Diagnostic yield from cardiac gene panel testing for inherited cardiac conditions in a large Irish cohort

Abstract Background Inherited cardiomyopathies (hypertrophic, dilated and arrhythmogenic) and cardiac ion channelopathies (long QT, Brugada and CPVT) predispose to sudden cardiac death/sudden arrhythmic death syndrome. Given their genetically heterogenous nature, multi-gene DNA sequencing panels are useful to aid genetic diagnosis. Purpose Investigate the diagnostic yield from cardiac gene panel testing undertaken in patients (including molecular autopsy in deceased patients) referred to four clinical services from 2002 to 2020. Methods Data was collected by interrogation of departmental databases, family charts, and review of molecular genetic diagnostic reports. Results We evaluated molecular genetic diagnostic results from 835 individuals (461 males, 374 females) from 824 families, including 58 deceased patients who underwent molecular autopsy. The median age of the cohort was 44 years (range 0.1–86 years). Testing for hypertrophic cardiomyopathy (HCM) and long QT syndrome (LQT) genes represented 36% and 32% of the cohort, respectively, with the remaining 32% accounting for other cardiomyopathies, arrhythmia syndromes or metabolic/syndromic diseases. The overall variant detection rate was 50% across all panel types. Three hundred and fifty patients (42%) carried a single variant, 68 patients (8%) carried multiple variants (up to a maximum of four), including two individuals who carried two actionable (pathogenic/likely pathogenic) variants each and 30 individuals (5%) with one actionable variant plus a variant of uncertain significance (VUS). The overall diagnostic yield of at least one actionable variant was 28%. At least one VUS was detected in 27% of the cohort. Molecular autopsy yielded an actionable variant in 10% of patients, while 30% of the subcohort carried at least one VUS (up to maximum of two). We found a positive association between female sex and the likelihood of detecting an actionable variant. By decade of age, detection of actionable variants ranged from 19% (60–69 years) to 41% (0–9 years). By panel type, actionable variants ranged from 14% (Brugada) to 35% (cardiomyopathy). The burden of VUS ranged from 22% (LQT) to 46% (dilated cardiomyopathy). Altogether 234 actionable variants were detected in 26 genes, including seven metabolic or syndromic disease genes. From those with non-metabolic/syndromic forms of disease, 84% of actionable variants were detected in well established ICC genes. Analysis of gene-disease associations for VUS detected from HCM and LQT panels revealed that 10–25% were detected in genes now deemed to have only moderate or limited evidence of disease causation. Conclusion Most actionable variants in this cohort were detected in well-established ICC genes, suggesting that large gene panels offer little extra sensitivity compared to historic smaller gene panels. Despite recent gene curation efforts, the high burden of VUS remains a considerable challenge in ICC management. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): National Children's Research Centre

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Benefits and safety of multigene panel testing in patients at risk for hereditary breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.28_suppl.16 ◽

2015 ◽

Vol 33 (28_suppl) ◽

pp. 16-16

Author(s):

Nimmi S. Kapoor ◽

Lisa D. Curcio ◽

Carlee A. Blakemore ◽

Amy K. Bremner ◽

Rachel E. McFarland ◽

...

Keyword(s):

Breast Cancer ◽

At Risk ◽

Genetic Testing ◽

Hereditary Breast Cancer ◽

Diagnostic Yield ◽

Gene Panel ◽

Panel Testing ◽

Gene Testing ◽

Gene Panel Testing ◽

Patients At Risk

16 Background: Recently introduced multi-gene panel testing including BRCA1 and BRCA2 genes (BRCA1/2) for hereditary cancer risk has raised concerns with the ability to detect all deleterious BRCA1/2 mutations compared to older methods of sequentially testing BRCA1/2 separately. The purpose of this study is to evaluate rates of pathogenic BRCA1/2mutations and variants of uncertain significance (VUS) between previous restricted algorithms of genetic testing and newer approaches of multi-gene testing. Methods: Data was collected retrospectively from 966 patients who underwent genetic testing at one of three sites from a single institution. Test results were compared between patients who underwent BRCA1/2testing only (limited group, n = 629) to those who underwent multi-gene testing with 5-43 cancer-related genes (panel group, n = 337). Results: Deleterious BRCA1/2 mutations were identified in 37 patients, with equivalent rates between limited and panel groups (4.0% vs 3.6%, respectively, p = 0.86). Thirty-nine patients had a BRCA1/2 VUS, with similar rates between limited and panel groups (4.5% vs 3.3%, respectively, p = 0.49). On multivariate analysis, there was no difference in detection of either BRCA1/2 mutations or VUS between both groups. Of patients undergoing panel testing, an additional 3.9% (n = 13) had non-BRCA pathogenic mutations and 13.4% (n = 45) had non-BRCA VUSs. Mutations in PALB2, CHEK2, and ATM were the most common non-BRCA mutations identified. Conclusions: Multi-gene panel testing detects pathogenic BRCA1/2 mutations at equivalent rates as limited testing and increases the diagnostic yield. Panel testing increases the VUS rate, mainly due to non-BRCA genes. Patients at risk for hereditary breast cancer can safely benefit from upfront, more efficient, multi-gene panel testing.

