Exome sequencing of extreme phenotypes identifies DCTN4 as a modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis.

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Emond et al are reporting in Nat Genetics the identification of DCTN4 as a modifier for P.aeruginosa infection in patients with cystic fibrosis. It is a well-established fact that the majority of patients with cystic fibrosis develop acute and chronic P.aerugonisa infections which are associated with a worse clinical outcome. The authors selected and exome sequenced 91 patients from the EPIC collection with cystic fibrosis and P.aeruginosa and after performing logistic regression adjusted for ancestry and for CFTR mutation risk group identified DCTN4 as the only modifier gene. Dynactin 4 is a component of the dynein-dependent motor that moves autophagosomes along microtubules into lysosomes for degradation as part of the autophagy process which has an essential role in the clearance of P. aeruginosa. The presence of at least one DCTN4 missense variant was significantly associated with both early age of first P. aeruginosa–positive culture and with early age at onset of chronic P. aeruginosa infection. The authors are also noticing that none of the identified variants could have been picked by a GWAS given the sample size of EPIC, the low frequency of the identified variants and their poor tagging by the commercially available platforms.

Periklis Makrythanasis, MD, PhD

OMMBID chapter 201: Cystic fibrosis

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