Jeremy Skepper, Multi‐imaging centre, Department of Anatomy, University of Cambridge, UK.
Figure 3. Members of the serine proteinase inhibitor or serpin superfamily, such as α1‐antitrypsin, may be considered to act as mousetraps. Following docking (a, left) the target proteinase (grey) is inactivated by movement from the upper to the lower pole of the protein (a, right). This is associated with insertion of the reactive loop (red) as an extra strand into β‐sheet A (green). The mousetrap mechanism may be triggered spontaneously by point mutations in association with disease. The Z mutation (Glu342 Lys) of α1‐antitrypsin is at the head of a strand of β ‐sheet A (green) and the base of the reactive loop. Mutations in this region can destabilise β‐sheet A to allow the insertion of a reactive loop of a second molecule (b, middle). This dimer then extends to form long chains of polymers (b, right). In this illustration, each molecule of α1‐antitrypsin in the polymer is illustrated by a different colour. It is these polymers which then tangle in the endoplasmic reticulum to cause inclusions that result in liver disease. (a,b) Reproduced from Lomas et al. © Nature Publishing Group. (c) An inclusion body (arrow) from the liver of a patient with α1‐antitrypsin deficiency (left). The inclusions are composed of chains of molecules of α1‐antitrypsin (right). Reproduced from Lomas et al. © The American Society for Biochemistry and Molecular Biology.
Figure 4. Birt–Hogg–Dubé syndrome is an autosomal dominant condition of lung cysts, benign skin tumours and renal cell carcinoma. Cysts can rupture to cause pneumothorax. Causative mutations are found in the Folliculin gene. Some Folliculin gene mutations appear to cause only the cystic lung disease without other features of Birt–Hogg–Dubé syndrome, as in the case illustrated. Note the irregular thin‐walled cysts (arrow heads). These are frequently found in a medial basal distribution.


Abolnik IZ , Lossos IS , Zlotogora J and Brauer R (1991) On the inheritance of primary spontaneous pneumothorax. American Journal of Medical Genetics 40 (2): 155–158.

Alder JK , Chen JJ , Lancaster L , et al. (2008) Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proceedings of the National Academy of Sciences of the United States of America 105 (35): 13051–13056.

Angulo I , Vadas O , Garçon F , et al. (2013) Phosphoinositide 3‐kinase δ gene mutation predisposes to respiratory infection and airway damage. Science 342: 866–871.

Bridges JP , Xu Y , Na CL , Wong HR and Weaver TE (2006) Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP‐C. Journal of Cell Biology 172 (3): 395–407.

Chambers JE , Dalton LE , Subramanian DN , et al. (2015) Spontaneous pneumothorax can be associated with TGFBR2 mutation. European Respiratory Journal 46: 1832–1835.

Chappell SL , Daly L , Lotya J , et al. (2011) The role of IREB2 and transforming growth factor beta‐1 genetic variants in COPD: a replication case‐control study. BMC Medical Genetics 12: 24.

Corbett E , Glaisyer H , Chan C , et al. (1994) Congenital cutis laxa with a dominant inheritance and early onset emphysema. Thorax 49 (8): 836–837.

Demeo DL , Mariani TJ , Lange C , et al. (2006) The SERPINE2 gene is associated with chronic obstructive pulmonary disease. American Journal of Human Genetics 78 (2): 253–264.

Gooptu B and Lomas DA (2008) Polymers and inflammation: disease mechanisms of the serpinopathies. Journal of Experimental Medicine 205 (7): 1529–1534.

Grange DK , Kaler SG , Albers GM , et al. (2005) Severe bilateral panlobular emphysema and pulmonary arterial hypoplasia: unusual manifestations of Menkes disease. American Journal of Medical Genetics Part A 139 (2): 151–155.

Guichard C , Harricane MC , Lafitte JJ , et al. (2001) Axonemal dynein intermediate‐chain gene (DNAI1) mutations result in situs inversus and primary ciliary dyskinesia (Kartagener syndrome). American Journal of Human Genetics 68: 1030–1035.

Hirano K , Sakamoto T , Uchida Y , et al. (2001) Tissue inhibitor of metalloproteinases‐2 gene polymorphisms in chronic obstructive pulmonary disease. European Respiratory Journal 18 (5): 748–752.

Holland SM , DeLeo FR , Elloumi HZ , et al. (2007) STAT3 mutations in the hyper‐IgE syndrome. New England Journal of Medicine 357 (16): 1608–1619.

Holloway JW , Yang IA and Holgate ST (2010) Genetics of allergic disease. Journal of Allergy and Clinical Immunology 125 (2 Suppl 2): S81–S94.

Hucthagowder V , Sausgruber N , Kim KH , et al. (2006) Fibulin‐4: a novel gene for an autosomal recessive cutis laxa syndrome. American Journal of Human Genetics 78 (6): 1075–1080.

