Year: 2022
Type: preprint
Study design: Case Report
Abstract: Li-Fraumeni syndrome (LFS) is one of the most common cancer predisposition syndromes that affects both children and adults. Individuals with LFS are at an increased risk of developing various types of cancer over their lifetime including soft tissue sarcomas, osteosarcomas, breast cancer, leukemia, brain tumors, and adrenocortical carcinoma. Heterozygous germline pathogenic variants in the tumor suppressor gene TP53 are the known causal genetic defect for LFS. Single nucleotide variants (SNVs) including missense substitutions that occur in the highly conserved DNA binding domain of the protein are the most common alterations, followed by nonsense and splice site variants. Gross copy number changes in TP53 are rare and account for less than 1% of all variants. Using next-generation sequencing (NGS) panels, we identified a paternally inherited germline intragenic duplication of TP53 in a child with metastatic osteosarcoma who later developed acute myeloid leukemia (AML). Transcriptome sequencing (RNA-Seq) demonstrated the duplication was tandem, encompassing exons 2-6 and 28 nucleotides of the untranslated region (UTR) upstream of the start codon in exon 2. The inclusion of the 28 nucleotides is expected to result in a frameshift with a stop codon 18 codons downstream of the exon 6, leading to a loss-of-function allele. This case highlights the significance of simultaneous identification of both significant copy number variants as well as SNVs/indels using NGS panels.
Source: Molecular Case Studies
DOI: 10.1101/mcs.a006181
Authors: Feng Xu, Erfan Aref-Eshghi, Jinhua Wu, Jeffrey Schubert, Gerald Wertheim, Tricia Bhatti, Jennifer Pogoriler, Maha Patel, Kajia Cao, Ariel Long, Zhiqian Fan, Elizabeth Denenberg, Elizabeth Fanning, Donna Wilmoth, Minjie Luo, Laura Conlin, Aleksandra Sarah Dain, Sarah Baldino, Kristin Zelley, Naomi J Balamuth, Suzanne Macfarland, Marilyn M Li, Yiming Zhong
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W4214602394