Primer immün yetmezliğe sahip hastaların klinik, immünolojik ve moleküler genetik değerlendirilmesi ve yeni tanımlanan varyantlar
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Tarih
2023
Yazarlar
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Yayıncı
Necmettin Erbakan Üniversitesi Meram Tıp Fakültesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Amaç: Primer İmmün Yetmezlik Hastalığı (PİYH), bağışıklık sisteminde görev alan unsurların, doğumsal ya da primer gelişim ve olgunlaşma basamaklarını ilgilendiren bozukluklar nedeniyle meydana gelen, otoimmünite, immündisregülasyon ve kronik ve/veya yineleyen enfeksiyonlarla sonuçlanan bir hastalık grubudur. Moleküler tanının zorluğu ve fenotipik sınıflandırmadaki değişiklikler nedeniyle özellikle farklı popülasyonlara ait genomik veri bugüne değin sınırlı kalmıştır. Bu çalışmada merkezimizce incelenen tüm hastaların fenotipik özellikleri ve genotipik altyapıları birlikte değerlendirilerek, Türk toplumunda görülen değişimlere dair fikir edinmek, insidental verilere ulaşmak, genotip-fenotip korelasyonuna dair içgörümüzü geliştirmek ve daha önce tanımlanmamış varyantları inceleyerek klinik veri ile korrelasyonlarını değerlendirmek amaçlanmıştır.
Yöntem: Çalışmamızda, 2017 ile 2021 yılları arasında Necmettin Erbakan Üniversitesi Meram Tıp Fakültesi Hastanesi Tıbbi Genetik Bölümü’ne immün yetmezlik ön tanısı ve/veya ilintili şikayetleriyle başvurmuş ve ön değerlendirmeden geçirdikten sonra, DNA izole edilmiş, ve immün yetmezliklerin tanı ve takibinde yeri olduğu gösterilmiş 64 adet geni içeren bir panel, NGS (Next Generation Sequencing – Yeni Nesil Dizileme) yöntemi ile genetik açıdan analiz edilmiş, ve nihayetinde hastaların fenotipik ve genotipik verileri değerlendirilmiştir. Buna ek olarak ebeveyn çalışmaları için belirlenen bölgelere Sanger dizi analizi çalışılmış ve analiz edilmiştir.
Bulgular: Bazı hastalarda birden çok gen değişimi raporlandığından, 224 hastada olası benign, önemi bilinmeyen varyant, olası patojenik ve patojenik sınıflarına dâhil olan toplam 354 varyant raporlandı. En sık raporlanan gen DOCK8 idi (36 hasta, 10,2%), bunu LRBA (25 hasta, 7.2%), ATM (24 hasta, 6.9%), TNFRSF13B (20 hasta, 5.8%) ve PRF1 (17 hasta, 4.9%) izlendi.
IV
Sonuç: Çalışmamızda, immün sistem bozuklukları ile ilişkili genlerdeki değişimlerin kapsamlı bir değerlendirmesi yapılmış, patojenitesi bugüne değin netleşmemiş veya literatürde daha önce hiç bildirilmemiş varyantlar tartışılarak yeni genotip fenotip ilişkilendirmeleri yapılmıştır. Elde edilen veriler, literatüre sağlayacağı katkının yanında bu alanda gelecekte planlanacak araştırmalar ve hastalara yaklaşm için yol gösterici olabilir.