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Expanded yield of multiplex panel testing in fully accrued prospective trial.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.1525 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 1525-1525

Author(s):

Gregory Idos ◽

Allison W. Kurian ◽

Charite Nicolette Ricker ◽

Duveen Sturgeon ◽

Julie Culver ◽

...

Keyword(s):

Risk Assessment ◽

Genetic Testing ◽

Cancer Risk ◽

Clinical Utility ◽

Diagnostic Yield ◽

Pathogenic Mutation ◽

Gene Panel ◽

Cancer Risk Assessment ◽

Panel Testing ◽

Gene Panel Testing

1525 Background: Genetic testing is a powerful tool for stratifying cancer risk. Multiplex gene panel (MGP) testing allows simultaneous analysis of multiple high- and moderate- penetrance genes. However, the diagnostic yield and clinical utility of panels remain to be further delineated. Methods: A report of a fully accrued trial (N = 2000) of patients undergoing cancer-risk assessment. Patients were enrolled in a multicenter prospective cohort study where diagnostic yield and off-target mutation detection was evaluated of a 25 gene MGP comprised of APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53. Patients were enrolled if they met standard testing guidelines or were predicted to have a ≥2.5% mutation probability by validated models. Differential diagnoses (DDx) were generated after expert clinical genetics assessment, formulating up to 8 inherited cancer syndromes ranked by estimated likelihood. Results: 1998/2000 patients had reported MGP test results. Women constituted 81% of the sample, and 40% were Hispanic; 241 tested positive for at least 1 pathogenic mutation (12.1%) and 689 (34.5%) patients carried at least 1 variant of uncertain significance. The most frequently identified mutations were in BRCA1 (17%, n = 41), BRCA2 (15%, n = 36), APC (8%, n = 19), CHEK2 (7%, n = 17), ATM (7%, n = 16). 39 patients (16%) had at least 1 pathogenic mutation in a mismatch repair (MMR) gene ( MLH1, n = 10; MSH2, n = 10; MSH6, n = 8; PMS2, n = 11). 43 individuals (18%) had MUTYH mutations – 41 were monoallelic. Among 19 patients who had mutations in APC – 16 were APC I1307K. Only 65% (n = 159) of PV results were included in the DDx, with 35% (n = 86) of mutations not clinically suspected. Conclusions: In a diverse cohort, multiplex panel use increased genetic testing yield substantially: 35% carried pathogenic mutations in unsuspected genes, suggesting a significant contribution of expanded multiplex testing to clinical cancer risk assessment. The identification of off-target mutations broadens our understanding of cancer risk and genotype-phenotype correlations. Follow-up is ongoing to assess the clinical utility of multiplex gene panel testing. Clinical trial information: NCT02324062.

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Australia and New Zealand renal gene panel testing in routine clinical practice of 542 families

npj Genomic Medicine ◽

10.1038/s41525-021-00184-x ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Hope A. Tanudisastro ◽

Katherine Holman ◽

Gladys Ho ◽

Elizabeth Farnsworth ◽

Katrina Fisk ◽

...

Keyword(s):

Clinical Practice ◽

New Zealand ◽

Genetic Testing ◽

Gene Panel ◽

Routine Practice ◽

Causative Variant ◽

Panel Testing ◽

Gene Panel Testing ◽

Gene Panels ◽

Clear Information

AbstractGenetic testing in nephrology clinical practice has moved rapidly from a rare specialized test to routine practice both in pediatric and adult nephrology. However, clear information pertaining to the likely outcome of testing is still missing. Here we describe the experience of the accredited Australia and New Zealand Renal Gene Panels clinical service, reporting on sequencing for 552 individuals from 542 families with suspected kidney disease in Australia and New Zealand. An increasing number of referrals have been processed since service inception with an overall diagnostic rate of 35%. The likelihood of identifying a causative variant varies according to both age at referral and gene panel. Although results from high throughput genetic testing have been primarily for diagnostic purposes, they will increasingly play an important role in directing treatment, genetic counseling, and family planning.

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Insights into Genetic Susceptibility to Melanoma by Gene Panel Testing: Potential Pathogenic Variants in ACD, ATM, BAP1, and POT1

Cancers ◽

10.3390/cancers12041007 ◽

2020 ◽

Vol 12 (4) ◽

pp. 1007 ◽

Cited By ~ 3

Author(s):

Lorenza Pastorino ◽

Virginia Andreotti ◽

Bruna Dalmasso ◽

Irene Vanni ◽

Giulia Ciccarese ◽

...

