FINDING THE GENETIC CAUSE OF RARE DISEASES
Exome diagnostics is the optimal genetic test for patients with complex, heterogeneous, and unspecific symptoms. It supports physicians in stating a diagnosis, often after their patients have experienced years of uncertainty.
The exome comprises all protein-coding regions (exons) of the approximately 23,000 genes in the human genome. Although the exome accounts for only about 1-2% of the whole genome, about 89% of all known disease-causing variants are located within the exons. Whole exome sequencing allows the simultaneous analysis of genes in any combination. If the exomes of additional family members are also sequenced, as in trio exome diagnostics, an exome-wide segregation analysis can be performed. This approach significantly increases the chances of finding the genetic cause of complex phenotypes in a shorter time compared to genetic testing of small gene sets.
We are committed to identifying the genetic cause of disease for every patient. Therefore, we have developed an innovative diagnostic approach that goes beyond the possibilities of regular exome diagnostics: ExomeFocus® and ExomeXtra® (Single & Trio) offer an efficient solution for every patient scenario and family constellation.
Our Diagnostic Services – All Constellations Possible
ExomeFocus®
Focused and cost-efficient singleton analysis with fast results in only 2 – 3 weeks
Single ExomeXtra®
Whole exome diagnostics of all clinically relevant genes
Trio ExomeXtra®
The most effective genetic test for patients with complex, heterogeneous, and unspecific symptoms
Prenatal ExomeXtra®
Comprehensive family testing with optimal solution rates
ALL ACHIEVEMENTS OF GENETIC TESTING INTEGRATED INTO OUR EXOME DIAGNOSTICS
More than 10 years ago, CeGaT introduced gene panels into clinical genetic diagnostics. Since then, our experts have continuously updated disease-specific panels for more than 250 diseases based on the latest literature and in close cooperation with experts from many medical fields – improving clinical design, analysis, and reporting of our genetic tests. ExomeXtra® and ExomeFocus® are the latest innovations in genetic diagnostics. Designed to generate the most comprehensive sequencing data, they provide an unmatched basis for the best genetic diagnostics available with outstanding features:
Extra smart clinical design
CeGaT’s exome enrichment is the sum of the many years of experience of CeGaT and our collaborators, combined with clinical knowledge. In contrast to standard whole exome sequencing (WES), CeGaT’s proprietary exome design covers not only the coding regions but all known disease-causing regions throughout the genome. With more than 28,500 intronic and intergenic variants, it contains all genomic regions described as disease-related in the Human Gene Mutation Database (HGMD) and ClinVar, the largest public database of genotype-phenotype relationships. Our exome enrichment also includes individual transcripts, flanking intronic sequences, cryptic exons, and the entire mitochondrial genome. It provides the ideal basis for genetic diagnostics.
Most complete coverage
Only sufficient coverage of all designed targets ensures that no relevant variant is missed. We use state-of-the-art in-solution hybridization technology. By continuously improving our wet lab process, we have achieved very uniform and complete coverage of all diagnostic targets. To increase sensitivity and to allow us to detect mosaicism, we sequence ExomeXtra® and ExomeFocus® with an average diagnostic coverage of >100x.
Smarter than genome
Whole genome sequencing (WGS) is sometimes described as the most comprehensive genetic analysis possible. However, coverage is often too low for reliable variant detection. ExomeXtra® and ExomeFocus® cover more relevant regions with higher coverage and deliver higher sensitivity than 30x WGS. This increases solution rates and even allows us to detect mosaicism, which is systematically missed in most WGS analyses. At the same time, it avoids thousands of irrelevant variant calls that usually occur in WGS analyses, improving diagnostic speed and accuracy.
Rapid advancement in science is constantly increasing our knowledge about genetic diseases and the potential of genetic analyses. New genomic regions with clinical relevance are identified every year. ExomeXtra® and ExomeFocus® are continuously updated according to the latest clinical findings to always cover all relevant regions. Whole genome sequencing is already a great tool for research. Until it is ready for diagnostic use, ExomeXtra® and ExomeFocus® provide clinical genome diagnostics to help patients today.