Background/Aim: Primary Immunodeficiency defines a group of disorders that occur due to congenital, developmental and/or maturational disruptions of immune system elements; resulting in autoimmunity, immune dysregulation, and chronic/recurrent infections. Diseases in this group occur as a result of inherited gene defects that damage the production or structure of the components involved in the functioning of the immune system. The significance of genetic tests has been increasingly understood in regard with many aspects of primary immunodeficiencies; including making a definitive diagnosis, overseeing the prognosis, choosing the treatment procedure and determining the subtype and finally, genetics has become an indispensable mainstay in the evaluation of this group of patients in recent years. In this study, by concurrently evaluating the phenotypic features and the genotypic backgrounds of all patients we aimed to gain an idea about the changes seen in the Turkish population, to access incidental data, and also to improve our insight into the genotype-phenotype correlation by reviewing the previously undefined variants with their clinical data. Methods: Patients that have applied to Necmettin Erbakan University Meram Medical Faculty Hospital, Department of Medical Genetics between 2017 and 2021 with pre-diagnosis of immunodeficiency and/or related complaints were included. After pre-evaluation step consisting of history and physical examination, patient DNAs were isolated using a previously defined DNA isolation method from at least 3cc blood in an EDTA tubes. After the isolation, NGS analysis was performed with the "Primary Immunodeficiency - Celemics Target Capture Kit" containing 64 genes that have been shown to be related with immunodeficiencies. The phenotypic and genotypic data of the patients were evaluated and were classified according to ACMG (American College of Medical Genetics) guidelines based on database searches and in-silico analyzes simulating protein function. Results: As multiple gene alterations were reported in some samples, a total of 354 variants were reported in 224 patients, falling into the classes of likely benign, variants of unknown VI significance, likely pathogenic, and pathogenic. The most frequently reported gene was DOCK8 (36 patients, 10.2%), followed by LRBA (25 patients, 7.2%), ATM (24 patients, 6.9%), TNFRSF13B (20 patients, 5.8%) and PRF1 (17 patients, 4.9%). Conclusion: A comprehensive evaluation of the changes in the genes associated with immune system disorders was made, and new genotype phenotype associations were established by discussing the variants whose pathogenicity has not been clarified until now or have never been reported in the literature before. The data obtained can be a guide for future research and approach to patients in this field, in addition to its contribution to the literature.
Background/Aim: Primary Immunodeficiency defines a group of disorders that occur due to congenital, developmental and/or maturational disruptions of immune system elements; resulting in autoimmunity, immune dysregulation, and chronic/recurrent infections. Diseases in this group occur as a result of inherited gene defects that damage the production or structure of the components involved in the functioning of the immune system. The significance of genetic tests has been increasingly understood in regard with many aspects of primary immunodeficiencies; including making a definitive diagnosis, overseeing the prognosis, choosing the treatment procedure and determining the subtype and finally, genetics has become an indispensable mainstay in the evaluation of this group of patients in recent years. In this study, by concurrently evaluating the phenotypic features and the genotypic backgrounds of all patients we aimed to gain an idea about the changes seen in the Turkish population, to access incidental data, and also to improve our insight into the genotype-phenotype correlation by reviewing the previously undefined variants with their clinical data. Methods: Patients that have applied to Necmettin Erbakan University Meram Medical Faculty Hospital, Department of Medical Genetics between 2017 and 2021 with pre-diagnosis of immunodeficiency and/or related complaints were included. After pre-evaluation step consisting of history and physical examination, patient DNAs were isolated using a previously defined DNA isolation method from at least 3cc blood in an EDTA tubes. After the isolation, NGS analysis was performed with the "Primary Immunodeficiency - Celemics Target Capture Kit" containing 64 genes that have been shown to be related with immunodeficiencies. The phenotypic and genotypic data of the patients were evaluated and were classified according to ACMG (American College of Medical Genetics) guidelines based on database searches and in-silico analyzes simulating protein function. Results: As multiple gene alterations were reported in some samples, a total of 354 variants were reported in 224 patients, falling into the classes of likely benign, variants of unknown VI significance, likely pathogenic, and pathogenic. The most frequently reported gene was DOCK8 (36 patients, 10.2%), followed by LRBA (25 patients, 7.2%), ATM (24 patients, 6.9%), TNFRSF13B (20 patients, 5.8%) and PRF1 (17 patients, 4.9%). Conclusion: A comprehensive evaluation of the changes in the genes associated with immune system disorders was made, and new genotype phenotype associations were established by discussing the variants whose pathogenicity has not been clarified until now or have never been reported in the literature before. The data obtained can be a guide for future research and approach to patients in this field, in addition to its contribution to the literature.
Açıklama
Anahtar Kelimeler
Genetik, Genotip-Fenotip Korelasyonu, Primer İmmün Yetmezlik, Varyant, Genetics, Genotype-Phenotype Correlation, Primary Immune Deficiency, Variant
Kaynak
WoS Q Değeri
Scopus Q Değeri
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Künye
Arslan. A. B. (2023). Primer immün yetmezliğe sahip hastaların klinik, immünolojik ve moleküler genetik değerlendirilmesi ve yeni tanımlanan varyantlar. (Yayınlanmamış tıpta uzmanlık tezi) Necmettin Erbakan Üniversitesi, Meram Tıp Fakültesi Dahili Tıp Bilimleri Bölümü Tıbbi Genetik Anabilim Dalı, Konya.
