SAT274 Multilocus Imprinting Disorder Due To Genome-wide Paternal Uniparental Disomy Associated With Adrenocortical Tumors

Abstract Disclosure: E.M. Pinto: None. E. Lalli: None. G. Wu: None. R. Ribeiro: None. G. Zambetti: None. Pediatric adrenocortical tumor (ACT) is an uncommon malignancy frequently associated with Li-Fraumeni syndrome, a familial cancer predisposition disorder caused by germline mutations in the tumor suppressor TP53. ACT is also associated with other genetic constitutional disorders, such as Beckwith-Wiedemann syndrome (BWS) which results from the deregulation of a gene cluster on chromosome 11p15. We report here the identification of three pediatric patients with ACT and additional tumors, two of which received a clinical diagnosis of BWS. Family histories of these two probands include multiple unsuccessful pregnancies. All patients have wild-type TP53 sequence and no evidence for germline chromosome 11p15 alterations. Molecular analyses by whole genome sequencing revealed genome-wide copy neutral loss of heterozygosity (cnLOH) in all tumors. Microsatellite STR and MS-MLPA confirmed genome-wide cnLOH with the selective loss of all maternal chromosomes and duplication of paternal chromosomes in each tumor. Analysis of skin fibroblasts showed mosaic paternal uniparental disomy with partial LOH for all chromosomes, while no LOH was detected in blood DNA. The most prominent clinical feature of genome-wide cnLOH is an unbalanced monoallelic and parent-of-origin specific expression of imprinted genes known as multilocus imprinting disorder (MID). MID has been associated with maternal-effect variants that alter the maintenance of methylation at germline-derived differentially methylated regions (DMRs) in early embryogenesis. In addition, causative trans-acting factors in imprinting disorders, including the subcortical maternal complex (SCMC), have the potential to affect multiple DMRs across the genome, resulting in a multilocus imprinting disorder. Our study identifies three pediatric patients who developed ACT and other tumors that have undergone genome wide cnLOH that specifically selected against all maternal chromosomes. None of three patients presented with germline alterations in TP53 or 11p15, typical of pediatric ACT. WGS data revealed a germline mutation (p.M573T) in the histone methyltransferase NSD1 in the mother of patient #2. NSD1 mutations are reportedly associated with recurrent miscarriages, tissue overgrowth and increased cancer risk. Alterations in other epigenetic regulators, such as SETD1B (p.R226C), a component of a histone methyltransferase complex and TNRC18 (p.P454L), that enables chromatin binding activity were observed in both mother and child in each family. Further analysis of maternal-effect variants associated with abnormal pregnancies and MID will be important for understanding the mechanisms underlying genome-wide cnLOH. Our results support the molecular testing of multiple loci in atypical clinical presentations of patients with pediatric ACT. Presentation: Saturday, June 17, 2023