Detection and evolutionary dynamics of somatic FAS variants in autoimmune lymphoproliferative syndrome: Diagnostic implications

• DOI: 10.3389/fimmu.2022.1014984
• Publication Date: 2022-11-18T08:01:41Z
• Authors: Laura Batlle-Masó; Marina Garcia-Prat; Alba Parra-Martínez; Clara Franco-Jarava; Aina Aguiló-Cucurull; Pablo Velasco; María Antolín; Jacques G. Rivière; Andrea Martín-Nalda; Pere Soler-Palacín; Mónica Martínez-G...; Roger Colobran
• Keywords: Sanger sequencing; Autoimmune lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is a rare primary immune disorder characterized by impaired apoptotic homeostasis. The clinical characteristics include lymphoproliferation, autoimmunity (mainly cytopenia), and an increased risk of lymphoma. A distinctive biological feature accumulation (>2.5%) abnormal cell subset composed TCRαβ + CD4 - CD8 T cells (DNTs). most common genetic causes ALPS are monoallelic pathogenic variants in the FAS gene followed somatic variants, mainly restricted to DNTs. Identification has been typically addressed Sanger sequencing isolated However, this approach can be costly technically challenging, may not successful patients with normal DNT counts receiving immunosuppressive treatment. In study, we identified novel mutation (c.718_719insGTCG) on purified CD3 cells. We then evolutionary dynamics variant along time NGS-based involving deep amplicon (DAS) at high coverage (20,000-30,000x). Over five years follow-up, obtained six blood samples for molecular study from pre-treatment (DNTs>7%) treatment (DNTs<2%) periods. DAS enabled detection all samples, even one after (DNTs: 0.89%). allele frequency (VAF) range was 4%-5% <1.5% there strong positive correlation between VAF (Pearson’s R: 0.98, p=0.0003). explored whether same could used discovery setting. last follow-up sample (DNT: 0.89%) performed calling exon 9 data whole using VarScan 2. c.718_719insGTCG both showed highest (0.67% blood, 1.58% cells) among >400 called. summary, our illustrates before during results show that use regardless their counts.