Multifocal Neuroblastoma in Rubinstein-Taybi Syndrome Harboring a Novel CREBBP Variant Identified by Paired Whole
Yuki Fushimi1, Yasuhiro Kawai1, Dai Keino2
1Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan.
Abstract:
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.
Insights
Rubinstein-Taybi syndrome (RTS) patients have increased tumor risk due to CREBBP/EP300 gene variants. This case highlights a young boy with RTS and neuroblastoma, linked to a new CREBBP gene variant, suggesting a tumor predisposition factor.
Area of Science:
- Genetics
- Oncology
- Developmental Biology
Background:
- Rubinstein-Taybi syndrome (RTS) is a genetic disorder caused by germline loss-of-function variants in CREBBP or EP300.
- These genes encode histone acetyltransferases and function as tumor suppressors, with RTS patients exhibiting increased susceptibility to various tumors.
- While neuroblastoma has been reported in five RTS patients, germline pathogenic variants were confirmed in only two.
Purpose of the Study:
- To report a case of neuroblastoma in a patient with Rubinstein-Taybi syndrome.
- To investigate the genetic underpinnings of tumor predisposition in this patient.
- To analyze the genomic profile of the neuroblastoma and germline DNA.
Main Methods:
- Whole genome sequencing of both tumor and germline DNA.
- Identification and characterization of germline and somatic variants.
- Histological evaluation and risk stratification of the neuroblastoma.
Main Results:
- A 2-year-old male with RTS and neuroblastoma was identified.
- A de novo missense variant (c.4862T>A p.(Leu1621Gln)) in the CREBBP histone acetyltransferase (HAT) domain was found in the germline.
- The neuroblastoma, diagnosed at 4 months, was classified as low risk and remained stable.
- No other contributing germline or somatic variants were found, besides polyploidy in chromosomes 7, 12, and 17.
Conclusions:
- Germline loss-of-function variants in CREBBP may contribute to tumor predisposition in RTS.
- The findings support the role of CREBBP and EP300 variants in neuroblastoma development.
- Paired tumor-normal genome sequencing is valuable for analyzing germline tumor predisposition and tumor genomic profiles.
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