104. A hematologic case with germline deletion of PMS2 and increased risk of HNPCC studied by optical genome mapping and NGS

Aly Abdelkareem

Jie Xu

Jie Xu, PhD, is ABMGG certified in Clinical Cytogenetics and Genomics and Laboratory Genetics and Genomics. He is Medical Director, Cytogenetics at Akron Children’s Hospital (ACH) and Professor of Pathology, Northeast Ohio Medical University. He signs out diagnostic reports for cytogenetics, molecular genetics and infectious diseases at ACH. He has 24 year experience in cytogenomics diagnostics in academic hospital and industrial labs. He has worked for >20 years as university faculty and contributed to education of undergraduate, graduate and medical students, fellows/residents, and lab staff. He has had 114 peer-reviewed publications, including 50 articles and 64 abstracts/posters. He is interested in development and utilization of new methods for diagnosis, prognosis, treatment, prevention and research of cytogenomics diseases.


Jie Xua, Melissa Stallinga, Mark Steelea, Daniel Petteea, Catherine Brownsteinb,c, Sarah Osslera, Carrie Costind

aAkron Children’s Hospital, Akron, OH, United States;  bGenetics, Boston Children’s Hospital, Boston, MA, United States; cHarvard Medical School, Boston, MA, United States; dGenetics, Akron Children’s Hospital, Akron, OH, United States

A 23-month-old male with known T-ALL had G-banding finding of monosomy 7 in 13 (59%) of the 22 metaphases analyzed from the bone marrow (BM). This, together with pathologic findings, confirmed the diagnosis of Juvenile myelomonocytic leukemia (infantile monosomy 7 syndrome).

BM studies of microsatellites statues and tumor mutational burden showed no findings of therapy or clinical trial options. BM NGS identified gene alterations, including 1) ASXL1-G646fs*12 (NM_015338; 1934_1935insG), with uncertain significance in treatment; and 2) NOTCH1-Q2459fs*18(NM_017617; 73775delC); mutation of the gene commonly seen in T-ALL with a poor prognosis.

Optical genome mapping studies of the BM confirmed monosomy 7 with 2 additional findings. 1). t(1;14)(q42.3;q22.1) had VAF=0.52, suggestive of germline translocation. The breakpoint at 14q22.1 involves the tumor suppressor gene GNG2; its expression was downregulated in multiple cancers (e.g. breast cancer, cervical squamous cell carcinoma, colonic adenocarcinoma). 2). ~5 Kb deletion in PMS2 gene at 7p22.1 with VAF=0.73. Testing of gDNA from cultured fibroblasts confirmed germline heterozygous deletion of exons 9-10 in PMS2; indicative of an increased risk of autosomal dominant HNPCC (Lynch) syndrome and autosomal recessive mismatch repair deficiency syndrome.

This case study emphasizes the significance of the application of comprehensive cytogenomic methods for studies of pediatric cancer cases with potential implications in germline alternations and management of both acquired and inherited disorders.