Sunghwan Shin, M.D., Hyeonju Oh, M.S., Hea Ree Park, M.D., Eun Yeon Joo, M.D., Ph.D., and Soo-Youn Lee, M.D., Ph.D.. Ann Lab Med 2021;41:108-13. https://doi.org/10.3343/alm.2021.41.1.108

Neurodevelopmental disorders (NDDs) have diverse phenotypes. Their genetic diagnoses are often challenged by difficulties of targeting causative genes due to heterogeneous genetic etiologies. The objective of this study was to perform genetic diagnosis of children with NDDs using whole genome sequencing. This study included 78 pediatric patients with NDDs and their 152 family members for whole genome sequencing (WGS). All cases except one were families with at least two members. Seventy-five patients had previously undergone other genetic tests besides WGS. Detected variants were classified according to the guidelines of the American College of Medical Genetics and Genomics. Among 78 probands, 26 patients were genetically diagnosed with NDDs through WGS, showing a diagnostic rate of 33.3%. Of them, 22 cases had de novo variants (DNVs) identified through trio analysis. Of these DNVs, half were novel variants. Three structural variants, including a multiexon deletion, a contiguous gene deletion involving 13 Mb, and a retrotransposon insertion, were revealed by WGS. All cases except one had defects in different genes, consistent with the phenotypically diverse nature of NDDs. In addition, three patients were inconclusive, two of them had one likely pathogenic variant in a gene associated with autosomal recessive disease and the other one had no clinical phenotypes associated with the detected DNV. Our experience demonstrates the advantage of WGS in the diagnosis of NDDs, including detection of copy number variations and also the advantage of trio sequencing for interpretation of DNVs.

Shin S, et al. Ann Lab Med. 2020 Mar;40(2):169-173. https://doi.org/10.3343/alm.2020.40.2.169

Sunghwan Shin, M.D., Jongwon Oh, M.D., and Hyung-Doo Park, M.D., Ph.D.. Ann Lab Med 2021;41:114-9. https://doi.org/10.3343/alm.2021.41.1.114

Objectives: Few studies have reported on delta checks for tumour markers, even though these markers are often evaluated serially. Therefore, this study aimed to establish a practical delta check limit in different clinical settings for five tumour markers: alpha-fetoprotein, cancer antigen 19-9, cancer antigen 125, carcinoembryonic antigen, and prostate-specific antigen. Methods: Pairs of patients’ results (current and previous) for five tumour markers between 2020 and 2021 were retrospectively collected from three university hospitals. The data were classified into three subgroups, namely: health check-up recipient (subgroup H), outpatient (subgroup O), and inpatient (subgroup I) clinics. The check limits of delta percent change (DPC), absolute DPC (absDPC), and reference change value (RCV) for each test were determined using the development set (the first 18 months, n=179,929) and then validated and simulated by applying the validation set (the last 6 months, n=66,332). Results: The check limits of DPC and absDPC for most tests varied significantly among the subgroups. Likewise, the proportions of samples requiring further evaluation, calculated by excluding samples with both current and previous results within the reference intervals, were 0.2–2.9% (lower limit of DPC), 0.2–2.7% (upper limit of DPC), 0.3–5.6% (absDPC), and 0.8–35.3% (RCV_99.9%). Furthermore, high negative predictive values >0.99 were observed in all subgroups in the in silico simulation. Conclusions: Using real-world data, we found that DPC was the most appropriate delta-check method for tumour markers. Moreover, Delta-check limits for tumour markers should be applied based on clinical settings.

Germline genetic context may play a significant role in the development and evolution of cancer, particularly in childhood cancers such as neuroblastoma. This study investigates the role of putatively functional germline variants in neuroblastoma, even if they do not directly increase disease risk. Our whole-exome sequencing analysis of 125 patients with neuroblastoma reveals a positive correlation between germline variant burden and somatic mutations. Moreover, patients with higher germline variant burden exhibit worse outcomes. Similar findings are observed in the independent neuroblastoma cohort where a higher germline variant burden correlates with a higher somatic mutational burden and a worse overall survival outcome. However, contrasting results emerge in adult-onset cancer, emphasizing the importance of germline genetics in neuroblastoma. The enrichment of putatively functional germline variants in cancer predisposition genes is borderline significant when compared to healthy populations (P = 0.077; Odds Ratio, 1.45; 95% confidence intervals, 0.94−2.21) and significantly more pronounced against adult-onset cancers (P = 0.016; Odds Ratio, 2.13; 95% confidence intervals, 1.10−3.91). Additionally, the presence of these variants proves to have prognostic significance in neuroblastoma (log-rank P < 0.001), and combining germline with clinical risk factors notably improves survival predictions.