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At the American Society of Human Genetics (ASHG) Annual Meeting this year, our esteemed speakers shared the ins and outs of how the SOPHiA DDM™ Platform, in combination with Alamut™ Visual Plus, adapted to their laboratories’ needs to provide sample-to-report workflows that streamlined the identification and interpretation of nuclear and mitochondrial variants associated with rare and inherited diseases, including hereditary cancers.
All SOPHiA GENETICS™️ products discussed in this article are for Research Use Only – not for use in diagnostic procedures. SOPHiA GENETICS™ does not facilitate and does not accept any liability for any validation of SOPHiA GENETICS™ products for clinical use by a third party.
Exome sequencing with combined mitochondrial genome sequencing for the detection of nuclear and mitochondrial DNA variants
Jessica Van Ziffle, PhD, FACMG Associate Clinical Professor, Pathology at University of California, San Francisco, California, United States
In the Pathology laboratory at the University of California, the proportion of positive/probably positive variants detected in pediatric and prenatal cases analyzed using the SOPHiA DDM™ Custom Whole Exome Solution (optimized for the Illumina NovaSeq 6000) was consistent with the literature (see charts). Approximately 70% of the positive pediatric cases were associated with autosomal dominant inheritance. Most reported variants were missense single nucleotide variants (SNVs), with the positive cases fairly equally split between frameshift, nonsense, and missense variants.
Proportion of positive/probably positive findings for pediatric and prenatal exome cases
Figure sourced from Jessica Van Ziffle’s presentation
With the goal of increasing the proportion of positive findings, Jessica and the team at UCSF explored what additional variants could be identified by exome sequencing to potentially solve the ∼10% of inconclusive cases and ∼65% of negative cases. First, the team investigated the impact of calling copy number variants (CNVs), specifically contiguous gene changes, whole gene changes, and exon-level changes. UCSF worked closely with SOPHiA GENETICS™ to optimize their exome sequencing to ensure high and even coverage for accurate CNV detection, and indeed doubled their sequencing depth to 80M reads to ensure the sensitive detection of CNVs 1-2 exons in size.
Next, UCSF wanted to be able to simultaneously call variants in mitochondrial DNA, which is especially relevant for metabolic diseases. Different cell types have different numbers of mitochondria, and each mitochondrion has its own genome that can have different variants in it (heteroplasmy). The UCSF team, therefore, wanted to assess the lower limit of detection for mitochondrial heteroplasmy through a mixing study, which concluded that exome testing could detect variants down to 5% variant allele fraction with high sensitivity.
Streamlining clinical implementation of hereditary cancer analysis and reporting with a custom application
Hong Wang, PhD, FCCMG, FACMG, DABMGG Laboratory Geneticist at North York General Hospital, Toronto, Ontario, Canada
Andrea Vaags, PhD, FCCMG Discipline Co-Lead and Laboratory Geneticist at Trillium Health Partners – Credit Valley Hospital, Mississauga, Ontario, Canada
Drs Wang and Vaags provided a step-by-step overview of how they developed a brand new hereditary cancer panel to meet the Ontario Health - Cancer Care Ontario criteria for hereditary cancer testing.
Laboratory and clinical working groups were established to evaluate evidence and identify key genes and non-coding variants to include in a cutting-edge custom hereditary cancer panel. Furthermore, genetic testing eligibility criteria were co-developed with the Hereditary Cancer Clinical Eligibility Working Group. The laboratory working group used an evidence-based framework to design a standardized 76-gene panel, organized into 13 larger disease site-linked panels, and 25 single/small gene panels. After designing the panel, the Ontario group worked with SOPHiA GENETICS™ to expeditiously develop and implement the custom SOPHiA DDMTM Hereditary Cancer application in academic community hospitals (see timeline).
Timeline of SOPHiA DDM™ Hereditary Cancer panel implementation in Ontario hospitals
Figure sourced from the Ontario hospital responsible for validating this product
Thanks to the streamlined end-to-end SOPHiA GENETICS™ workflow, hereditary cancer testing approximately doubled, according to Dr Vaags.
The workflow for each batch of 70 samples (plus one control) in the Ontario group laboratories, consists of DNA preparation, automated 3-day library preparation using the SOPHiA GENETICS program on the Hamilton STARlet, and sequencing on a NextSeq® 550 using mid-output. Sequencing data are automatically uploaded to the SOPHiA DDM™ cloud for processing ahead of analysis. For additional time savings, genes requiring special consideration due to the presence of pseudogenes are flagged with a warning in the SOPHiA DDM™ Platform and the SOPHiA GENETICS™ support team is on hand to answer queries on unusual findings. The cloud-based software for data management enables the laboratories to streamline data access, storage, and archiving back-up. Dr Wang shared that the time saved through this workflow has been instrumental in maintaining turnaround times, especially with significant understaffing during challenging periods.
