Universal Multi Gene Panel Testing For Individuals With Pheochromocytomas And Paragangliomas

Abstract Background: Pheochromocytomas (PCCs) and paragangliomas (PGLs) (PPGLs) are a genetically heterogeneous entity, with roughly 25-40% of cases found to harbor a pathogenic or likely pathogenic germline alteration. Existing practice guidelines advocating for the use of a sequential gene testing strategy to identify individuals with hereditary PPGL are driven by the presence of specific clinical features and predate the routine use of multigene panel testing (MGPT). Here we describe results of MGPT for hereditary PPGL in a clinically and ancestrally diverse cohort from a diagnostic laboratory. Methods: Demographic and clinical information of individuals undergoing targeted MGPT for hereditary PPGL were collected from test requisition forms and supporting clinical documents provided by the ordering clinician and retrospectively reviewed. Individuals underwent MGPT of 10-12 genes depending on test order date. From August 2013 through May 2015, 560 individuals had targeted MGPT that included 10 genes (NF1, MAX, SDHA/B/C/D/AF2, RET, TMEM127, and VHL), and from May 2015 through December 2019, 1167 individuals had panel testing of 12 genes due to the addition of MEN1 and FH. 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. Out of all PVs, most were identified in SDHB (40.4%), followed by SDHD (21.1%), SDHA (10.1%), VHL (7.8%), SDHC (6.7%), RET (3.8%), 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, diagnosis before the age of 45 years, multiple tumors, and positive family history (fhx) of PPGL. Affected individuals with a fhx of PPGL were the most likely to have a PV (70.6% of individuals with PCC + fhx; 85.9% of individuals with PGL + fhx). The positive rate in nearly all clinical subgroups even without predictors of a PV remained over 10%, including individuals with a single tumor (PCC = 16.7%; PGL = 46.7%) and those without a fhx (PCC and negative fhx = 15.8%; PGL and negative fhx = 43.7%). Restricting genetic testing of hereditary PPGL to only SDHB/C/D genes misses a third (31.8%) of individuals with PVs. Among individuals with PVs in syndromic genes, over half (41.5%) did not have any additional syndromic features beyond PPGL reported by the ordering clinician. Conclusion: Our data demonstrate a high diagnostic yield in individuals with and without established risk factors, a low inconclusive result rate, numerous individuals with syndromic PVs presenting with isolated PPGL, and a substantial contribution to diagnostic yield from rare genes when included in testing. These findings support updating practice guidelines to incorporate universal testing of all individuals with PPGL and the use of concurrent MGPT as the ideal platform.

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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgac014 ◽

2022 ◽

Author(s):

Carolyn Horton ◽

Holly LaDuca ◽

Ashley Deckman ◽

Kate Durda ◽

Michelle Jackson ◽

...

Keyword(s):

Family History ◽

Age Of Onset ◽

Diagnostic Yield ◽

Positive Family History ◽

The United States ◽

Substantial Contribution ◽

Clinical Predictors ◽

Variant Of Uncertain Significance ◽

High Diagnostic Yield ◽

Panel Testing

Abstract 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.

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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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BAP1 tumor predisposition syndrome: Preliminary data from a laboratory-based multigene panel testing cohort.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.490 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 490-490

Author(s):

Carrie Horton ◽

Holly LaDuca ◽

Patrick Reineke

Keyword(s):

Skin Cancer ◽

Kidney Cancer ◽

Clinical Laboratory ◽

Cancer Genes ◽

Diagnostic Laboratory ◽

Similar Frequency ◽

Panel Testing ◽

Non Melanoma Skin Cancer ◽

Gene Panel Testing ◽

Melanoma Skin

490 Background: Germline mutations in BAP1 have recently been shown to cause a tumor predisposition syndrome characterized by renal cell carcinoma (RCC), uveal melanoma, cutaneous melanoma, and mesothelioma. However, mutations have thus far been identified in highly enriched cohorts and the tumor spectrum among individuals with a broader phenotype undergoing multi-gene panel testing (MGPT) has not been described. Other genes associated with familial RCC have been established, such as FLCN (Birt-Hogg Dube syndrome) and VHL (von Hippel Lindau), but the proportion of BAP1 mutations in individuals with RCC is not yet known. Here we aim to describe the clinical features of individuals with BAP1 mutations identified from a clinical laboratory cohort, and to estimate the frequency of BAP1 mutations in individuals with kidney cancer. Methods: Since May 2015, a total of 6956 tests have been ordered that include BAP1 at our diagnostic laboratory. Retrospective data review yielded molecular and clinical details for individuals with identified mutations. Results: Thirteen individuals with BAP1 mutations have been identified. Cancer diagnoses in probands and family members consist of breast cancer (reported in 69.2% of kindreds), RCC (61.5%), melanoma (61.5%), mesothelioma (46.2%), lung cancer (46.2%), non-melanoma skin cancer (30.8%), and cholangiocarcinoma (15.4%). Among probands with kidney cancer undergoing MGPT (n = 1012), there is no difference in mutation rate of BAP1 compared to VHL (n = 3; OR 2.01 p = 0.51) or FLCN (n = 10; OR 0.598 p = 0.45). Conclusions: Cancer histories in our laboratory-selected cohort of BAP1 mutation carriers are consistent with those reported in the clinical literature, lending credence to the notion that BAP1 tumor predisposition syndrome is highly penetrant and consists of a constellation of several core cancers. The observation of breast, lung, non-melanoma skin cancer, and cholangiocarcinoma has also been reported in the literature and warrants further study. Our results suggest that BAP1 mutations are found at a similar frequency as other well-known kidney cancer genes, supporting its position as an important differential when considering genetic testing for RCC.

