Medulloblastomas with Pathogenic Variants: A Weakly Penetrant Syndrome with a Restricted Spectrum in a Limited Age Window

Background: pathogenic variants (PV) have been recently identified as the most frequent variants predisposing to Sonic Hedgehog (SHH) medulloblastomas (MB); however, guidelines are still lacking for genetic counseling in this new syndrome.

Methods: We retrospectively reviewed clinical and genetic data of a French series of 29 -mutated MB.

Results: All patients developed SHH-MB, with a biallelic inactivation of found in 24 tumors. Other recurrent alterations encompassed the pathway and activation of signaling. The median age at diagnosis was 7.3 years (range: 3-14). -mutated MB behave as sporadic cases, with similar distribution within clinical and molecular risk groups and similar outcomes (5 y - OS = 86%); no unusual side effect of treatments was noticed. Remarkably, a germline PV was identified in all patients with available constitutional DNA ( = 26); moreover, all tested familial trio ( = 11) revealed that the PVs were inherited. Two of the 26 index cases from the French series had a family history of MB; pedigrees from these patients and from 1 additional Dutch family suggested a weak penetrance. Apart from MB, no cancer was associated with PVs; second tumors reported in 4 patients occurred within the irradiation fields, in the usual time-lapse for expected radiotherapy-induced neoplasms.

Conclusions: The low penetrance, the "at risk' age window limited to childhood and the narrow tumor spectrum, question the actual benefit of genetic screening in these patients and their family. Our results suggest restricting germline sequencing to patients with SHH-MB, depending on the parents" request.