By applying Virtual Panels and custom filters, the teams can analyze from as little as a single variant to as many as 76 genes using a single workflow. The high analytical sensitivity and specificity enable the laboratories to pick up unusual findings, such as Alu insertions, Boland inversions, and low-level mosaicism of copy number changes. And finally, the one-step secondary and tertiary analysis for concurrent detection of SNVs and CNVs allows the teams to significantly speed up their analysis, and the pseudogene pipeline enables the laboratories to minimize reflex testing. In summary, the custom SOPHiA DDM™ Hereditary Cancer application provides the Ontario laboratories with a one-size-fits-all solution.
Screening for genetic variants in hereditary cancer syndromes using the end-to-end SOPHiA DDM™ workflow
Mark Williams, FHGSA – Chief Scientist at Genomic Diagnostics, Heidelberg, Victoria, Australia
Speaker Mark Williams began his talk by highlighting that a key goal of the Genomic Diagnostics lab is to facilitate equal access to hereditary cancer testing. To do this, the lab set multiple criteria that were highly important to them when developing a new hereditary cancer application. Employing the complete SOPHiA GENETICS™ workflow for Hereditary Cancer allowed the team at Genomic Diagnostics to successfully meet these testing criteria.
In collaboration with Genomic Diagnostics, the custom SOPHiA DDM™ Hereditary Cancer application was designed to include genes that align with current practice guidelines. It was important to the lab that the pipeline could detect SNVs, Indels, and copy number variations (CNVs) in a single workflow. Mark confirmed that the resultant application effectively detects CNVs and is scalable, with turnaround times that meet their needs, even with testing volumes increasing year-on-year. In addition, the solution provides high-quality, consistent results, a full record of curation, visualization of BAM files, and is easily accessible and usable by all laboratory staff.
Like numerous other SOPHiA GENETICS™️ customers, Mark concluded that the SOPHiA DDM™ Platform offers a robust, automated, and secure bioinformatics pipeline that meets Australia’s privacy regulations. In addition, the software is extremely user-friendly, from its visual interface to the detailed QC metrics, annotation information, and links to databases. All laboratory personnel can effectively use the end-to-end solution, even without prior bioinformatics expertise.
The integrated workflow and affordable price allowed Genomic Diagnostics to expand access to the custom SOPHiA DDM™ Hereditary Cancer application (see chart), meeting Genomic Diagnostics’ goal of facilitating equal access to hereditary cancer testing.
Increasing access to hereditary cancer genomic testing over time
Figure sourced from Mark Williams’ presentation
We thank all our speakers for sharing their research stories at our ASHG symposium this year. We’re delighted to hear how their integrated SOPHiA DDM™ workflows are reducing workloads, expanding access, and continuing to discover new variants associated with rare diseases and hereditary cancers.
At ESMO 2022, oncology experts gathered in Paris and online to share and debate the new developments in the field of medical oncology. This year's program featured more than 20 tracks covering all tumor types, therapeutic innovations, translational research, patient advocacy, public policy, and more...
Discover our summary of three compelling talks showcasing the journey towards precision therapy in various tumor types.
Genomic profiling and molecular targeting of lung cancer brain metastases1
Haiying Cheng, Dept. Medical Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA
Approximately 57% of patients with non–small-cell lung cancer (NSCLC) present with metastatic disease2. Among them, brain metastases (BM) affect up to 45% of all cancer patients and arise from lung cancers in 40-50% of the cases3. There have been limited studies investigating the genetic signatures of LC BM, and with small cohorts so far.
Assembling a large number of lung cancer cases (47215 NSCLC; 29438 lung adenocarcinoma), Dr Cheng and colleagues looked for key genetic alterations in loco-regional lesions (Loco), extracranial metastases (EM), and BM with comprehensive genomic profiling (CGP). They found significantly more genetic alterations in the PI3K/AKT/mTOR pathway in BM (Loco 13.0% vs EM 14.5% vs BM 18.1%), primarily driven by RICTOR amplification (Loco 3.6% vs EM 6.2% vs BM 8.6%).
RICTOR amplification is the most enriched actionable genomic target in NSCLC brain metastases.
Furthermore, in vitro genetic knockdown and pharmacological inhibition of RICTOR significantly reduced migration and invasion in RICTOR-amplified NSCLC cells, whereas RICTOR upregulation promoted these processes, modulating the AKT, MET, EMT, and CXCL12 chemokine-CXCR4 pathways. Finally, in vivo studies in orthotopic mouse models revealed that both RICTOR and mTOR1/2 inhibition significantly reduced lung cancer tumor growth and spread in the brain.
Dr Cheng provided evidence for the benefit of further investigation on the development of RICTOR-targeted therapeutic strategies for the treatment and/or prevention of lung cancer BM. This study is a good example of how genomic profiling, combined with functional analyses, can identify new potential therapeutic targets.
Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study4.
Myriam Chalabi, Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
Mismatch repair deficiency (dMMR) is observed in ~15% of colorectal cancers (CC)5 and 1/3 is associated with Lynch Syndrome. This characteristic genetic signature is marked by high levels of microsatellite instability (MSI) and resistance to standard-of-care neoadjuvant chemotherapy (5-7% pathological response (≤50% residual viable tumor; PR)). NICHE-1 exploratory study showed the potential of neoadjuvant immunotherapy in patients with dMMR CC with extraordinary PR in 100% of the patients6.
