Novel Findings in Pediatric and Adolescent Patients With Cancer and a Germline SMARCA4 Variant

SMARCA4 is a known susceptibility gene for malignant rhabdoid tumors (MRT) in children and small cell carcinoma of the ovary hypercalcemic type (SCCOHT) in young females and women. Recently, a novel association between germline SMARCA4 variants and predisposition to neuroblastoma was proposed.

We present a single-center study summarizing the clinical and genetic data of pediatric and adolescent cancer patients with a germline SMARCA4 variant diagnosed with and/or treated for an MRT, SCCOHT, or neuroblastoma.

We identified nine patients with germline SMARCA4 variants, including one patient with an MRT, four patients with a SCCOHT, and four patients with a neuroblastoma. We observed two novel pathogenic SMARCA4 variants that were initially missed using diagnostic testing: a low-mosaic pathogenic SMARCA4 variant in the patient with an MRT, and a germline SMARCA4 partial gene deletion, encompassing the promoter region, in a patient with a SCCOHT. The patients with neuroblastoma in our cohort had a strikingly old age at diagnosis (range: 10-22 years old). In three of four patients with neuroblastoma, the germline SMARCA4 variant was a variant of unknown significance (VUS). In two of their neuroblastomas, we observed loss of heterozygosity at the SMARCA4 locus, and loss of BRG1 expression was found in one of these.

This study highlights that awareness is needed for easy-to-miss germline variants in SMARCA4 and that knowledge about variant types, cancer spectrum, and cancer penetrance in individuals with a germline SMARCA4 variant is still evolving.