Upfront whole genome and transcriptome sequencing to improve diagnosis in inherited bone marrow failure syndromes

Upfront genome and transcriptome sequencing on non-hematopoietic DNA, detecting among others retrotransposon-mediated gene disruption

Upfront whole genome and transcriptome sequencing (WGTS) was evaluated in 237 patients with suspected inherited bone marrow failure syndrome, using non-hematopoietic DNA, in an accredited setting with real-time return of results. Median age was 29 years and 34.6% were under 18. A molecular diagnosis was established in 87 patients (36.7%), spanning hereditary thrombocytopenia, telomere biology disorders, Diamond-Blackfan anemia, severe congenital neutropenia, Shwachman-Diamond syndrome and Fanconi anemia, among others. Four patients received a non-hematological genetic diagnosis and seven had secondary actionable findings; novel mechanisms, including retrotransposon-mediated gene disruption, and gene-disease associations (THRA, MEIS1, TUBB) were established.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

In a field where clinical overlap between entities and with acquired aplastic anemia is the rule, upfront genome sequencing avoids stacking panels and captures mechanisms beyond the reach of the exome. The transcriptome adds a functional readout that helps interpretation. The claimed superiority over other approaches, however, rests on an indirect comparison, with no comparator arm in the cohort.

Analysis by Dr Thibaut Benquey