Dr Chalabi presented the NICHE-2 investigator-initiated study, conducted in 6 hospitals in the Netherlands. 107 patients with non-metastatic untreated dMMR CC and mainly high-risk tumors received injections of nivolumab and ipilimumab within 6 weeks prior surgery. The impressive pathological tumor regression was shown in a waterfall plot that led to a standing ovation! 95% of the treated patients showed PR, and 67% had no residual viable tumor (complete PR; cPR), contrasting with the neoadjuvant chemotherapies in the same patient population. Only 4% experienced grade 3-4 immune-related adverse events and 98% of patients underwent timely surgery, meeting the safety primary endpoint. To date, no disease recurrence has been observed and the 3 years disease-free survival data are expected next year.
Neoadjuvant immunotherapy has the potential to become standard of care for patients with dMMR colon cancer.
NICHE-2 trial opens the possibility that a surveillance approach may be possible for some patients with early dMMR CC and gives a glimpse at the potential of translational research to identify predictive biomarkers in pre- and post-treatment samples. While those preliminary results are extremely promising and we surely wait for the longer-term follow-up data to confirm them, patient selection remains crucial. Indeed, neoadjuvant decisions are based on radiological assessment of the tumor, particularly difficult in dMMR cancers, as well as the biopsy, and Dr Chalabi highlighted the need for improvement in the imaging techniques and circulating DNA analyses.
Final overall survival results from the phase III PAOLA-1/ENGOT-ov25 trial evaluating maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced ovarian cancer7.
Isabelle Ray-Coquard, Department Of Medical Oncology, Centre Léon Bérard, and GINECO, Lyon, France
The late diagnosis of advanced ovarian cancer (AOC) is often accompanied by relapse, despite surgery and platinum-based chemotherapy. Treatment with olaparib (ola), a poly(adenosine diphosphate–ribose) polymerase inhibitor (PARPi), provided progression-free survival (PFS) benefit as maintenance therapy in patients with AOC carrying mutations in BRCA1 or BRCA2 (BRCAm)8. Besides, the incorporation of the antiangiogenic agent bevacizumab (bev) is a recognized option in addition to chemotherapies9.
PAOLA-1 investigators conducted a phase III trial where 806 patients with AOC and after first-line platinum-based chemotherapy plus bev were randomly assigned in a 2:1 ratio to ola + bev or placebo (pbo) + bev treatment. The primary endpoint was the PFS. They showed that combined treatment with ola + bev reduced the risk of relapse by 41% compared to bev alone, reducing by 67% in HRD+ patients (exhibiting BRCAm and/or genomic instability score ≥42)10.
Here, Dr Ray-Coquard presented the final overall survival (OS) results, a key secondary endpoint. She showed that the OS rate after 5 years was not different between the two arms (47.3% vs 41.5%) but significantly increased for HRD+ patients treated with ola + bev (65.5% vs 48.4%), regardless of BRCAm status. Also, PFS was significantly increased in the same population (46.1% vs 19.2%).
Maintenance therapy with olaparib plus bevacizumab improved survival in HRD+ patients with newly diagnosed advanced ovarian cancer.
With the absence of new safety signals and major adverse effects, these data confirmed the benefit of olaparib and bevacizumab combination as a standard of care for HRD+ patients and reinforced the importance of precision medicine and biomarker testing to guide treatment decisions.
At ASCO 2022, oncology professionals gathered in Chicago, Illinois, and online to discuss the latest advances in research and care for patients with cancer. This year's program featured over 200 sessions on Advancing Equitable Cancer Care Through Innovation. The presentations spanned from care delivery and regulatory policy to developmental therapeutics, gastrointestinal cancer, lung cancer, pediatric oncology, and beyond. Here, discover our summary of four outstanding ASCO presentations focusing on breast cancer treatment, diagnosis and follow-up, showcasing the power of precision medicine in healthcare.
Targetable genomic mutations in young women with advanced breast cancer1.
Norin Ansari, Yale New Haven Hospital, New Haven, CT
Advanced breast cancers (BC) in young women (under 40 years old) are often more aggressive and with worse prognoses than in older women. As treatment strategies can be dictated by the type of genomic alteration (GA), knowledge of BC genetic profiles across ages can greatly improve guidance and outcomes. In her poster presentation, Norin Ansari analyzed over 2,000 BC using hybrid-capture based comprehensive genomic profiling (CGP) to evaluate subtypes of GA and confirmed via immunohistochemistry (IHC) hormone receptors (HR) and PD-L1 status.
