Universal Germline Panel Testing for Individuals with Pheochromocytoma and Paraganglioma Produces High Diagnostic Yield

Background Practice guidelines to identify individuals with hereditary pheochromocytomas and paragangliomas (PPGLs) advocate for sequential gene testing strategy guided by specific clinical features and predate the routine use of multigene panel testing (MGPT). Objective To describe results of MGPT for hereditary PPGL in a clinically and ancestrally diverse cohort. Setting Commercial laboratory based in the United States. Methods Clinical data and test results were retrospectively reviewed in 1727 individuals who had targeted MGPT due to suspicion of hereditary PPGL from August 2013 through December 2019. Results Overall, 27.5% of individuals had a pathogenic or likely pathogenic variant (PV), 9.0% had a variant of uncertain significance, and 63.1% had a negative result. Most PVs were identified in SDHB (40.4%), followed by SDHD (21.1%), SDHA (10.1%), VHL (7.8%), SDHC (6.7%), RET (3.7%), and MAX (3.6%). PVs in FH, MEN1, NF1, SDHAF2, and TMEM127 collectively accounted for 6.5% of PVs. Clinical predictors of a PV included extra-adrenal location, early age of onset, multiple tumors, and positive family history of PPGL. Individuals with extra-adrenal PGL and a positive family history were the most likely to have a PV (85.9%). Restricting genetic testing to SDHB/C/D misses a third (32.8%) of individuals with PVs. Conclusion Our data demonstrate a high diagnostic yield in individuals with and without established risk factors, a low inconclusive result rate, and a substantial contribution to diagnostic yield from rare genes. These findings support universal testing of all individuals with PPGL and the use of concurrent MGPT as the ideal platform.

A method for variant agnostic detection of SARS-CoV-2, rapid monitoring of circulating variants, detection of mutations of biological significance, and early detection of emergent variants such as Omicron

The rapid emergence of new SARS-CoV-2 variants raises a number of public health questions including the capability of diagnostic tests to detect new strains, the efficacy of vaccines, and how to map the geographical distribution of variants to better understand patterns of transmission and possible load on healthcare resources. Next-Generation Sequencing (NGS) is the primary method for detecting and tracing the emergence of new variants, but it is expensive, and it can take weeks before sequence data is available in public repositories. Here, we describe a Polymerase Chain Reaction (PCR)-based genotyping approach that is significantly less expensive, accelerates reporting on SARS-CoV-2 variants, and can be implemented in any testing lab performing PCR. Specific Single Nucleotide Polymorphisms (SNPs) and indels are identified that have high positive percent agreement (PPA) and negative percent agreement (NPA) compared to NGS for the major genotypes that circulated in 2021. Using a 48-marker panel, testing on 1,128 retrospective samples yielded a PPA and NPA in the 96.3 to 100% and 99.2 to 100% range, respectively, for the top 10 most prevalent lineages. The effect on PPA and NPA of reducing the number of panel markers was also explored. In addition, with the emergence of Omicron, we also developed an Omicron genotyping panel that distinguishes the Delta and Omicron variants using four (4) highly specific SNPs. Data from testing demonstrates the capability to use the panel to rapidly track the growing prevalence of the Omicron variant in the United States in December 2021.

Increased use of genetic health care in Iceland 2012-2017

INTRODUCTION: A genetic counselling unit at Landspitali hospital (LSH) was established in 2006. Meanwhile, genetic testing has become an integral part of general health care. In this article we detail the outcome of genetic testing at the Department of Genetic and Molecular Medicine (DGM) at Landspitali over a five year period (2012-2017). Factors that were analyzed for the time period were: Number of patients, reason for referral, reason for genetic testing without genetic counselling and yield (proportion of positive tests) of genetic testing. METHODS: Data was analysed from two medical record databases, Shire and Saga, used by the DGM in the time period. RESULTS: The number of individuals coming for genetic counselling increased every year over the time period. Reasons for referral were cancer-related in two-thirds of cases. Other reasons for referral included various other familial disorders. Most common were autosomal dominant disorders like myotonic dystrophy, hypertrophic cardiomyopathy and autosomal recessive disorders like spinal muscular atrophy (SMA) and GM1-gangliosidosis. Most common reasons for genetic testing outside of the LSH GC unit was because of managable diseases like hemochromatosis and F5/Prothrombin-related thrombophilia. Yield of genetic testing was assessed for a) known mutation testing / carrier testing, b) single gene testing, c) gene panel testing and d) whole genome and whole exome sequencing. Known mutation testing was positive in 33% of cases and single gene testing in 46% of cases. The yield of gene panel testing for cancer was found to be lower (20%) than gene panel testing for other disorders (40%). The yield of whole exome and whole genome sequencing was 46%.

