Familial platelet disorder due to germline exonic deletions in <i>RUNX1</i>: a diagnostic challenge with distinct alterations of the transcript isoform equilibrium.

Germline pathogenic variants in <i>RUNX1</i> are associated with familial platelet disorder with predisposition to myeloid malignancies (FPD/MM) with intragenic deletions in <i>RUNX1</i> accounting for almost 7% of all reported variants. We present two new pedigrees with FPD/MM carrying two different germline <i>RUNX1</i> intragenic deletions. The aforementioned deletions encompass exons 1-2 and 9-10 respectively, with the exon 9-10 deletion being previously unreported. RNA sequencing of patients carrying the exon 9-10 deletion revealed a fusion with <i>LINC00160</i> resulting in a change in the 3' sequence of <i>RUNX1</i>. Expression analysis of the transcript isoform demonstrated altered <i>RUNX1a/b/c</i> ratios in carriers from both families compared to controls. Our data provide evidence on the impact of intragenic <i>RUNX1</i> deletions on transcript isoform expression and highlight the importance of routinely performing copy number variant analysis in patients with suspected MM with germline predisposition.