The study showed a mutations stratification within the population of BC depending on patient's age. Indeed, younger patients had higher rates of BRCA1, BRCA2, and RB1 mutations and lower rates of CDH1 and PIK3CA mutations than did older patients. Differences were statistically significant in BRCA1, CDH1, and PIK3CA. Norin Ansari also showed that breast tumors in younger women were less likely to be estrogen receptor positive (ER+) and more likely to be triple negative while no clear age-related pattern for HER2 status could be highlighted. Finally, younger women were more often PD-L1 positive and had lower tumor mutational burden (TMB) than their older counterparts.
Different mutational profiles may support differential use of targeted and immune therapies.
With increasing availability of targeted and immune therapies, knowing which GA each group of women has allows to better tailor therapies and leads to more effective treatments. For instance, BRCA1 mutations may lend to PARP inhibitor use while PIK3CA mutations may indicate the benefit of alpelisib prescription. The difference in genetic mutations between age groups can give a head start when treating women with breast cancer and CGP can refine the approach for better results.
Alpelisib + fulvestrant in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: Biomarker analyses by next-generation sequencing from the SOLAR-1 study2.
Dejan Juric, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
PIK3CA mutations account for approximately 40% of the hormone receptor positive (HR+), HER2-negative (HER2-) advanced BC. PIK3CA encodes for a subunit of PI3K, key of a highly interconnected pathway regulating growth and cell survival. PI3K pathway alterations are associated with endocrine therapy resistance, hence the poor prognosis for HR+, HER2– advanced BC.
Dejan Juric introduced the SOLAR-1 phase 3 study, a randomized controlled study testing the efficacy of the combined administration of alpelisib (ALP, a PI3Kα-selective inhibitor and degrader) and fulvestrant (FUL, a selective estrogen receptor degrader) in HR+, HER2- advanced BC patients. SOLAR-1 shows improved progression-free survival (PFS) in ALP + FUL treated patients versus placebo + FUL of 11.0 and 5.7 months, respectively. Going one step further, they measured the efficacy outcomes in patients with specific gene alterations (GA) in a PIK3CA-altered cohort, applying a retrospective exploratory biomarker analysis.
SOLAR-1 baseline tumor samples were tested by next-generation sequencing (NGS) and clinical benefit was assessed using PFS and hazard ratio based on TMB and GA status in the PIK3CA-altered cohort. While ALP + FUL clinical benefit was seen across TMB quartiles, it was more pronounced in patients with a low TMB (PFS of 18.5 months with ALP versus 3.2 months with placebo). They also observed that, despite improved PFS with ALP + FUL treatment in all PIK3CA-altered patients, the level of benefit may depend on the mutation status of other genes involved in MAPK pathway, PI3K pathway, in endocrine therapy or CDK4/6 inhibitors resistance. For instance, greater benefit was observed with altered FGFR1/2 but limited in MYC- and RAD21-altered cohorts. Besides, ALP + FUL efficacy was independent of GA in TP53, ESR1, CCND1, MAP3K1 and ARID1A.
Clinical benefit of ALP + FUL was maintained regardless of alterations in most biomarkers.
To conclude, Dejan Juric showed that ALP + FUL treatment was beneficial in patients with HR+, HER2– advanced BC, especially with a low TMB, but that a comprehensive understanding of the unique mutational profile of each tumor via biomarkers analysis may explain the level of success and thus dictate further care.
Trastuzumab deruxtecan versus treatment of physician’s choice in patients with HER2-low unresectable and/or metastatic breast cancer: Results of DESTINY-Breast04, a randomized, phase 3 study3.
Shanu Modi, Memorial Sloan Kettering Cancer Center, Memorial Hospital, New York, NY, USA
Metastatic breast cancers (mBC) are classified according to the detection of certain receptors in the tumor cells, dictating the type of treatment to offer to the patients. Thus, mBC with an abnormally high quantity of human epidermal growth factor receptor-2 (HER2+) benefit from therapies targeting HER2 protein with monoclonal antibodies, while HER2- mBC receive treatment based on their HR status. However, the dichotomy between HER2+ and HER2- mBC does not suffice to find effective therapies for patients with low level of HER2 (HER2-low) currently treated as HER2-. The limited options and modest benefits of chemotherapy confirm the need for an adapted targeted strategy.
Trastuzumab deruxtecan (T-DXd) is part of a new generation of antibody-drug conjugates that delivers precision-focused chemotherapy directly to the cancer cells. Its activity was shown in tumors across a broad range of HER2 expression and a phase 1 trial showed promising efficacy of T-DXd in patients previously heavily treated with HER2-low mBC. Here, Shanu Modi presented us the DESTINY-Breast04 study, the first randomized phase 3 study of T-DXd for HER2-low mBC and its auspicious results.
Measuring the median progression-free survival (mPFS) in HR-positive mBC patients as primary endpoint, they observed statistically significant and clinically meaningful improvement for patients with HER2-low mBC compared to standard chemotherapy (mPFS 10.1 versus 5.4 months respectively: p<0.0001). Similar benefit was seen in all patients, regardless of their HR status, with T-DXd treatment through PFS and overall survival (OS) compared to standard chemotherapy.
