Monogenic diseases

Monogenic diseases (table 1) are rare diseases attributable to genetic variants with large effects on disease status. Because of the high penetrance of such variants, the disease is typically inherited in a classical Mendelian fashion (e.g. dominant or recessive). The best-known monogenic respiratory diseases are CF and α1-antitrypsin deficiency, but hundreds of rare monogenic diseases affecting the respiratory system have been described. We refer the interested reader to the Online Mendelian Inheritance in Man (OMIM) website, which is a comprehensive, authoritative and continuously updated compendium of human genes and genetic phenotypes (see Further reading).

Gene/locus Gene name Chromosomal
location#
Gene product: protein function Disease
CFTR CF transmembrane conductance
regulator
7q31.2 Ion channel: chloride transport CF
SERPINEA1 α1-antitrypsin 14q32.13 Serine protease inhibitor α1-antitrypsin deficiency (COPD,
emphysema, liver disease)
DNAI1 Dynein, axonemal, intermediate
chain 1
9p13.3 Dynein arm: ciliary function CILD1, with or without situs inversus (Kartagener syndrome)
CYBB p91-phox (phagocyte oxidase): beta
subunit of cytochrome b, component
of the phagocyte NADPH oxidase
complex
Xp11.4 Killing of microbes in phagocytes by
generation of reactive oxygen species
CGD, X-linked
CYBA p22-phox (phagocyte oxidase): alpha
subunit of cytochrome b, component
of the phagocyte NADPH oxidase
complex
16q24.3 Killing of microbes in phagocytes by
generation of reactive oxygen species
CGD, autosomal recessive
SFTPC Surfactant, pulmonary-associated
protein C
8p21.3 Surfactant proteins are essential for
lung function, preventing lung collapse
by lowering surface tension
Respiratory distress syndrome of
prematurity
SFTPB Surfactant, pulmonary-associated
protein B
2p11.2 Surfactant proteins are essential for
lung function, preventing lung collapse
by lowering surface tension
Respiratory distress syndrome of
prematurity
Table 1 – Monogenic respiratory diseases (inherited in a Mendelian fashion). Only seven out of more than 100 known monogenic respiratory diseases are presented as illustration. #: p refers to the short arm of the chromosome. q refers to the long arm of the chromosome. The location numbers after p and q reflect the relative distance to the centromeres of the chromosomes (numbering by convention). CF: cystic fibrosis; COPD: chronic obstructive pulmonary disease; CILD1: ciliary dyskinesia, primary 1; NADPH: nicotinamide adenine dinucleotide phosphate; CGD: chronic granulomatous disease.

Cystic fibrosis

CF is an autosomal recessive genetic disorder (i.e. both inherited copies of the gene need to be mutated in order for disease to result; or to put it another way, one healthy copy of the gene is enough to prevent CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR ) gene on chromosome 7. The CFTR protein is an ion channel that regulates transport of chloride ions (Cl-) in epithelial cells in the airways, as well as in the pancreas, liver, intestine and skin. More than 1000 mutations of the CFTR gene have been described. In Europe, the most common is the ΔF508 mutation (a deletion of three DNA bases). The resulting CFTR protein has a missing amino acid (phenylalanine) in position 508. One in 25 people of European descent carries one mutant allele of CFTR, and one person in 2000–3000 is affected by CF. The various CFTR mutations cause different CFTR protein defects, which impair transport of chloride and sodium across epithelial surfaces, leading to thick viscous secretions (e.g. mucus or phlegm).

CFTR modulators and potentiators are drugs that aim to correct the underlying defect that leads to CF by modifying the function of the CFTR protein. Since the therapeutic effects of CFTR modulators are based on individual protein defects, knowledge of the genotype of both alleles of the CFTR gene is necessary for appropriate patient selection. As an example, ivacaftor, which was approved for use by the US Food and Drug Administration in January 2012, targets the specific CFTR mutation G551D (in which glycine in position 551 is substituted with aspartic acid), improves lung function and reduces respiratory symptoms and pulmonary exacerbations in patients with CF who have at least one G551D CFTR mutation.

α1-antitrypsin deficiency

α1-antitrypsin is a protease inhibitor, produced mainly in the liver, which protects the lungs against proteolytic damage by the enzyme neutrophil elastase. α1-antitrypsin is encoded by the SERPINA1 gene (also known as PI). Like CF, α1-antitrypsin deficiency is an autosomal recessive inherited disorder affecting 1 in 2000–5000 persons in Europe. It increases the risk of liver disease, COPD and emphysema. Those with two copies of the most severe “Z” mutation (PI ZZ genotype) have very low serum protein levels of α1-antitrypsin. Cigarette smoking greatly increases the risk of COPD in α1-antitrypsin-deficient patients, leading to severe, early-onset emphysema due to destruction of alveolar septa in the lung as a consequence of the protease–antiprotease imbalance.

Primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD), or immotile cilia syndrome, is a genetically heterogeneous autosomal recessive disorder, caused by loss of function of different parts of the cilia, which line the epithelial cells of the airway mucosa and are responsible for clearing secretions and foreign material. Patients with PCD suffer from recurrent upper and lower respiratory tract infections, often leading to bronchiectasis, an abnormal widening of the airways. About half of people with PCD have Kartagener syndrome, in which PCD is combined with situs inversus (a condition in which the position of the major organs is a mirror image of the normal arrangement).

Other monogenic diseases encompass diseases caused by mutations in surfactant proteins, which are crucial in decreasing tension forces during breathing. Dysfunction of surfactant caused by mutations in surfactant protein genes leads to respiratory distress syndrome of prematurity. Mutations in cytochrome b, an enzyme involved in killing microbes in phagocytic cells, predispose individuals to recurrent respiratory infections (see the section on chronic granulomatous diseases later in this chapter).

See the entire Genetic Susceptibility Chapter