Hunninghake GM , Cho MH , Tesfaigzi Y , et al. (2009) MMP12, lung function, and COPD in high‐risk populations. New England Journal of Medicine 361 (27): 2599–2608.

Hutyrova B , Pantelidis P , Drabek J , et al. (2002) Interleukin‐1 gene cluster polymorphisms in sarcoidosis and idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 165: 148–151.

Ito I , Nagai S , Handa T , et al. (2005) Matrix metalloproteinase‐9 promoter polymorphism associated with upper lung dominant emphysema. American Journal of Respiratory and Critical Care Medicine 172 (11): 1378–1382.

Kelleher CM , Silverman EK , Broekelmann T , et al. (2005) A functional mutation in the terminal exon of elastin in severe, early‐onset chronic obstructive pulmonary disease. American Journal of Respiratory Cell and Molecular Biology 33 (4): 355–362.

Lambrechts D , Buysschaert I , Zanen P , et al. (2010) The 15q24/25 susceptibility variant for lung cancer and chronic obstructive pulmonary disease is associated with emphysema. American Journal of Respiratory and Critical Care Medicine 181 (5): 486–493.

Lawson WE , Crossno PF , Polosukhin VV , et al. (2008) Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection. American Journal of Physiology. Lung Cellular and Molecular Physiology 294 (6): L1119–L1126.

Loeys B , Van Maldergem L , Mortier G , et al. (2002) Homozygosity for a missense mutation in fibulin‐5 (FBLN5) results in a severe form of cutis laxa. Human Molecular Genetics 11 (18): 2113–2118.

Lomas DA , Evans DL , Finch JT and Carrell RW (1992) The mechanism of Z a1‐antitrypsin accumulation in the liver. Nature 357: 605–607.

Lomas DA , Finch JT , Seyama K , Nukiwa T and Carrell RW (1993) a1‐Antitrypsin Siiyama (Ser53 Phe); further evidence for intracellular loop‐sheet polymerisation. Journal of Biological Chemistry 268: 15333–15335.

McCloskey SC , Patel BD , Hinchliffe SJ , et al. (2001) Siblings of patients with severe chronic obstructive pulmonary disease have a significant risk of airflow obstruction. American Journal of Respiratory and Critical Care Medicine 164 (8 Pt 1): 1419–1424.

Minematsu N , Nakamura H , Tateno H , Nakajima T and Yamaguchi K (2001) Genetic polymorphism in matrix metalloproteinase‐9 and pulmonary emphysema. Biochemical and Biophysical Research Communications 289 (1): 116–119.

Moffatt MF , Kabesch M , Liang L , et al. (2007) Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448 (7152): 470–473.

Mulugeta S , Nguyen V , Russo SJ , Muniswamy M and Beers MF (2005) A surfactant protein C precursor protein BRICHOS domain mutation causes endoplasmic reticulum stress, proteasome dysfunction, and caspase 3 activation. American Journal of Respiratory Cell and Molecular Biology 32 (6): 521–530.

Mulugeta S , Maguire JA , Newitt JL , et al. (2007) Misfolded BRICHOS SP‐C mutant proteins induce apoptosis via caspase‐4‐ and cytochrome c‐related mechanisms. American Journal of Physiology. Lung Cellular and Molecular Physiology 293 (3): L720–L729.

Nikolić MZ and Marciniak SJ (2017) Familial pneumothorax. Respiratory Disease in Practice 25: 8–11.

Nogee LM , Garnier G , Dietz HC , et al. (1994) A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds. Journal of Clinical Investigation 93: 1860–1863.

Nogee LM , Dunbar AE , Wert SE , et al. (2001) A mutation in the surfactant protein C gene associated with familial interstitial lung disease. New England Journal of Medicine 344: 573–579.

Olbrich H , Haffner K , Kispert A , et al. (2002) Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left–right asymmetry. Nature Genetics 30: 143–144.

Patel BD , Coxson HO , Pillai SG , et al. (2008) Airway wall thickening and emphysema show independent familial aggregation in COPD. American Journal of Respiratory and Critical Care Medicine 178: 500–505.

Pennarun G , Escudier E , Chapelin C , et al. (1999) Loss‐of‐function mutations in a human gene related to Chlamydomonas reinhardtii dynein IC78 result in primary ciliary dyskinesia. American Journal of Human Genetics 65: 1508–1519.

Pillai SG , Ge D , Zhu G , et al. (2009) A genome‐wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genetics 5 (3): e1000421.

Revencu N , Quenum G , Detaille T , et al. (2004) Congenital diaphragmatic eventration and bilateral uretero‐hydronephrosis in a patient with neonatal Marfan syndrome caused by a mutation in exon 25 of the FBN1 gene and review of the literature. European Journal of Pediatrics 163 (1): 33–37.