Your most powerful diagnostic option
| WGS | CeGaT Exome | |
|---|---|---|
| Average diagnostic coverage | ~30x | ~110x |
| Total GB sequenced | 95 | 15 |
| Coding sequences covered >20x | 87.7% | 97.8% |
| Disease-causing non-coding mutations covered >20x | 89.8% | 99.4% |
| Coding sequences covered >30x | 27.1% | 97.5% |
| Disease-causing non-coding mutations covered >30x | 27.2% | 99.0% |
Covered refers to average clinical usable coverage after alignment filtering (uniquely mapping, removal of duplicate and overlapping read ends).
Extra thorough analysis
CeGaT’s data analysis goes beyond normal exome diagnostics and increases solution rates. We account for variants in genes with reduced penetrance, variable expressivity and even account for imprinting effects. We also assess copy number variants, also including compound heterozygous combinations of sequence variants (SNV, INDELs) with CNVs. All family constellations can be analyzed as we can include various numbers of family members in the analysis, such as duo (2) or trio (3).
Extra insightful results
CeGaT combines human know-how with bioinformatic analysis. The in-house developed software generates data that are evaluated by multiple scientific experts – creating the best possible medical report. CeGaT’s interdisciplinary team of PhDs uses the most recent literature for data interpretation; complex constellations are discussed with bioinformaticians, and the final report is revised by medical doctors and geneticists to maximize medical usability.
Detailed side-by-side comparison of our diagnostic services:
ExomeFocus®
Proprietary exome enrichment
✓
In-house data analysis and variant calling
✓
2-3 weeks turnaround time
✓
ACMG Classes:
3/4/5
VUS re-evaluation
✗
Manual curation of variants
✗
IVERP Variants
✗
Discussion
✗
Costs
€
Solving Rate
☆☆☆
Single ExomeXtra®
Proprietary exome enrichment
✓
In-house data analysis and variant calling
✓
2-3 weeks turnaround time
✓
ACMG Classes:
3/4/5
VUS re-evaluation
✓
Manual curation of variants
✓
IVERP Variants
✗
Discussion
✓
Costs
€€
Solving Rate
☆☆☆☆
Duo/Trio ExomeXtra®
Proprietary exome enrichment
✓
In-house data analysis and variant calling
✓
2-3 weeks turnaround time
✓
ACMG Classes:
3/4/5
VUS re-evaluation
✓
Manual curation of variants
✓
IVERP Variants
✓
Discussion
✓
Costs
€€€
Solving Rate
☆☆☆☆☆
Prenatal ExomeXtra®
Proprietary exome enrichment
✓
In-house data analysis and variant calling
✓
2-3 weeks turnaround time
✓
ACMG Classes:
4/5
VUS re-evaluation
✗
Manual curation of variants
✓
IVERP Variants
✓
Discussion
✓
Costs
€€€
Solving Rate
☆☆☆☆☆
Add-On Modules
ACMG genes
This additional screening of the ACMG genes (SF v3.1; Miller et al., 2022, PMID: 35802134) allows the detection of relevant pathogenic variants outside the phenotype in a defined group of genes with therapeutic relevance. In all ExomeXtra®-services, this option is free of charge for the index patient. For ExomeFocus®, it is available at an additional charge. If selected, we issue a separate report for each person indicating our findings within the ACMG genes.
Upgrade ExomeFocus® or Single ExomeXtra® to Trio ExomeXtra®
Trio ExomeXtra® is the test that offers the highest chances of identifying the genetic cause of disease. In cases where the treating physician starts with a singleton exome and later wants to expand to Trio ExomeXtra®, this is offered at a reduced price.
Pharmacogenetics
Pharmacogenetic analysis detects genetic changes that influence the efficacy of drugs. If genetic variants affect proteins responsible for the metabolization of substances, their tolerability and efficacy can be severely altered. These drugs include antidepressants, painkillers, neuroleptics, chemotherapeutics, AIDS drugs, thrombosis drugs, anesthetics, beta-blockers, or statins.
A specific enzyme’s reduced activity can lead to increased drug levels at the standard dosage, which is not infrequently accompanied by undesirable side effects. In the case of pharmaceuticals that are only activated by metabolization, the therapeutic effect may be absent altogether. Similarly, increased enzyme activity, due to the resulting increased drug degradation rate, leads to insufficient efficacy of the therapy.
The pharmacogenetics option analyzes known variants in 22 genes involved in drug metabolism. If certain gene variants are detected, the treating physician can adjust the therapy individually. With the help of pharmacogenetic analysis, serious side effects can be minimized, and treatment failure avoided.
