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)