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Speaker: Dr. rer. nat. Tobias Bethge, Genetica AG, Zurich, Switzerland
About this webinar
Variants of uncertain significance (VUS) remain one of the most persistent bottlenecks in hereditary cancer testing - particularly those located near splice sites, in non-coding regions, or affecting copy number. In this talk, Tobias Bethge shares how Genetica AG, a genetic counseling and diagnostics laboratory in Zurich, has incorporated targeted RNA sequencing alongside DNA-based testing to functionally resolve such variants.
Tobias opens with the practical groundwork: how RNA-seq can functionally interrogate variants predicted to affect splicing, how it can indirectly flag deep intronic, regulatory, and structural events that DNA sequencing alone may miss, and the real constraints labs face - from limited gene expression in accessible tissues, to the sampling and library preparation decisions that shape data quality. He then introduces a targeted capture-panel approach developed in collaboration with SOPHiA GENETICS, built around an 18-gene RNA panel spanning the lab's broader 83-gene hereditary cancer panel, designed to enrich relevant transcripts while reducing background and sequencing cost.
The talk is grounded in four real test cases from Genetica's cohort. A BRCA2 missense variant at the edge of an exon boundary is shown to cause exon skipping in roughly half of transcripts - supporting a pathogenic classification. Two non-coding BRCA1 variants near exon 1 illustrate how seemingly similar splice-site predictions can resolve very differently: one shown to be a benign splicing polymorphism also present in controls, the other showing partial allelic loss consistent with a likely pathogenic, possibly hypomorphic effect - a distinction made possible by tracking heterozygous SNPs across DNA and RNA. A final case demonstrates how RNA-seq can confirm that a PALB2 exon 11 duplication detected by CNV analysis and MLPA sits in tandem and disrupts the reading frame, supporting a pathogenic call.
You will learn:
SOPHiA DDM™ applications and Alamut™ Visual Plus are For Research Use Only unless otherwise specified. The RNA-seq capture panel solution discussed is part of an ongoing research collaboration and is not yet commercially available. The opinions expressed are those of the speaker and may not represent the opinions of SOPHiA GENETICS.
Speaker: Gorka Alkorta-Aranburu, PhD, CIMA LAB Diagnostics, Clínica Universidad de Navarra, Pamplona, Spain
About this webinar
Targeted gene panels remain efficient and affordable, but they carry known blind spots: deep intronic variants, complex structural rearrangements, and non-coding regulatory elements that fall outside their design. In this talk, Gorka Alkorta-Aranburu shares CIMA LAB Diagnostics' early experience moving from targeted panel testing toward whole genome sequencing (WGS), as part of an Early Access Program (EAP) with SOPHiA GENETICS, and the operational and analytical questions that came with it.
Gorka walks through the practical barriers labs face when considering WGS - data volume, compute demands, multi-variant-type detection, and the challenge of finding clinically relevant variants among millions of calls - and how a structured, four-phase EAP (platform familiarization, data quality assessment, singleton validation, and family trio analysis) helped his team evaluate whether SOPHiA DDM™ for WGS could meet the standards required for routine use.
The talk is grounded in real validation data and test cases from CIMA LAB's cohort. Raw data quality assessment across blood and saliva-derived samples revealed how DNA source materially affects coverage, including the impact of microbial DNA content in saliva samples on overall human coverage. Known variant call concordance testing showed high accuracy across SNVs, indels, and structural variants. Three singleton cases then illustrate where WGS closed gaps left by panel and exome testing: a compound heterozygous GJB2/GJB6 hearing loss case combining a point mutation with a regulatory deletion missed by exome sequencing; a pathogenic mitochondrial variant resolved with precision despite the risk of NUMT-related false positives; and a single-exon BRCA1 deletion resolved at nucleotide-level resolution where an exome panel could not separate signal from noise. Finally, Gorka presents early results from applying SOPHiA DDM™ familial variant analysis to 11 previously untested WGS trios, with high parental concordance rates supporting its use in variant prioritization.
You will learn:
SOPHiA DDM™ applications are For Research Use Only unless otherwise specified. The opinions expressed are those of the speaker and may not represent the opinions of SOPHiA GENETICS.
Speaker: Minna Paavola, Ph.D., Clinical Laboratory Geneticist, Turku University Hospital, Turku, Finland
About this webinar
Whole exome sequencing (WES) presents distinct challenges depending on where in the clinical spectrum it's applied - from fetal phenotypes with limited available data, to longstanding unresolved cases in adults. In this talk presented at ESHG 2026, Minna Paavola shares how the germline rare disease team at Turku University Hospital has built a scalable, consistent WES workflow that spans both ends of that spectrum.
Minna will walk through the lab's end-to-end process - from library preparation using the SOPHiA DDM™ Whole Exome Solution through analysis and variant classification in SOPHiA DDM™, with Alamut™ Visual Plus supporting interpretation - and explain the team's approach to filtering, prioritization, and variant flagging across referral types. The talk also draws on two research cases from the lab's practice: a prenatal trio in which compound heterozygous variants in the GLE1 gene - one a Finnish founder variant for Herva disease - were identified in a fetus presenting with severe fetal akinesia; and an adult solo case resolved after decades, in which biallelic MRE11 variants explained a complex neurological phenotype initially complicated by childhood cerebral palsy. Both cases illustrate how careful attention to population-specific allele frequencies, inheritance patterns, and HPO-guided filtering can surface clinically significant findings that initial automated classification may underweight.
Minna will also discuss the Finnish Disease Heritage - a group of approximately 40 rare monogenic disorders at elevated frequency in Finland due to historical population bottlenecks - and how awareness of founder variants shapes the team's analytical approach.
You will learn:
SOPHiA DDM™ Exome applications and Alamut™ Visual Plus are For Research Use Only. The opinions expressed are those of the speaker and may not represent the opinions of SOPHiA GENETICS.
SOPHiA GENETICS products are for Research Use Only and not for use in diagnostic procedures unless specified otherwise.
SOPHiA DDM™ Dx Hereditary Cancer Solution, SOPHiA DDM™ Dx RNAtarget Oncology Solution and SOPHiA DDM™ Dx Homologous Recombination Deficiency Solution are available as CE-IVD products for In Vitro Diagnostic Use in the European Economic Area (EEA), the United Kingdom and Switzerland. SOPHiA DDM™ Dx Myeloid Solution and SOPHiA DDM™ Dx Solid Tumor Solution are available as CE-IVD products for In Vitro Diagnostic Use in the EEA, the United Kingdom, Switzerland, and Israel. Information about products that may or may not be available in different countries and if applicable, may or may not have received approval or market clearance by a governmental regulatory body for different indications for use. Please contact us at [email protected] to obtain the appropriate product information for your country of residence.
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