HLA typing
HLA typing can determine tissue compatibility for allogenous transplants, individual drug response (PGX), and differential diagnosis. HLA typing can also be used to judge susceptibility to disease (e.g., HLA-B27: inflammatory and autoimmune disorders). You will receive an additional report stating the HLA alleles.
CeGaT‘s Premium Service
CNV analysis, VUS re-evaluation, and personal consultation included. CeGaT aims for the most complete diagnostics and thus always apply the most comprehensive approach.
Copy number variations (CNVs)
All our exome analyses automatically include a deletion/ duplication screening using the copy number variation (CNV) analysis – without extra fees.
Not only single nucleotide variants (SNVs) and small insertions and deletions (INDELs) can be causative for a particular phenotype, but also copy number variants. Genetic testing without screening for deletions and duplications is, therefore, incomplete and may result in incorrect medical reports. All our exome analyses automatically include a deletion/ duplication screening using the copy number variation (CNV) analysis – without extra fees.
Our CNV analysis in combination with our customized enrichment greatly increases the diagnostic yield.
Our CNV evaluation allows us to detect single exon deletions with a sensitivity of >81%, larger deletions of three or more exons will be detected with >96% sensitivity. In addition, we validate our analysis using MLPA or qPCR whenever we find deletions or duplications associated with the patient’s phenotype. The deletion/duplication analysis contributes to CeGaT’s high-quality medical reports to provide you with all available analysis options.
CeGaT’s analysis strategy enables us to call CNV/SNV combinations to provide even more detailed and important information.
Furthermore, we always determine and describe the quality of the CNV analysis within our medical report. We recommend sending fresh EDTA blood to achieve the highest sensitivity of CNV calling.
CNV analysis principle
We use reference samples to build a model of the expected coverage that represents wet-lab biases as well as inter-sample variation (red). CNV calling is performed by computing the sample’s normalized coverage profile (blue) and its deviation from the expected coverage. Genomic regions are called copy number variants if they deviate significantly from the expected coverage.
VUS re-evaluation
CeGaT’s VUS re-evaluation reassesses previously reported variants of uncertain clinical significance (VUS) as soon as new scientific evidence on the pathogenicity of the variant is available. This leads to an even higher number of diagnoses being made by CeGaT.
Genetic research is making great progress and is constantly improving our knowledge of disease-causing variants. Therefore, it is likely that over time a VUS will be better understood and classified as pathogenic (“likely pathogenic” / “pathogenic”) or benign (“likely benign” / “benign”).
In the event of such a VUS re-evaluation, CeGaT proactively informs the treating physicians. In addition, the re-evaluated variant is interpreted by our specialists with reference to the patient’s clinical picture and a revised medical report will be prepared, without extra fees (ExomeXtra®).
The re-evaluation is critical for the care and treatment of patients and family members.
Sample case
Patient: boy, 11 months
Clinical symptoms: benign infantile epilepsy with tonic-clonic seizures
Primary report (November 2019): SCN8A c.802A>T (het.) VUS
VUS re-evaluation:
- triggered by HGMD update in Januay 2021
- based on publication Medlin et al., 2020
➔ Variant can now be classified as likely pathogenic. New report has been issued.
Knowledge
Flyer
All important information about our Exome Diagnostics Services at a glance
Brochure
Finding the genetic cause of complex, heterogeneous, and unspecific symptoms.
CeGaT’s exome is designed to generate the most comprehensive sequencing data. It provides the unsurpassed basis for the best genetic diagnostics and goes beyond regular exome diagnostics. For a detailed understanding, please download our brochure.
Tech note
The best possible exome
ExomeXtra® covers all known disease-causing regions of the entire genome and thus provides the best data basis for analyzing our diagnostic panels. For a detailed comparison, please read our tech note.
Case report
Saving a little girl‘s life.
An exact diagnosis is the basis for an optimal treatment. This is a case from our daily work where exome diagnostics saved a little girl’s life.
Saskia Biskup about ExomeXtra®
All accomplishments of genetics in one test
Saskia Biskup, Ph.D., Ph.D., co-founder and managing director of CeGaT, explains why ExomeXtra® is the best method to find the genetic cause of the disease.
