About
Exome diagnostics is the genetic testing approach of choice 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 about 23,000 genes in the human genome. Although the exome makes up only about 1-2% of the whole genome, approximately 89% of all known disease-causing mutations are identified to be located within the exons.
Sequencing of the whole exome allows the simultaneous analysis of a very large number of genes in any combination. It substantially increases the chances of finding the genetic cause of complex phenotypes in shorter time compared to genetic tests of small gene subsets.
As CeGaT aims to solve all genetically-caused cases, we created an innovative diagnostic approach that goes even beyond the great possibilities of regular exome diagnostics: CeGaT Exome Xtra.
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All accomplishments of genetics in one single test
CeGaT has been utilizing the power of genetic diagnostics for more than a decade. More than 10 years ago, CeGaT introduced gene panels to clinical genetic diagnostics. Since then, our experts have constantly been updating disease-specific panels for more than 250 diseases based on the newest literature and in close cooperation with experts from many medical fields – improving clinical design, analysis, and reporting of our genetic tests. CeGaT Exome Xtra is the latest innovation in genetic diagnostics – the entire body of genetic science in one genetic test.
Better than exome, smarter than genome
CeGaT Exome Xtra achieves the maximum diagnostic yield to solve patient cases. It combines the advantages of whole-exome sequencing (WES) and whole-genome sequencing (WGS), while avoiding their disadvantages. CeGaT’s many years of experience as a pioneer of next-generation sequencing in diagnostics have been combined into CeGaT Exome Xtra to achieve:
Your most powerful diagnostic option
CeGaT Exome Xtra outperforms WGS and the most used WES approaches in every aspect.
Covered refers to average clinical usable coverage after alignment filtering (uniqueky mapping, removal of duplicate and overlapping read ends).
Extra smart clinical design
In contrast to standard WES, CeGaT Exome Xtra considers all known disease-causing regions including intronic disease relevant regions throughout the complete genome. It provides the ideal basis for genetic diagnostics and can be understood as a clinical genome providing the most comprehensive sequencing data. More information
Extra thorough analysis
CeGaT’s data analysis goes beyond regular exome diagnostics and increases solution rate. We account for variants in genes with reduced penetrance, variable expressivity, and even consider 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, like duo (2) or trio (3). More information
Extra insightful results
CeGaT combines human know-how with bioinformatic analysis. The in-house developed software generates data that are evaluated by a total of four 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. More information
Our diagnostic products – all constellations possible
Single Exome Diagnostics
The patient’s whole exome is sequenced. Based on a precise description of the patient’s phenotype, an individual list of candidate genes associated with the symptoms is created. CeGaT uses the Human Phenotype Ontology (HPO) and internal databases. Detected variants within these candidate genes get evaluated.
Duo Exome Diagnostics
Duo exome diagnostics allows the comparative genetic analysis of two family members. It can be applied to analyze an index patient and one parent only or to diagnose other constellations of affected/affected or affected/ unaffected family members (e.g. siblings).
Trio Exome Diagnostics
Classical trio exome diagnostics is applied to diagnose an affected patient with unaffected parents. Including both unaffected parents in the analysis highly increases the chances of diagnostic success. The exomes of the parents and the index patient are sequenced, which allows a comparative analysis with the highest solution rates. Trio Exome Diagnostics is particularly time and cost effective, because the number of variants to evaluate is minimized, and numerous and cost-intensive segregation analyses of single variants are avoided.
Clinical Trio Exome Diagnostics
The clinical trio exome comprises the same advantages as our trio exome diagnostics and thus includes full exome and mtDNA sequencing of both index patient and parents. The diagnostic evaluation, however, is focused on a predefined set of genes which have a clear disease association. This set is based on public and in-house databases and currently comprises approximately 6,500 genes. We regularly update this set of genes based upon the latest scientific findings.
Prenatal Exome Diagnostics
Fetal structural anomalies are found in up to 3% of all pregnancies following routine prenatal care ultrasound screening (Edwards and Hui, 2017, PMID: 29233624). Making a diagnosis is difficult due to the limited available phenotypic information, but is crucial to gain information about disease prognosis.
The analysis of the fetus and both parents (trio exome diagnostics) hereby allows the most efficient evaluation and increases the chance of identifying disease-causing variants. We have analyzed more than 500 prenatal cases and identified the disease-causing alteration in about 36% of cases (Gabriel et al., ESHG 2020, C01.6 Trio exome/ whole exome sequencing in prenatal diagnosis).