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Multigene hereditary cancer panel testing for patients with pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.244 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 244-244

Author(s):

Anna K McGill ◽

Sheila R Solomon ◽

Megan L Marshall ◽

Lisa Susswein ◽

Corrine Fillman ◽

...

Keyword(s):

Family History ◽

Hereditary Cancer ◽

Diagnostic Yield ◽

Ductal Adenocarcinoma ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Panel Testing ◽

History Of ◽

Brca1 Brca2 ◽

Cancer Panel

244 Background: Pancreatic ductal adenocarcinoma (PC) is associated with multiple hereditary cancer syndromes. Genes implicated in hereditary PC include ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2 and PMS2. The advent of multi-gene hereditary cancer panel testing streamlines diagnoses and medical management for clinicians and patients. Our objective was to assess the yield of pathogenic/likely pathogenic variants (PV/LPV) in individuals with PC undergoing panel testing as an initial test at GeneDx. Methods: We retrospectively reviewed panel test results of 605 individuals reporting a personal history of PC. Panel testing evaluated up to 32 genes associated with hereditary cancer. Individuals reporting neuroendocrine pathology or previous BRCA1/BRCA2 testing were excluded. Results: In this cohort, 61 PV/LPV were detected in 57 individuals in the following genes: ATM (17), BRCA2 (14), BRCA1 (5), CDKN2A (5), PALB2 (5), CHEK2 (4), MLH1 (2), MUTYH (2), PMS2 (2), BARD1 (1), FANCC (1), MSH2 (1), RAD51D (1) and TP53 (1), corresponding to a positive yield of 9.4% (57/605). Fifty-one of 61 PV/LPV were detected in genes associated with PC (84%) while 10 PV/LPV (16%) were identified in other genes including BARD1, CHEK2, FANCC, MUTYH, and RAD51D. The diagnostic yield among those reporting a family history of PC (33/294, 11.2%) was not statistically different from those without a reported family history (24/311, 7.7%). However, PV/LPV in ATM were detected more often in individuals reporting a family history of PC compared to those without a family history (4.1% vs. 1.6%, p=0.018). Conclusions: In total, 9.4% of patients with PC tested positive for PV/LPV in 14 different genes by panel testing. Although the majority of PV/LPV were identified in known PC genes, 16% of positive findings occurred in genes not typically associated with PC. ATM was most commonly implicated and more frequently reported in patients reporting family histories of PC. Assessing whether these genes are indeed causally related to PC and/or are possibly associated with other cancer types requires further investigation. Based on our results we conclude multi-gene panel testing may be considered as a first option for patients with PC regardless of their family history.

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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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Multicenter Prospective Cohort Study of the Diagnostic Yield and Patient Experience of Multiplex Gene Panel Testing For Hereditary Cancer Risk

JCO Precision Oncology ◽

10.1200/po.18.00217 ◽

2019 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Gregory E. Idos ◽

Allison W. Kurian ◽

Charité Ricker ◽

Duveen Sturgeon ◽

Julie O. Culver ◽

...

Keyword(s):

Response Rate ◽

Diagnostic Yield ◽

Prophylactic Surgery ◽

University Of Southern California ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Panel Testing ◽

Uncertain Significance ◽

Multicenter Prospective Cohort Study ◽

Multicenter Prospective Cohort

Purpose Multiplex gene panel testing (MGPT) allows for the simultaneous analysis of germline cancer susceptibility genes. This study describes the diagnostic yield and patient experiences of MGPT in diverse populations. Patients and Methods This multicenter, prospective cohort study enrolled participants from three cancer genetics clinics—University of Southern California Norris Comprehensive Cancer Center, Los Angeles County and University of Southern California Medical Center, and Stanford Cancer Institute—who met testing guidelines or had a 2.5% or greater probability of a pathogenic variant (N = 2,000). All patients underwent 25- or 28-gene MGPT and results were compared with differential genetic diagnoses generated by pretest expert clinical assessment. Post-test surveys on distress, uncertainty, and positive experiences were administered at 3 months (69% response rate) and 1 year (57% response rate). Results Of 2,000 participants, 81% were female, 41% were Hispanic, 26% were Spanish speaking only, and 30% completed high school or less education. A total of 242 participants (12%) carried one or more pathogenic variant (positive), 689 (34%) carried one or more variant of uncertain significance (VUS), and 1,069 (53%) carried no pathogenic variants or VUS (negative). More than one third of pathogenic variants (34%) were not included in the differential diagnosis. After testing, few patients (4%) had prophylactic surgery, most (92%) never regretted testing, and most (80%) wanted to know all results, even those of uncertain significance. Positive patients were twice as likely as negative/VUS patients (83% v 41%; P < .001) to encourage their relatives to be tested. Conclusion In a racially/ethnically and socioeconomically diverse cohort, MGPT increased diagnostic yield. More than one third of identified pathogenic variants were not clinically anticipated. Patient regret and prophylactic surgery use were low, and patients appropriately encouraged relatives to be tested for clinically relevant results.

