MDB-32. Siblings with SHH-Medulloblastoma and a Germline <i>EPL1</i> Pathologic Variant: A Case Study and Familial Implications

Abstract Background Medulloblastoma (MB), the most common malignant brain tumor in children, is categorized into four molecular groups: WNT-activated, SHH-activated, group 3, and group 4. Next-generation sequencing (NGS) has revealed pathogenic variants (PVs) in germline cancer predisposition genes in approximately 5% of MB patients. MB-SHH, in particular, is linked to Gorlin syndrome (PTCH1, SUFU) and Li-Fraumeni syndrome (TP53). Recently, germline heterozygous PVs in Elongator Complex Protein 1 (ELP1) were identified in 15% of MB-SHH patients. Despite this, the risk of developing MB in ELP1 PV carriers is low (1%), and no screening guidelines have been established. Here, we present two half-siblings with MB-SHH, both carrying a germline ELP1 PV. Methods A retrospective review of medical records was performed to collect clinical and genetic data on the siblings and their family. Case A 10-year-old boy was diagnosed with MB-SHH (TP53 wild-type) at our institution. Tumor profiling via NGS revealed biallelic deletion in PTCH1, FANCC, and DDX3X, while paired germline sequencing was normal. Enhanced exome sequencing through the NCI Molecular Characterization Initiative identified a germline PV in ELP1 (c.4C&amp;gt;T; p.Arg2Ter). A year earlier, his 4-year-old half-sister had been diagnosed with MB-SHH, also carrying the same ELP1 germline PV. Familial testing confirmed the germline ELP1 PV in their mother and two additional siblings. MRI screening for mutation-positive children is ongoing. Discussion This case highlights an important association between germline heterozygous ELP1 PVs and MB-SHH risk. Although the reported risk of MB-SHH in ELP1 PV carriers is low, it is significantly higher than the general population risk (0.007–0.011%). As ELP1 is a newly identified MB-SHH susceptibility gene, its associated risk may be underestimated. Incorporating ELP1 into sequencing panels for MB-SHH and cascade testing for at-risk relatives of mutation-positive individuals is recommended.