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%.

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.

Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing

Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing are urgently required. Most prior research has been based on women selected for high-risk features and more data is needed to make inference about breast cancer risk for women unselected for family history, an important consideration of population screening. We tested 1464 women diagnosed with breast cancer and 862 age-matched controls participating in the Australian Breast Cancer Family Study (ABCFS), and 6549 healthy, older Australian women enroled in the ASPirin in Reducing Events in the Elderly (ASPREE) study for rare germline variants using a 24-gene-panel. Odds ratios (ORs) were estimated using unconditional logistic regression adjusted for age and other potential confounders. We identified pathogenic variants in 11.1% of the ABCFS cases, 3.7% of the ABCFS controls and 2.2% of the ASPREE (control) participants. The estimated breast cancer OR [95% confidence interval] was 5.3 [2.1–16.2] for BRCA1, 4.0 [1.9–9.1] for BRCA2, 3.4 [1.4–8.4] for ATM and 4.3 [1.0–17.0] for PALB2. Our findings provide a population-based perspective to gene-panel testing for breast cancer predisposition and opportunities to improve predictors for identifying women who carry pathogenic variants in breast cancer predisposition genes.

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

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

Whole genome sequencing in the diagnosis of primary ciliary dyskinesia

Background It is estimated that 1–13% of cases of bronchiectasis in adults globally are attributable to primary ciliary dyskinesia (PCD) but many adult patients with bronchiectasis have not been investigated for PCD. PCD is a disorder caused by mutations in genes required for motile cilium structure or function, resulting in impaired mucociliary clearance. Symptoms appear in infancy but diagnosis is often late or missed, often due to the lack of a “gold standard” diagnostic tool and non-specific symptoms. Mutations in > 50 genes account for around 70% of cases, with additional genes, and non-coding, synonymous, missense changes or structural variants (SVs) in known genes presumed to account for the missing heritability. Methods UK patients with no identified genetic confirmation for the cause of their PCD or bronchiectasis were eligible for whole genome sequencing (WGS) in the Genomics England Ltd 100,000 Genomes Project. 21 PCD probands and 52 non-cystic fibrosis (CF) bronchiectasis probands were recruited in Wessex Genome Medicine Centre (GMC). We carried out analysis of single nucleotide variants (SNVs) and SVs in all families recruited in Wessex GMC. Results 16/21 probands in the PCD cohort received confirmed (n = 9), probable (n = 4) or possible (n = 3) diagnosis from WGS, although 13/16 of these could have been picked up by current standard of care gene panel testing. In the other cases, SVs were identified which were missed by panel testing. We identified variants in novel PCD candidate genes (IFT140 and PLK4) in 2 probands in the PCD cohort. 3/52 probands in the non-CF bronchiectasis cohort received a confirmed (n = 2) or possible (n = 1) diagnosis of PCD. We identified variants in novel PCD candidate genes (CFAP53 and CEP164) in 2 further probands in the non-CF bronchiectasis cohort. Conclusions Genetic testing is an important component of diagnosing PCD, especially in cases of atypical disease history. WGS is effective in cases where prior gene panel testing has found no variants or only heterozygous variants. In these cases it may detect SVs and is a powerful tool for novel gene discovery.