Shinawi M , Boileau C , Brik R , Mandel H and Bentur L (2005) Splicing mutation in the fibrillin‐1 gene associated with neonatal Marfan syndrome and severe pulmonary emphysema with tracheobronchomalacia. Pediatric Pulmonology 39 (4): 374–378.

Siedlinski M , Tingley D , Lipman PJ , et al. (2013) Dissecting direct and indirect genetic effects on chronic obstructive pulmonary disease (COPD) susceptibility. Human Genetics 132: 431–441.

Silverman EK , Chapman HA , Drazen JM , et al. (1998) Genetic epidemiology of severe, early‐onset chronic obstructive pulmonary disease. Risk to relatives for airflow obstruction and chronic bronchitis. American Journal of Respiratory and Critical Care Medicine 157 (6 Pt 1): 1770–1778.

Tekin M , Cengiz FB , Ayberkin E , et al. (2007) Familial neonatal Marfan syndrome due to parental mosaicism of a missense mutation in the FBN1 gene. American Journal of Medical Genetics Part A 143 (8): 875–880.

Tsakiri KD , Cronkhite JT , Kuan PJ , et al. (2007) Adult‐onset pulmonary fibrosis caused by mutations in telomerase. Proceedings of the National Academy of Sciences of the United States of America 104 (18): 7552–7557.

Urban Z , Gao J , Pope FM and Davis EC (2005) Autosomal dominant cutis laxa with severe lung disease: synthesis and matrix deposition of mutant tropoelastin. Journal of Investigative Dermatology 124 (6): 1193–1199.

Watkin LB , Jessen B , Wiszniewski W , et al. (2015) COPA mutations impair ER‐Golgi transport and cause hereditary autoimmune‐mediated lung disease and arthritis. Nature Genetics 47 (6): 654–660.

Whyte M , Hubbard R , Meliconi R , et al. (2000) Increased risk of fibrosing alveolitis associated with interleukin‐1 receptor antagonist and tumor necrosis factor‐a gene polymorphisms. American Journal of Respiratory and Critical Care Medicine 162: 755–758.

Zhou M , Huang SG , Wan HY , et al. (2004) Genetic polymorphism in matrix metalloproteinase‐9 and the susceptibility to chronic obstructive pulmonary disease in Han population of south China. Chinese Medical Journal 117 (10): 1481–1484.

Zhu G , Warren L , Aponte J , et al. (2007) The SERPINE2 gene is associated with chronic obstructive pulmonary disease in two large populations. American Journal of Respiratory and Critical Care Medicine 176 (2): 167–173.

Further Reading

Afzelius BA (1998) Immotile cilia syndrome: past, present, and prospects for the future. Thorax 53: 894–897.

Afzelius BA (2000) Ciliary structure in health and disease. Acta Oto‐Rhino‐Laryngologica Belgica 54: 287–291.

Baba M , Hong SB , Sharma N , et al. (2006) Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proceedings of the National Academy of Sciences of the United States of America 103 (42): 15552–15557.

Carrell RW and Lomas DA (2002) Alpha1‐antitrypsin deficiency: a model for conformational diseases. New England Journal of Medicine 346: 45–53.

Cole FS , Hamvas A and Nogee LM (2001) Genetic disorders of neonatal respiratory function. Pediatric Research 50: 157–162.

Floros J and Kala P (1998) Surfactant proteins: molecular genetics of neonatal pulmonary diseases. Annual Review of Physiology 60: 365–384.

Gunji Y , Akiyoshi T , Sato T , et al. (2007) Mutations of the Birt–Hogg–Dubé gene in patients with multiple lung cysts and recurrent pneumothorax. Journal of Medical Genetics 44 (9): 588–593.

Katzenstein A‐LA and Myers JL (1998) Idiopathic pulmonary fibrosis. Clinical relevance and pathological classification. American Journal of Respiratory and Critical Care Medicine 157: 1301–1315.

Lomas DA (2002) Alpha1‐antitrypsin deficiency and the serpinopathies. In: Warrell DA , Cox TM and Firth J (eds) Oxford Textbook of Medicine, 4th edn. Oxford, UK: Oxford University Press. DOI: 10.1093/med/9780199204854.003.1213_update_001

Lomas DA and Mahadeva R (2002) Alpha‐1‐antitrypsin polymerisation and the serpinopathies: pathobiology and prospects for therapy. Journal of Clinical Investigation 110: 1585–1590.

Marciniak SJ and Lomas DA (2009) What can naturally occurring mutations tell us about the pathogenesis of COPD? Thorax 64: 359–364.

Seaton A , Seaton D and Leitch AG (eds) (1989) Crofton and Douglas's Respiratory Diseases, 4th edn. Oxford, UK: Blackwell Science Ltd.

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Marinicak, Stefan J, and Lomas, David A(Aug 2017) Inherited Pulmonary Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005517.pub3]