DESTINY-Breast04 establishes HER2-low mBC as a targetable patient population with T-DXd as a new standard of care, with the potential to improve the survival for ~50% of all mBC patients.
We expanded the benefits of HER2 targeted therapy to a new population of breast cancer patients and established T-DXd as the new standard of care for HER2-low mBC.
These ground-breaking results presented at the 2022 ASCO Annual Meeting, and simultaneously published in the New England Journal of Medicine4, were acknowledged with a standing ovation from the audience of specialists. Anticipating these results to be practice changing, the study gives hope for many oncology professionals and patients.
Circulating tumor DNA and late recurrence in high-risk, hormone receptor–positive, HER2-negative breast cancer (CHiRP)5.
Marla Lipsyc-Sharf, Dana-Farber Cancer Institute, Boston, MA
Over half of metastatic recurrences in HR+ BC are late (occurring over 5 years from diagnosis) and thought to arise from minimal residual disease (MRD), a small number of cancer cells left in the body after treatment, hence the benefit of adjuvant therapy. MRD detection via circulating tumor DNA (ctDNA) is associated with high risk of BC recurrence in the early adjuvant setting across tumor subtypes. Little is known, however, about ctDNA for later settings.
Marla Lipsyc-Sharf presented the CHiRP prospective study of late recurrence in patients with high-risk HR+ BC without prior recurrence. 83 patients were followed with whole exome sequencing on primary tumor samples and plasma collection every 6-12 months to be processed with personalized RaDaRTM assay (12-51 variants) to detect ctDNA. Patients did not undergo routine surveillance body imaging or other circulating biomarkers testing. 68.7% of the patients had stage 3 disease and most received chemotherapy (90.4%) and adjuvant endocrine therapy (100%).
8 of 83 (10%) patients had detectable ctDNA at any timepoint during this study. As of last follow-up, 6 of them developed metastatic recurrence at various sites, 6-14 years after primary diagnosis, and one patient with detected ctDNA developed a locoregional recurrence.
All distant recurrences were detectable via ctDNA prior the recurrence with a median lead time of ~1 year.
Despite the low yet steady rate of recurrence in this small cohort with limited follow-up and infrequent plasma sampling (every 6-12 months), this study, published in Journal of Clinical Oncology6, shows that liquid biopsy can provide precious indication on the risk of relapse and thus point towards earlier intervention after MDR detection, improving patients' survival and quality of life.
1 https://meetings.asco.org/abstracts-presentations/210258
2 https://meetings.asco.org/abstracts-presentations/209230
3 https://meetings.asco.org/abstracts-presentations/209021
4 Modi S, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer [published online ahead of print, 2022 Jun 5]. N Engl J Med. 2022;10.1056/NEJMoa2203690. doi:10.1056/NEJMoa2203690
5 https://meetings.asco.org/abstracts-presentations/209216
6 Lipsyc-Sharf M, de Bruin EC, Santos K, et al. Circulating Tumor DNA and Late Recurrence in High-Risk Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer [published online ahead of print, 2022 Jun 4]. J Clin Oncol. 2022;JCO2200908. doi:10.1200/JCO.22.00908
This year, ESHG was pleased to reunite face-to-face from June 11-14 in Vienna, Austria for the 55th Annual European Human Genetics Conference. ESHG provided a hybrid platform for the dissemination of the most exciting advancements in the field of human genetics, with an engaging program covering emerging concepts, mechanisms, and technologies in human genetics.
Read our summary of three presentations that explored the role of genetic testing in the diagnosis and care of sick children across the world. Specifically, we discover how next-generation sequencing of specific genes, whole exomes, and even whole genomes can play a role in advancing research and improving the healthcare and outcomes of pediatric patients.
Incidence of pediatric cancer predisposition in Czechia
Lucie Slamova, Michal Zapotocky, Lucie Šrámková, Martina Bittoova, Leona Cerna, Monika Koudová
Genetic predisposition plays an important role in the onset of cancers, especially those not related to environmental factors. However, pediatric cancer predisposition is not fully understood. This study by Slamova et al. used targeted next-generation sequencing to examine predisposing genetic variants in a pediatric cancer population in the Czech Republic.
The investigators adapted targeted panels covering 226 genes to include an additional 64 genes specific to the pediatric cohort. These panels were used to evaluate genetic variants in 217 children with cancer. Pathogenic variants related to cancer predisposition were detected in 31/217 patients (14%) in the TP53, NF1, RB1, PALB2, EXT2, BRCA1, WNR, ABRAXAS1, STK11, HOXB13, NBN, MUTYH, ATM, CHEK2, FANCA, SBDS, FANCG, and FANCI genes. Variants in MUTYH, CHEK2, and WRN were particularly prevalent in the neuro-oncology subgroup. Likely pathogenic variants were detected in 14/217 patients (6%), in the ALK, BRIP1, ERCC3, FANCD2, FANCL, LIG4, MSH2, SMARCE1, SMARCA4, RECQL, and RECQL4 genes. Therefore, pathogenic or likely pathogenic variants related to cancer predisposition were identified in 20.7% of children with cancer in this Czech cohort, with variants of uncertain significance (VUS) discovered in an additional 55 patients (25%).
