Naslov
Contribution of the whole exome sequencing in the identification of genetic variants associated with childhood-onset systemic lupus and IgA vasculitis

Autori
Šestan, Mario

Vrsta, podvrsta i kategorija rada
Ocjenski radovi, doktorska disertacija

Fakultet
Medicinski fakultet

Mjesto
Zagreb

Datum
25.07

Godina
2022

Stranica
244

Mentor
Jelušić, Marija ; Vinuesa G. Carola

Ključne riječi
Kabuki Syndrome ; Disease Resistance ; IgA Vasculitis ; Leukocytes ; Mononuclear ; Skin Pigmentation ; Lupus Erythematosus ; Systemic

Sažetak
Introduction and aim. Childhood-onset systemic lupus erythematosus (cSLE) and IgA vasculitis (IgAV) are two complex autoimmune diseases with etiopathogenesis which are not fully understood. This research aimed to identify novel and rare gene variants using whole exome sequencing (WES) in patients with cSLE and IgAV which may contribute to the etiopathogenesis of these diseases, and to expand existing genetic databases. Subjects and methods. WES was performed on 17 "trio" groups containing a proband case with cSLE and parents (including other informative family members) and on 3 "trios" containing a proband case with IgAV, and parents with severe, atypical clinical features, syndromic characteristics, early onset of the disease, resistance to conventional therapy and/or a family pattern of occurrence. After completion of WES, data analysis and the identification of all the genetic variants of interest, the presence of an interferon gene expression signature in peripheral blood mononuclear cell samples was investigated on one patient. Results. After performing WES and analysis of gene variants, novel and/or rare variants were detected in 8 patients. Among them, there were 7 patients diagnosed with cSLE and 1 patient with IgAV, while 1 patient was diagnosed with cSLE and IgAV in a different period. A total number of 20 variants were prioritised for more detailed analysis. WES analysis yielded a new pathogenic variant in the histone-lysine N- methyltransferase 2D gene (KMT2D), NM_003482.3:c.8626delC, predicted to truncate the protein (p.Gln2876Serfs*34) resulting in KMT2D loss of function, explaining a previously unrecognised syndrome which features in a patient with Kabuki syndrome and cSLE. In addition, likely pathogenic variants were identified in the adenosine deaminase acting on the RNA gene (ADAR1), NM_001111.3:c.2815A>G, predicted to encode the protein (p.Ile939Val) in a patient with dysmorphic features, skin pigmentation changes and cSLE, only partially explaining the very complex phenotype, as well as in the B lymphocyte kinase gene (BLK), NM_001715.2 ; c.211G>A, predicted to encode (p.Ala71Thr) in a patient with severe cSLE and multisystemic involvement with the same disease in her mother which is worth further functional analysis. Among the number of variants of uncertain significance (VUS) in patients with cSLE and IgAV, the most promising, in terms of contribution to the development of the disease and the impact on the clinical picture, are recombination activating 2, RAG2 (NM_000536.3:c.1393A>G) predicted to encode (p.The465Ala), tyrosine-protein kinase 2, TYK2 (NM_003331.4:c.2492A>T) predicted to encode (p.Asp810Val), B-cell lymphoma 2 associated antagonist of cell death, BAD (NM_004322.3:c.462G>C) predicted to encode (p.Trp154Cys), and DExH-box helicase 58, DHX58 (NM_024119.2:c.560A>G) predicted to encode (p.Gln187Arg), making them candidates for further function analyses. Conclusion. In the new epoch of personalised medicine, implementation of next generation sequencing has improved the diagnostics and treatment of patients with autoimmune diseases. Nevertheless, such quantities of data raised the problem of interpretation of genetic variants and their use for therapeutic purposes. Undeniably, pathogenic variants often represent only a small percentage of all the variants reported, while there is growing number of variants which we are still not able to clearly define and use in a clinical context, such as VUS, which limit the clinical utility of genetic information. This has to prompt the scientific community to develop methods to properly categorise VUS and escalate the amount of practicable information from next generation sequencing.

Izvorni jezik
Engleski

Znanstvena područja
Kliničke medicinske znanosti

POVEZANOST RADA