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A Collaborative Effort to Define Classification Criteria for ATM Variants in Hereditary Cancer Patients

Clinical Chemistry ◽

10.1093/clinchem/hvaa250 ◽

2020 ◽

Author(s):

Lidia Feliubadaló ◽

Alejandro Moles-Fernández ◽

Marta Santamariña-Pena ◽

Alysson T Sánchez ◽

Anael López-Novo ◽

...

Keyword(s):

Hereditary Cancer ◽

Diagnostic Yield ◽

Clinical Information ◽

Variant Classification ◽

Collaborative Effort ◽

Variants Of Uncertain Significance ◽

Large Gene ◽

Gene Panel Testing ◽

Uncertain Significance ◽

Risk Of Cancer

Abstract Background Gene panel testing by massive parallel sequencing has increased the diagnostic yield but also the number of variants of uncertain significance. Clinical interpretation of genomic data requires expertise for each gene and disease. Heterozygous ATM pathogenic variants increase the risk of cancer, particularly breast cancer. For this reason, ATM is included in most hereditary cancer panels. It is a large gene, showing a high number of variants, most of them of uncertain significance. Hence, we initiated a collaborative effort to improve and standardize variant classification for the ATM gene. Methods Six independent laboratories collected information from 766 ATM variant carriers harboring 283 different variants. Data were submitted in a consensus template form, variant nomenclature and clinical information were curated, and monthly team conferences were established to review and adapt American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria to ATM, which were used to classify 50 representative variants. Results Amid 283 different variants, 99 appeared more than once, 35 had differences in classification among laboratories. Refinement of ACMG/AMP criteria to ATM involved specification for twenty-one criteria and adjustment of strength for fourteen others. Afterwards, 50 variants carried by 254 index cases were classified with the established framework resulting in a consensus classification for all of them and a reduction in the number of variants of uncertain significance from 58% to 42%. Conclusions Our results highlight the relevance of data sharing and data curation by multidisciplinary experts to achieve improved variant classification that will eventually improve clinical management.

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Clinical and genetic variability in children with partial albinism

Scientific Reports ◽

10.1038/s41598-019-51768-8 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Patrick Campbell ◽

Jamie M. Ellingford ◽

Neil R. A. Parry ◽

Tracy Fletcher ◽

Simon C. Ramsden ◽

...

Keyword(s):

Molecular Diagnosis ◽

Diagnostic Yield ◽

Skin Pigmentation ◽

Diagnostic Challenge ◽

Ocular Albinism ◽

Functional Polymorphisms ◽

Panel Testing ◽

Gene Panel Testing ◽

Significant Enrichment ◽

Foveal Hypoplasia

Abstract Individuals who have ocular features of albinism and skin pigmentation in keeping with their familial background present a considerable diagnostic challenge. Timely diagnosis through genomic testing can help avert diagnostic odysseys and facilitates accurate genetic counselling and tailored specialist management. Here, we report the clinical and gene panel testing findings in 12 children with presumed ocular albinism. A definitive molecular diagnosis was made in 8/12 probands (67%) and a possible molecular diagnosis was identified in a further 3/12 probands (25%). TYR was the most commonly mutated gene in this cohort (75% of patients, 9/12). A disease-causing TYR haplotype comprised of two common, functional polymorphisms, TYR c.[575 C > A;1205 G > A] p.[(Ser192Tyr);(Arg402Gln)], was found to be particularly prevalent. One participant had GPR143-associated X-linked ocular albinism and another proband had biallelic variants in SLC38A8, a glutamine transporter gene associated with foveal hypoplasia and optic nerve misrouting without pigmentation defects. Intriguingly, 2/12 individuals had a single, rare, likely pathogenic variant in each of TYR and OCA2 – a significant enrichment compared to a control cohort of 4046 individuals from the 100,000 genomes project pilot dataset. Overall, our findings highlight that panel-based genetic testing is a clinically useful test with a high diagnostic yield in children with partial/ocular albinism.

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

European Heart Journal ◽

10.1093/eurheartj/ehab724.1746 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

J M Murphy ◽

C W Kirk ◽

J Galvin ◽

D Ward ◽

T Prendiville ◽

...

Keyword(s):

Diagnostic Yield ◽

Molecular Genetic ◽

Gene Panel ◽

Long Qt ◽

Molecular Autopsy ◽

Panel Testing ◽

Gene Panel Testing ◽

Cardiac Gene ◽

Gene Panels ◽

Actionable Variants

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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