Webinar
Better than exome, smarter than genome
In this webinar recording, we explain how exome diagnostics help you solve patient cases and determine the best therapeutic option. Learn more about ExomeXtra® and ExomeFocus®, the latest innovations in genetic diagnostics, and see cases from clinical practice.
Trio exome diagnostics
One of the most powerful tools in genetic diagnostics
Stefan Griesbach, Ph.D., talks about the benefits of trio exome diagnostics and how it is applied.
Prenatal exome diagnostics
Identify the disease-causing alteration in a fetus
Heinz Gabriel, Ph.D., recommends trio exome analysis to detect disease-causing alterations in a fetus.
ExomeXtra®
Designing the best possible exome
Our Director of Development Florian Battke, Ph.D., explains in detail what we focused on during the design of ExomeXtra®.
A case from our daily work
Exome diagnostics saved a little girl’s life
Alexander Pepler, Ph.D., tells the story of how CeGaT’s exome diagnostics saved a little girl’s life.
Frequently Asked Questions
Can I talk with an expert from CeGaT before or after the report in case I have questions?
Yes, of course. We are happy to support you with any questionsyou may have regarding your patient. This may include recommendations for the most appropriate genetic tests or help with the interpretation and implications of our medical report. Please contact us anytime at diagnostic-support@cegat.com.
Which tissues can you process?
Our recommendation is to provide 1-2 ml EDTA blood.We are also able to handle a variety of tissues like saliva, buccal swabs, or isolated DNA. We are happy to assist you with alternative materials. Please contact us at diagnostic-support@cegat.com.
How long does the test take?
Our turnaround time is approximately 2-3 weeks after sample receipt at the headquarters in Tübingen, Germany. For prenatal cases or other medical urgencies (e.g. ICU), we always prioritize the complete process. This service is free of charge.
How can I send the sample to you?
CeGaT provides sample collection boxes upon request. These boxes can be used for transport and can be requested free of charge by mail or phone. Most samples can be shipped at room temperature from all over the world.
One of the parents is not available for trio exome diagnostics. Can I send another family member instead?
Classical trio exome diagnostics provides the most promising results when both unaffected parents are included in the analysis. Nevertheless, we have also established a reliable exome pipeline, far cases where one parent is unavailable or similarly affected as the index. Inclusion of further family members is also possible. If you are unsure which approach is most suitable for your patient, please contact us at diagnostic-support@cegat.com.
Who can order the test and receive the medical report?
In accordance with the German Genetic Diagnostic Act, a patient needs to obtain genetic counseling before and after genetic testing. Therefore, it is mandatory that the patient’s physician orders a genetic test at CeGaT. After data evaluation, the medical report is sent to the treating physician, as we must ensure that the patient receives appropriate genetic counseling.
Is whole genome sequencing a more comprehensive approach for patients with a complex phenotype?
ExomeXtra® outperforms WGS in several features in current diagnostics. The lower coverage of WGS does not permit reliable diagnosis. ExomeXtra® also includes all known pathogenic and likely pathogenic non-coding regions. Please find detailed technical information at cegat.com/betterthanWGS.
Can ExomeXtra® detect deletions/duplications?
Yes, our CNV analysis allows us to identify single exon deletions with a sensitivity of >81%, larger deletions of three or more exons are detected with >96% sensitivity. We always automatically include CNV analysis in all our NGS analyses, also comprising SNV/CNV combinations. This service is free of charge.
Is the analysis of mitochondrial DNA included?
We always include mitochondrial DNA as part of our exome enrichment. Thus, all mitochondrial genes are sequenced. The analysis of mitochondrial genes is based on the clinical description of the patient. For prenatal cases, the analysis of mtDNA is always included to determine potential metabolic disorders.
Are you able to detect intronic variants?
Yes. Our data and analysis cover all clinically relevant, known pathogenic and likely pathogenic variants, such as non-coding variants in the flanking regions, deep intronic, and intergenic variants.
Can a trio be solved even if no variant fits the inheritance pattern?
Yes, by considering reduced penetrance, variable expressivity, and imprinting effects, we are able to solve cases that cannot be solved by classical trio analysis.
What if a case cannot be solved?
ExomeXtra® provides the most comprehensive genetic diagnostics. If a case could not be solved, CeGaT offers to further assist in a scientific context, for example, by calling structural variants based on whole genome sequencing.
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