Keyword(s):

Rare Variants ◽

Diagnostic Yield ◽

Susceptibility Genes ◽

Gene Panel ◽

Missing Heritability ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Panel Testing ◽

Novel Variants ◽

Uncertain Significance

The contribution of recently established or candidate susceptibility genes to melanoma missing heritability has yet to be determined. Multigene panel testing could increase diagnostic yield and better define the role of candidate genes. We characterized 273 CDKN2A/ARF and CDK4-negative probands through a custom-designed targeted gene panel that included CDKN2A/ARF, CDK4, ACD, BAP1, MITF, POT1, TERF2IP, ATM, and PALB2. Co-segregation, loss of heterozygosity (LOH)/protein expression analysis, and splicing characterization were performed to improve variant classification. We identified 16 (5.9%) pathogenic and likely pathogenic variants in established high/medium penetrance cutaneous melanoma susceptibility genes (BAP1, POT1, ACD, MITF, and TERF2IP), including two novel variants in BAP1 and 4 in POT1. We also found four deleterious and five likely deleterious variants in ATM (3.3%). Thus, including potentially deleterious variants in ATM increased the diagnostic yield to about 9%. Inclusion of rare variants of uncertain significance would increase the overall detection yield to 14%. At least 10% of melanoma missing heritability may be explained through panel testing in our population. To our knowledge, this is the highest frequency of putative ATM deleterious variants reported in melanoma families, suggesting a possible role in melanoma susceptibility, which needs further investigation.

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WEScover: selection of whole exome sequencing vs. gene panel testing

10.1101/367607 ◽

2018 ◽

Author(s):

William Jefferson Alvarez ◽

In-Hee Lee ◽

Carles Hernandez-Ferrer ◽

Kenneth D. Mandl ◽

Sek Won Kong

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Web Application ◽

Gene Panel ◽

False Negatives ◽

Panel Testing ◽

Whole Exome ◽

Gene Panel Testing ◽

Gene Panels ◽

Targeted Gene Panel Testing

AbstractMotivationWhole exome sequencing (WES) is widely adopted in clinical and research settings. However, there is potential for false negatives due to incomplete breadth and depth of coverage for several exons in clinically implicated genes. In some cases, a targeted gene panel testing may be a dependable option to ascertain true negatives for genomic variants in known phenotype associated genes. We developed a tool for quickly gauging whether all genes of interest would be reliably covered by WES or whether targeted gene panel testing should instead be considered to minimize false negatives in candidate genes.ResultsWEScover is a novel web application that provides an interface for discovering breadth and depth of coverage across population scale WES datasets, searching either by phenotype, by targeted gene panels and by gene(s). Moreover, the application shows metrics from the Genome Aggregation Database to provide gene-centric view on breadth of coverage.ConclusionWEScover allows users to efficiently query genes and phenotype for exome coverage of associated exons, and recommends use of panel tests for genes that are potentially not well covered by WES.

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Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability

BMC Medical Genetics ◽

10.1186/s12881-015-0224-8 ◽

2015 ◽

Vol 16 (1) ◽

Cited By ~ 32

Author(s):

Thalia Antoniadi ◽

Chris Buxton ◽

Gemma Dennis ◽

Natalie Forrester ◽

Debbie Smith ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Diagnostic Yield ◽

Gene Panel ◽

High Diagnostic Yield ◽

Panel Testing ◽

Gene Panel Testing

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AML multi-gene panel testing: A review and comparison of two gene panels

Pathology - Research and Practice ◽

10.1016/j.prp.2016.02.004 ◽

2016 ◽

Vol 212 (5) ◽

pp. 372-380 ◽

Cited By ~ 2

Author(s):

G. Thakral ◽

K. Vierkoetter ◽

S. Namiki ◽

S. Lawicki ◽

X. Fernandez ◽

...

Keyword(s):

Gene Panel ◽

Panel Testing ◽

Gene Panel Testing ◽

Gene Panels

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Extended gene panel testing in lobular breast cancer

Familial Cancer ◽

10.1007/s10689-021-00241-5 ◽

2021 ◽

Author(s):

Elke M. van Veen ◽

D. Gareth Evans ◽

Elaine F. Harkness ◽

Helen J. Byers ◽

Jamie M. Ellingford ◽

...

Keyword(s):

Breast Cancer ◽

Genetic Testing ◽

Detection Rate ◽

Gene Panel ◽

Lobular Breast Cancer ◽

Germline Variants ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Panel Testing ◽

Increased Risk

AbstractPurpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58–23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2. Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

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