For the first time, this study determines the incidence of cancer predisposition in the Czech pediatric cancer population, demonstrating the value and utility of genetic testing in childhood cancers.
Mainstreaming genomic testing for children with undiagnosed inborn errors of immunity
Tatiane Yanes, Anna Sullivan, Pasquale Barbaro, Kristian Brion, Jane Peake, Peter McNaughton
A genetic diagnosis in patients with pediatric inborn errors of immunity (IEI) can influence management decisions and clinical outcomes by opening the door to targeted and curative treatments. However, in Queensland, Australia, children with undiagnosed IEI have historically been referred to a state-wide clinical genetic service, delaying genomic testing and increasing the burden on the genetics clinic. In this study, Yanes et al. examined the feasibility and efficacy of a mainstream model of care that they developed in Brisbane, Australia to allow timely access to genomic testing for pediatric IEI.
21 custom virtual gene lists were developed for whole-exome sequencing (WES). In addition, a genetic councelor was embedded within the pediatric immunology service, and fortnightly multidisciplinary team meetings, and variant prioritization meetings were held.
Overall, the program ran between Nov 2020 and Sep 2021, with 9/43 children (21%) receiving a genetic diagnosis. All diagnosed children underwent changes in their management, such as curative hematopoietic stem cell transplantation (n = 4) and IVIg infusions (n = 2). An additional five children were referred for further investigation of a variant of uncertain significance (VUS). On average, 14 healthcare providers attended the multidisciplinary team meetings, demonstrating engagement with the program.
This novel program demonstrated that WES can be successfully mainstreamed for pediatric IEI in Queensland, Australia. The program improved access to genomic testing and facilitated treatment decision-making, including access to curative therapies.
NAGENpediatrics: Rapid whole genome sequencing in neonatal/pediatric intensive care in Navarra, Spain
Monica Arasanz Armengol, Sara Ciria Abad, Leslie Matalonga, Gemma Bullich Vilanova, Ida Paramonov, Edurne Urrutia Lafuente, Oscar Teijido Hermida, Alberto Maillo, Maria Miranda Perez, Iranzu González Borja, Gonzalo Etayo Nagore, Mercè Artigas López, Juan Jose Beloqui Lizaso, Angel Alonso Sanchez, Nerea Gorria-Redondo, Josune Hualde Olascoaga
Approximately 2-3% of newborns have a congenital anomaly, with at least 50% having a genetic cause. Rapid genomic testing (with a 2-3-week turnaround) has been found to facilitate the diagnosis of ∼21-26% of critically ill children, influencing their clinical outcomes. This pioneering study by Armengol et al. aimed to evaluate the diagnostic and therapeutic utility of rapid whole-genome sequencing (WGS) for acutely sick children in Navarra, Spain.
The ongoing study involved 34 trios in the first year, supported by a multidisciplinary team. Extensive clinical and phenotypic data were collected and rapid WGS was performed on germline DNA to identify potential causative variants. Each family received a detailed genetic counselling consultation. Pathogenic variants associated with clinical manifestations were identified in 14 families, for a diagnostic yield of 41%. The genetic results were delivered in an average of 2-3 weeks, significantly reducing the diagnostic odyssey for these patients, and influencing clinical decisions.
This study identified new genetic variants associated with rare diseases which would not have been found using other diagnostic methods in rapid turnaround times. The results demonstrated that rapid WGS was successful in enabling the delivery of precision medicine to children in Navarra, Spain, with potential extensive benefits for patients, clinicians, and the Regional Health System.
At ACMG 2022, leading geneticists gathered in Nashville, Tennessee and online to share exciting advances in the fields of medical genetics and genomics. The research topics spanned from laboratory research, to prenatal genetics, clinical genetics and therapeutics, public health, and beyond. Here, we summarize hot-off-the-press findings from human exome sequencing, showcasing the potential utility of this technology in the future of healthcare.
Yan Lyu, MD, Peking Union Medical College Hospital, Yulin Jiang, MD, Qingwei Qi, MD, Xiya Zhou, MD, Qi Guo, MD, Na Hao, BS, Juntao Liu, MD
With the increased utility of exome sequencing for prenatal diagnosis, Peking Union Medical College Hospital conducted a large, multi-center prospective clinical study. Lyu and colleagues investigated the diagnostic yield of exome sequencing (via trio analysis) for 306 fetal ultrasound anomalies which were undiagnosed with karyotyping or chromosomal microarray analysis (CMA).
