Identifying Deleterious Variants Within Overgrowth Syndromes Related Genes in Pediatric Brain...

Identifying Deleterious Variants Within Overgrowth Syndromes Related Genes in Pediatric Brain Tumor Patientsʼ Germline Genomic Data

Authors: Yiran Guo, PhD, Adam Resnick, PhD, Center for Data Driven Discovery in Biomedicine, Children's Hospital of Philadelphia


Abstract: Brain tumors are among the most deadly pediatric cancers and Childrenʼs Brain Tumor Tissue Consortium  (CBTTC) has been created to facilitate research into this disease. Overgrowth syndromes (OSs) involve abnormal  cell cycle, migration and apoptosis, which are also observed in cancer development. To explore whether OS  genes are mutated in pediatric cancer genomes, we utilized the whole genome sequencing (WGS) data from  germline DNA in CBTTC patients, and identified variants in a list of genes that have been implicated in the  development of human OSs. WGS data of 893 vcf files were collected and annotated using Annovar with  population allele frequencies and in silico predictions of variantsʼ deleteriousness. Five sources were consulted  to generate a list of 407 OS genes, a) 321 genes related to overgrowth in Human Phenotype Ontology (HPO), b)  70 genes included in Online Mendelian Inheritance in Man (OMIM), c) 25 genes in OS publications as catalogued  in Human Gene Mutation Database (HGMD), d) 59 genes listed in a 2018 review paper by Kamien et al. in  Molecular Syndromology (Kamien), and e) 34 genes captured by the Somatic Overgrowth and Vascular  Malformations Panel offered through the Genetic Diagnostic Lab at University of Pennsylvania School of  Medicine (PennMedicine). We then classified the OS genes into three confidence groups, those with either  HGMD, Kamien or PennMedicine support as high confidence, those with OMIM support but not high confidence  as medium, and the remaining as low. Among 71 of the total 87 high confidence OS genes, we detected 395  unique rare variants (MAF < 0.0001) which were either i) predicted loss-of-function, ii) predicted deleterious by  at least 8 out of the 12 scores for missense variants (SIFT, Polyphen2 etc), iii) cataloged in ClinVar, or iv) labeled  DM(?) for "disease causing mutations" by HGMD. 15 high confidence OS genes contain more than 10 variants,  with the most being PTCH1 (33 variants) and TP53 (25). 19 patients have more than 3 deleterious variants in the  high confidence OS genes; top histologies are low-grade glioma/astrocytoma (WHO grade I/II) with six patients,  high-grade glioma/astrocytoma (WHO grade III/IV) with three, and Ganglioglioma with two (all other tumor  types correspond to one patient). Using tumor WGS data we also observed five cases that harbor somatic  variants in different high confidence OS genes, suggesting complex interplay between the germline and the  tumor genomes. The current investigation identified OS gene variants in the germline WGS data from a pediatric  brain tumor cohort, and highlighted key genes, esp. TP53 and others, that are at the intersection of both OSs  and pediatric cancer of the central nervous system.

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