Kulturális és Innovációs Minisztérium Új Nemzeti Kiválósági Ösztöndíja(ÚNKP-22-5-SE-25)
Támogató: Kulturális és Innovációs Minisztérium
(ÚNKP-23-5-SE-16)
(NRDI NKFI-FK135065)
(ÚNKP-23-5-SE-4)
Multigene panel tests (MGPTs) revolutionized the diagnosis of Lynch syndrome (LS),
however noncoding pathogenic variants (PVs) can only be detected by complementary
methods including whole genome sequencing (WGS). Here we present a DNA-, RNA- and
tumor tissue-based WGS prioritization workflow for patients with a suspicion of LS
where MGPT detected no LS-related PV. Among the 100 enrolled patients, MGPT detected
28 simple PVs and an additional 3 complex PVs. Among the 69 MGPT-negative patients,
the lack of somatic MLH1 promoter methylation in a patient with a distinguished MLH1
allelic imbalance selected this sample for WGS. This returned a germline deep intronic
MLH1 variant, with further functional studies confirming its' pathogenicity. Interestingly,
all three complex PVs and the MLH1 deep intronic PV were found to be recurrent at
our center. Our straightforward and cost-effective prioritization workflow can optimally
include WGS in the genetic diagnosis of LS.