Mainstreaming Genetic Testing for Epithelial Ovarian Cancer by Oncology Providers: A Survey of Current Practice

PURPOSE With limitations in early detection and poor treatment response, ovarian cancer is associated with significant morbidity and mortality. Up to 25% of epithelial ovarian cancer (EOC) is related to a hereditary predisposition. Current National Comprehensive Cancer Network guidelines recommend that all individuals diagnosed with EOC be offered germline genetic testing. Although this would ideally be performed by genetics professionals, a shortage of genetic counselors can affect timely access to these services. This study sought to investigate the current genetic testing practices of oncology providers to determine the feasibility of oncologist-led genetic testing for patients with EOC. METHODS A survey was distributed to members of the Society of Gynecologic Oncologists with questions regarding timing, frequency, and type of cancer genetic testing, referrals to genetics professionals, confidence with aspects of genetic testing, and any barriers to these processes. RESULTS We received 170 evaluable responses. Eighty-five percent of providers always ordered genetic testing for patients with EOC. Most providers ordered germline multigene panel testing (95.8%), generally at diagnosis (64.5%). Provider confidence with the genetic testing process was generally high and significantly differed by providers' testing practices, namely, respondents who reported always ordering genetic testing tended to be more confident in ordering testing ( P = .008), interpreting results ( P = .005), and counseling a patient ( P = .002). Patient disinterest and concerns for insurance coverage were commonly cited as barriers to testing and referrals. CONCLUSION The findings from this study suggest that oncologist-led genetic testing for patients with EOC, with referrals to genetics professionals when appropriate, has the potential to be a viable alternative service delivery model to increase access to genetic testing for patients diagnosed with EOC.

Investigating the Genetic Profile of the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia (ALS-FTD) Continuum in Patients of Diverse Race, Ethnicity and Ancestry

Preliminary evidence suggests that commonly used genetic tests may be less likely to identify a genetic etiology for ALS-FTD in patients of underrepresented race, ethnicity, and ancestry (REA), as compared to European REA. Patients of underrepresented REA may therefore be less likely to receive accurate and specific genetic counseling information and less likely to have access to gene-targeted therapies currently in clinical trials. We compiled outcome data from 1911 ALS-FTD patients tested at a commercial laboratory over a seven-year period for C9orf72 hexanucleotide repeat expansion (HRE) alone or C9orf72 and multigene sequencing panel testing. We compared the incidence of pathogenic (P), likely pathogenic (LP), and uncertain variants in C9orf72 and other ALS-FTD genes, as well as age at testing, in patients of different REA. The diagnostic rate in patients of European REA (377/1595, 23.64%) was significantly higher than in patients of underrepresented REA (44/316, 13.92%) (p < 0.001). Patients of European REA were more likely to have the C9orf72 HRE (21.3%) than patients of underrepresented REA (10.4%) (p < 0.001). The overall distribution of positive test outcomes in all tested genes was significantly different between the two groups, with relatively more P and LP variants in genes other than C9orf72 identified in patients of underrepresented REA. The incidence of uncertain test outcomes was not significantly different between patients of European and underrepresented REA. Patients with positive test outcomes were more likely to be younger than those with negative or uncertain outcomes. Although C9orf72 HRE assay has been advocated as the first, and in some cases, only genetic test offered to patients with ALS-FTD in the clinical setting, this practice may result in the reduced ascertainment of genetic ALS-FTD in patients of diverse REA.

Next-generation Sequencing-based Test for Resectable Colorectal Cancer in Real-world Clinical Practice

Purpose: This study aimed to evaluate the significance of Next-generation sequencing (NGS)-based gene panel testing in resectable colorectal cancers (CRC)s by analyzing real-world data collected prospectively from patients. Methods: Patients with CRC who underwent surgery from July 2018 to February 2020 at our institution were included, and correlations between various NGS data and clinicopathological findings were evaluated. Results: Overall, 107 patients were included in this study. The tumor stage was I in 28 cases (26.2%), II in 40 cases (37.4%), III in 32 cases (29.9%), and IV in 7 cases (6.5%). Actionable gene alterations were found in 97.2% of the cases. Co-alteration analysis suggested that either TP53- or APC-related alterations were more frequently found in early-stage tumors (stage I). The copy number alteration count was significantly lower in right side colon tumors than in tumors in other locations (P < 0.05). Homologous recombination deficiency (HRD) was more often identified in stage IV tumors than in stage I or II tumors (P < 0.05). Moreover, high HRD status was suggested to be useful for identifying high-risk stage II tumors (P < 0.05). Conclusion: In this study, real-world NGS data represented the biological features of CRCs. HRD was identified as a useful result of gene panel testing with novel utility in clinical practice.