Genetic carriers (+/-) with one copy of a good gene often do not manifest in notable disease phenotypes. However, marriages between two carrier individuals can result in the birth of children with two copies of the mutant genes (-/-) that manifest as a disease. Discovering new rare disease are often facilitated by studying families of cousin marriages. 

Our recent study of a pediatric patient with recurrent lung infection resulted in the discovery of a novel disease with multiple lung symptoms including bronchiectasis. Genetic analysis of the patient, siblings and parents showed that a single mutation in MUC5B gene was responsible for this disease [1,2,3]. MUC5B is a gel-forming mucin, important for proper mucociliary clearance of bacteria and dead immune cells from the airways of the lung. Two children born to a related cousin marriage resulted in recurrent lung infection and subsequent death of these children before the age of 28 years. Analyses of the family members showed that the patient often gets Staphylococcus aureus Gram-positive bacterial infection of the lungs, and accumulate dead and dying cells in the airways.

Another group also identified genetic mutations in various lung-specific genes including MUC5B, among the family members who marry within close relatives. The affected patient also had lung alterations at alveolar level [4]. 

Therefore, the identification of this mutation lead to the discovery a novel lung disease caused by the deficiency of MUC5B, and warrants doing genetic analyses of children who have unexplained recurrent lung infections to identify this disease. Early identification of this disease could help treat these patients appropriately.

 References: 

1. Liu, Z., Costain, G., Goczi, A., Albulescu, A., Walker, S., Ngan, B., Hall, D.A., Marshall, C.R., Mennella, V., Kesimer, M., Knowles, M., Zariwala, M.A., Dell, S.D. (2020) Hereditary Mucin Deficiency Caused by Biallelic Loss-of-Function of MUC5B Defines a Novel Category of Lung Disease. Am Thor Soc International Conference, May 15-20, 2020 - Philadelphia, PA, USA
2. Costain G, Liu Z, Mennella V, Radicioni G, Goczi AN, Albulescu A, Walker S, Ngan B, Manson D, Vali R, Khan M, Palaniyar N, Hill DB, Hall DA, Marshall CR, Knowles M, Zariwala MA, Kesimer M, Dell SD. (2022). Hereditary Mucin Deficiency Caused by Biallelic Loss of Function of MUC5B. Am J Respir Crit Care Med. 2022 Apr 1;205(7):761-768. doi: 10.1164/rccm.202106-1456OC. PMID: 35023825
3. Liegeois, MA, Fahy JV (2022). Editorial: The Mucin Gene MUC5B Is Required for Normal Lung Function. Am J Respir Crit Care Med Vol 205, Iss 7, pp 737–750, Apr 1, 2022. DOI: 10.1164/rccm.202201-0064ED
4. Alsamri MT, Alabdouli A, Alkalbani AM, Iram D, Tawil MI, Antony P, Vijayan R, Souid A-K (2021) Genetic variants of small airways and interstitial pulmonary disease in children. Sci Rep. 2021 Feb 1;11(1):2715. doi: 10.1038/s41598-021-81280-x. PMID: 3352688