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

Germline pathogenic variants in are associated with familial platelet disorder with predisposition to myeloid malignancies (FPD/MM) with intragenic deletions in accounting for almost 7% of all reported variants. We present two new pedigrees with FPD/MM carrying two different germline 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 resulting in a change in the 3' sequence of . Expression analysis of the transcript isoform demonstrated altered ratios in carriers from both families compared to controls. Our data provide evidence on the impact of intragenic deletions on transcript isoform expression and highlight the importance of routinely performing copy number variant analysis in patients with suspected MM with germline predisposition.