Genetic Testing
A next-generation sequencing (NGS) based panel of genes associated with inherited thrombocytopenia was performed at Versiti Diagnostic Laboratories in a blood sample of patient B. The germline heterozygousETV6 c.1085A>G (p.Asp362Gly) missense variant was identified. This variant occurs in a well-conserved nucleotide and is located in the ETS domain, the functional domain in ETV6 that binds DNA. The variant had not been reported in the literature or in the general population. Due to limited evidence, using the criteria developed by the American College of Medical Genetics (ACMG) and the Association for Molecular Pathology (AMP), the variant was classified as a variant of uncertain significance (VUS). However, it was suspected to be implicated in the low platelet counts seen in this family.
Familial testing to provide additional evidence for variant classification using segregation was undertaken (Figure 1 ). The variant segregated with the thrombocytopenic trait in all individuals tested. Those who were ETV6 wild type had normal platelet counts. Subtle elevations in red blood cell size were noted and considered part of the collective additional evidence. Familial studies provided sufficient evidence to reach a likely pathogenic classification for the familial variant.
FIGURE 1 Pedigree showing the segregation of the ETV6c.1085A>G variant within the extended family of the proband (patient B)