Evaluation of the implementation of whole exome sequencing (WES) followed by a virtual gene panel for diagnosis of inherited thrombocytopenias (IT)

KAMIYA LJ; GOETTE NP; VEBER E; ALTUNA D; LAGROTTA P; GLEMBOTSKY AC; MARTA RF; BASAK N; NEGRO F; ARRIETA ME; HELLER MV; GANIEWICH D; DE LUCA, GERALDINE; DONATO H; MARTI A; LLERA A

Mar del Plata

Congreso; Reunión anual de Biociencias 2022 y LXVII Reunión anual de Sociedad Argentina de Investigación Clínica; 2022

Sociedad Argentina de Investigación Clínica

IT are a heterogeneous group of rare disorders caused by defects in genes involved in platelet production and function. Although 50 genes have been described, the defect is unknown in a large proportion of cases. Development of extrahematological manifestations or leukemia in certain disorders highlights the importance of accurate diagnosis allowing personalized follow-up. Introduction of NGS has revolutionized IT diagnosis.We describe our experience on IT diagnosis after implementation of WES. Patients (n=31) from 20 IT families were included after ethical approval. Clinical and platelet phenotype were obtained and WES was performed in an Illumina sequencer and analyzed following good bioinformatic practices. Variants from a virtual panel of IT-related genes were selected for curation and confirmed by Sanger sequencing.Twenty variants were found in 10 genes:MYH9,NBEAL2,WAS,GP1BA,GP1BB, ACTN1,RUNX1,IKZF5,ITGB3,ITGA2B, 6 of them were novel. According to ACMG guidelines, 6 variants were classified as pathogenic and 9 as likely pathogenic, yielding a diagnostic rate of 65% (13/20 families): MYH9-related disorder, 5 families; Gray Platelet Syndrome, 3; monoallelic Bernard-Soulier, 3; Wiskott-Aldrich, 1; ACTN1 related-thrombocytopenia, 1. The phenotype matched the genetic diagnosis in 77% of these families, while in 23% WES was essential for diagnosis, as there was no previous clinical suspicion.Variants of uncertain significance (n=5) were found in 4 other families. Analysis of the rest of the exome in cases without causative variants failed to identify candidate variants in genes currently unrelated to IT.In conclusion, combination of clinical and platelet phenotypic characterization with genomic techniques proved to be fundamental for IT diagnosis. Our diagnostic rate compared favorably with other centers, indicating the feasibility of this approach in our setting. Considering there are no similar local initiatives, this would cover unmet medical need in our region.