Candidate genes and sequence variants for susceptibility to mycobacterial infection identified by whole-exome sequencing

Alexander Varzari*, Igor V. Deyneko, Gitte Hoffmann Bruun, Maja Dembic, Winfried Hofmann, Victor M. Cebotari, Sergei S. Ginda, Brage S. Andresen, Thomas Illig


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Inborn errors of immunity are known to influence susceptibility to mycobacterial infections. The aim of this study was to characterize the genetic profile of nine patients with mycobacterial infections (eight with BCGitis and one with disseminated tuberculosis) from the Republic of Moldova using whole-exome sequencing. In total, 12 variants in eight genes known to be associated with Mendelian Susceptibility to Mycobacterial Disease (MSMD) were detected in six out of nine patients examined. In particular, a novel splice site mutation c.373–2A>C in STAT1 gene was found and functionally confirmed in a patient with disseminated tuberculosis. Trio analysis was possible for seven out of nine patients, and resulted in 23 candidate variants in 15 novel genes. Four of these genes - GBP2, HEATR3, PPP1R9B and KDM6A were further prioritized, considering their elevated expression in immune-related tissues. Compound heterozygosity was found in GBP2 in a single patient, comprising a maternally inherited missense variant c.412G>A/p.(Ala138Thr) predicted to be deleterious and a paternally inherited intronic mutation c.1149+14T>C. Functional studies demonstrated that the intronic mutation affects splicing and the level of transcript. Finally, we analyzed pathogenicity of variant combinations in gene pairs and identified five patients with putative oligogenic inheritance. In summary, our study expands the spectrum of genetic variation contributing to susceptibility to mycobacterial infections in children and provides insight into the complex/oligogenic disease-causing mode.

TidsskriftFrontiers in Genetics
StatusUdgivet - 20. okt. 2022

Bibliografisk note

Funding Information:
This study was supported by the Hannover Unified Biobank. Alexander Varzari was sponsored by the Alexander von Humboldt Foundation (Georg Forster Research Fellowship) and by the Moldovan State Program Particularităţile recidivei tuberculozei pulmonare (theme No. 20.80009.8007.23). The research of Igor Deyneko was carried out within the assignment of Ministry of Science and Higher Education (theme No. 122042700043-9) and development of bioinformatics methods by RSF grant (project No. 22-14-00057).

Publisher Copyright:
Copyright © 2022 Varzari, Deyneko, Bruun, Dembic, Hofmann, Cebotari, Ginda, Andresen and Illig.


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