They found that the diagnostic yield of exome sequencing was 39%, and was slightly higher in fetuses with recurrent anomalies (55%) than in those with multisystem anomalies (34%). Among fetuses with isolated anomalies, the diagnostic yield was highest for skeletal (49%) and lowest for cardiac (18%) anomalies. 44% of diagnosed fetuses had a de novo variant and 56% had an inherited variant, with causative copy number variations (CNVs) found in 3.3%. De novo variants were most frequent in fetuses with cerebral (86%), multisystem (71%), or skeletal (65%) anomalies. Causative variants in some genes were present in multiple fetuses – COL1A1 and FGFR3 for skeletal anomalies, TSC2 for cardiac anomalies, L1CAM for cerebral anomalies, and KMT2D for multisystem anomalies (Kabuki syndrome).
These findings demonstrate that exome sequencing can successfully identify the underlying genetic cause of ultrasound anomalies, even when karyotyping or CMA cannot. Furthermore, the details relating to specific anomaly types and causative genes will guide clinicians and parents to manage current pregnancies and inform future pregnancies, while also paving the way for more research in this important field.
Charlotte Sherlaw-Sturrock, West Midlands Genetics Services, Birmingham Women's and Children's Hospital, Birmingham, UK, Helen McDermott, MB ChB, MRCPCH, Julia Baptista, BSc (Hons), PhD, DipRCPath, Lorraine Hartles-Spencer, BSc, Swati Naik, MBBS, DCH, MRCPCH, CSER
National rapid exome sequencing was introduced to NHS England in October 2019 for acutely unwell children with a likely monogenic disorder, or for pregnancies in mothers with a previously affected fetus or child.
The West Midlands Regional Genetics Centre assessed the impact of this rapid exome sequencing service on children and their families. Over the 12-month study period, 95 probands had rapid exome sequencing, 89% with trio analysis. The median turnaround time for preliminary reports was 11 days, with a diagnostic yield of 40% (microarray assisted the diagnosis in 4 patients). The diagnostic rate was highest for patients with neuro-regression, skeletal dysplasia, and neuromuscular or neurometabolic conditions.
The study found that a rapid genetic diagnosis for critically unwell children can have a significant impact on acute and long-term management. A genetic diagnosis helped families to come to terms with their child’s medical condition, enabled referral to the most appropriate specialist, informed clinical management (such as initiation of targeted treatments or transplant), and in some cases helped to predict long-term prognosis while avoiding invasive investigations such as muscle biopsy and post-mortem examination. In addition, recurrence risk counselling was provided, and prenatal diagnosis was made possible for many families.
Overall, NHS England’s rapid exome sequencing service successfully revolutionized the clinical management of many critically unwell children, and will continue to do so.
Wei-Liang Chen, Seattle Children's Hospital and University of Washington, Andrew Timms, PhD, Emily Pao, MPH, Jessica Chong, PhD, Michael J. Bamshad, MD, Debbie Nickerson, PhD, Dan Doherty, MD, Edward Novotny, MD, Russell Saneto, MD, Richard Ellenbogen, MD, Jason Hauptman, MD, Jeff Ojemann, MD, William Dobyns, MD, Kimberly Aldinger, PhD, Ghayda M. Mirzaa, MD
Brain malformations are associated with high rates of morbidity and mortality and their genetic landscape is poorly understood. It is difficult to obtain a molecular genetic diagnosis for individuals with these developmental brain disorders, due to complex clinical and neuroimaging features and their rarity as individual disorders.
To better understand the genetic basis of brain malformations, Seattle Children’s Hospital and the University of Washington conducted a comprehensive analysis of exome sequencing and neuroimaging data. The group enrolled 566 individuals from 526 families for exome sequencing, 78% of which underwent trio analysis. The overall diagnostic yield was 36.7%, increasing to 49.4% when combined with families for whom a candidate gene was already identified. The diagnostic yield was highest (close to 50%) in individuals with megalencephaly and microcephaly, and lowest in those with developmental encephalopathies (25.6%). Pathogenic variants that likely contributed to the onset of certain developmental brain disorders were identified in the novel candidate genes MACF1, CEP85L, RELN, PIK3CA, AKT3, PIK3R2, PDHA1, GRIN2B, TUBB1, and AP1S2.
This detailed analysis of clinical, neuroimaging, and genetics data found that exome sequencing has a high diagnostic yield in individuals with brain malformations and further expands the known genetic and phenotypic spectrum of developmental brain disorders. Furthermore, the results highlight the combinatorial strength of genetic analysis coupled with detailed phenotyping by neuroimaging when diagnosing brain malformations.
Last week, more than 7000 people gathered from around the globe to digitally attend the Festival of Genomics & Biodata (FoG). The diverse sessions spanned the entire genomics workflow, with the ultimate mission of sharing knowledge to benefit patients. Here, we summarize three FoG talks on the future of genomics for rare and inherited disorders: we aim to show the big picture, walk you through a specific medical condition, and then provide an in-depth description of an individual case.
Over the last 30+ years, there has been an almost exponential increase in the number of rare and inherited diseases with a molecular diagnosis. Between 1989 and today, ∼7000 new gene-phenotype descriptions and 600 targeted therapies have been identified, with orphan drugs representing >50% of all U.S. drug approvals. Encouragingly, the life expectancies of people with these conditions are also steadily increasing, largely due to healthcare professionals collaborating on developing standards of care for similar conditions.
