Multifocal Neuroblastoma in Rubinstein-Taybi Syndrome Harboring a Novel CREBBP Variant Identified by Paired Whole Genome Sequencing.

Rubinstein-Taybi syndrome (RTS) is caused by germline loss-of-function variants of CREBBP or EP300, which function as histone acetyltransferases and act as tumor suppressors. Various benign or malignant tumors have been reported in RTS, suggesting tumor predisposition. To date, five patients with RTS complicated by neuroblastoma have been reported, and pathogenic germline variants were confirmed in two of the patients. We report a 2-year-old male with neuroblastoma and RTS harboring a germline CREBBP missense variant at the histone acetyltransferase (HAT) domain. Neuroblastoma was diagnosed at 4 months of age, and histological evaluation classified the tumor as low risk. The neuroblastoma was stable at 2 years of age. His dysmorphic features and developmental delay were consistent with phenotypes of RTS. Whole genome sequencing of both tumor and germline identified a de novo missense variant of CREBBP (NM_004380.3:c.4862T>A p.(Leu1621Gln)). No other contributing germline or somatic variants were identified, except for polyploidy involving chromosomes 7, 12, and 17. Our results suggest that germline loss-of-function of CREBBP may contribute to tumor predisposition factor since somatic variants of CREBBP and EP300 have been identified in neuroblastoma. Paired tumor-normal genome sequencing enabled comprehensive analysis of germline tumor predisposition, as well as genomic profiles of tumor tissue.