Rare and inherited diseases require a unique model of science and medicine due to a set of unique challenges. Due to their genetic nature, most are not limited to specific organs or systems and span an entire lifetime. In U.S. children’s hospitals, 34% of patients have inherited disorders which account for 81% of hospital bills, a clear financial impact on the health system. Rare disease research is based on small numbers of patients, and the care model is complex, involving multiple specialties with workforce challenges, so that patients and their families are often the experts on their condition.
Rare disease research is based on small numbers of patients, and the care model is complex, involving multiple specialties with workforce challenges, so that patients and their families are often the experts on their condition.
Collaboration, new care models, and technology are needed to navigate these unique challenges associated with rare and inherited diseases. New tactics to speed up and improve the patient pathway include digital triage, newborn screening, facial recognition software for identification of specific syndromes, more research to identify gene-phenotype relationships for molecular genetic testing, and increased involvement of primary care providers throughout the pathway. Telemedicine (fully trialled during the COVID-19 pandemic) also has a multitude of benefits, such as decreases in wait times, increased convenience, the ability for patients with autism to be seen in the comfort of their own home, and the ability for multiple specialists to easily collaborate remotely. In addition, certain barriers to care are removed, such as transportation (especially for geographically remote patients), childcare, missed work, and infection risk for vulnerable patients.
Continued innovation and collaboration provides optimism for a brighter future for patients with rare and inherited diseases.
A new preventive genomics cardiology clinic at Mass General empowered people to better understand, predict, and prevent heart attacks based on their genetic information.
Most people are aware of the clinical and lifestyle factors associated with heart attacks – for example, smoking, diet, exercise, and cholesterol levels. Genomic factors such as monogenic and polygenic drivers also play a critical role.
Monogenic risk of heart attack results from rare but high-risk single gene defects in the LDL “bad” cholesterol pathway. Whereas polygenic risk results from the cumulative effect of millions of relatively common, moderate-risk variants. Polygenic risk scoring identifies people who are at risk of having a heart attack but could have otherwise “flown under the radar” as their LDL cholesterol levels were normal. Indeed, out of every 100 people who have a heart attack at a young age, 2 have monogenic and 20 have polygenic genomic drivers.
Out of every 100 people who have a heart attack at a young age, 2 have monogenic and 20 have polygenic genomic drivers.
Integrating these genomic drivers with clinical and lifestyle risk factors is the most accurate way to identify people at high risk of having a heart attack. Indeed, a favorable lifestyle halves the risk of coronary events in people with a high monogenic or polygenic risk.
At the preventive genomics clinic at Mass General, 45 people took a new genetic test for heart attack risk. About half were referred by their cardiologist and half self-referred. 25% of all participants were found to have a high genomic risk for heart attack: 20% due to polygenic drivers and 5% due to combined monogenic and polygenic factors. Clinical action was taken for half of these high-risk participants – e.g., some were given statins for the first time, had a statin dose increase, or had coronary imaging.
These changes in clinical care based on a simple genetic test could ultimately prevent heart attacks in people who did not previously know that they were at risk.
Peter’s wife and son have undiagnosed, debilitating, rare and inherited conditions, and Peter is determined to do everything in his power to provide them with the care that they desperately need. In fact, this devoted husband and father spent 8 hours a day for the past 6 months pouring over sequencing data to try and find the cause of their suffering.
Now in their 70’s and 30’s, Peter’s wife and son have been chronically ill since puberty. Hormonal imbalance, urticaria, clinical depression, chronic pain, exercise intolerance, extreme fatigue, edema, and myotonia are just a few of their symptoms. All of which are exacerbated by the stress of being in constant pain and discomfort, and vary from one day to the next. Over the years, a complex combination of drugs (muscle relaxants, antihistamines, opioids, beta-blockers…) has been cobbled together to help ease some of their symptoms, but not completely or consistently.
The family’s diagnostic odyssey is confounded by the public health system, which even with the very best intentions, makes it extremely difficult for patients with intermittent symptoms that span numerous specialties to get the help that they need. Neurologists, psychiatrists, pain specialists, and pulmonologists have all contributed to the pair’s growing library of medical records, but long waiting times and a lack of the “full picture” severely limits the quality of care that they can provide.
In a recent attempt to end the diagnostic odyssey, the family had their whole genomes sequenced and analyzed, but to no avail. This is when Peter decided to take matters into his own hands. He sat down with the raw sequencing data and started to analyze it himself. With just a basic background in science and bioinformatics, he took it upon himself to examine their exome sequences line by line to try and identify pathogenic variants - using various tools and consulting various experts along the way. Truly an inspiration, Peter has started to identify variants that look to be involved in causing his family’s rare disease but has a long way to go. He hopes that the Festival of Genomics & Biodata will connect him with more researchers and experts that can help with his mission. Peter has hope in the power of genomics for people with rare and inherited diseases – he will not give up.
Peter has hope in the power of genomics for people with rare and inherited diseases – he will not give up.
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