All prenatal analyses are automatically prioritized. Prenatal testing is limited to cases that fulfill certain criteria such as abnormal ultrasound findings or a known familial disease causing variant. Reported variants are limited to pathogenic and likely pathogenic variants associated with the clinical phenotype of the index, according to current scientific understanding.
We advise to contact us directly prior to analysis in order to perform the most suitable approach for genetic testing.
If performing trio exome diagnostics isn’t possible, please include a sample of the biological mother. This is needed in order to exclude maternal cell contamination (MCC). Alternatively, we require a statement that the MCC test has already been performed and the sample isn’t contaminated.
ACMG Genes
This additional screening of ACMG genes allows the detection of relevant pathogenic variants outside the phenotype in a certain set of genes with a therapeutic relevance. This option is completely free of charge for the index patient. If this option is chosen, we issue a separate report for each person stating our findings within the ACMG genes.
Extra Smart Clinical Design
CeGaT Exome Xtra is designed to generate the most comprehensive sequencing data – an unmatched basis for the best genetic diagnostics available. It goes beyond standard whole exome sequencing as it comprises all known disease- causing regions throughout the complete genome.
All targets covered
CeGaT Exome Xtra is sum of the many years of experience of CeGaT and our collaborators, combined with scientific knowledge – on top of regular exome enrichment. All relevant gene regions are included: While commercial off-the-shelf exome enrichments are limited to the coding regions, CeGaT Exome Xtra also comprises all disease- causing non-coding variants and covers individual transcripts, cryptic exons, and intronic variants.
Most complete coverage
Only sufficient coverage on all designed targets ensures that no relevant variant is missed. We use state-of-the-art in-solution hybridization technology. Continuously improving our wet-lab process, we have achieved very uniform and complete coverage on all diagnostic targets. To improve sensitivity and allow us to detect mosaicism, we sequence CeGaT Exome Xtra to an average diagnostic coverage of >100x.
All knowledge incorporated
In addition to our team‘s and collaborators‘ knowledge, we use data from the Human Gene Mutation Database (HGMD) and ClinVar. HGMD is a curated database covering all published genetic variants that are known or suspected to cause disease. ClinVar is the largest public database of genotype-phenotype relationships built by medical experts around the globe.
With approximately 20,000 intronic and intergenic variants, CeGaT Exome Xtra contains all genomic regions described as disease-related in HGMD and ClinVar.
Besides coding sequences, flanking intronic sequences as well as all known non-coding and intergenic variants, CeGaT Exome Xtra also includes the complete mitochondrial genome – it is the most complete exome available.
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.
CeGaT Exome Xtra covers more relevant regions at higher coverage and delivers higher sensitivity than 30x WGS. This boosts solution rates and even allows us to detect mosaicism, which is systematically missed in most WGS analyses.
At the same time, thousands of irrelevant variant calls usually obtained by WGS analyses are avoided, improving diagnostic speed and accuracy.
Always state-of-the-art
The rapid advancement of science is constantly increasing our knowledge about genetic diseases and the potential of genetic analyses. New genomic regions with clinical relevance are identified each year. CeGaT Exome Xtra is continuously updated according to the latest scientific findings to always cover all relevant regions.
Whole-genome sequencing is already a great tool for research. Until it is ready for diagnostic use, CeGaT Exome Xtra provides the clinical genome diagnostics to help patients today.
CeGaT Exome Xtra Enrichment:
- Expert-curated design covering all known genes
- All relevant intronic and intergenic targets included
- Complete mitochondrial genome
- Highly uniform diagnostic coverage, greater than 100x on average
- Frequent updates
- Most cost efficient
Extra thorough analysis
Our unique analysis strategy allows us to reliably perform single exome diagnostics as well as comparative exome diagnostics for several family constellations – scenarios that are often ignored in regular trio exome diagnostics. For the highest solution rates, we additionally account for variants in genes with reduced penetrance, variable expressivity, and imprinting effects.
All cases possible
Comparative family exome diagnostics involves the sequencing of not only the affected patient but also other relatives. The most commonly performed analysis is the trio exome: Including both unaffected parents of the index patient highly increases the chances of diagnostic success to be approximately twice as high compared to single exome diagnostics (Farwell et al., 2015).
In family constellations where it is not possible to have a sample of both genetic parents, or one parent might be affected as well, the adaptive CeGaT Exome Xtra bioinformatic pipeline allows us to analyze all kinds of family combinations, like duos.
This goes beyond commonly performed analyses of private and shared variants between two persons. Our additional analyses are the best approach for solving cases with only one parent (affected or unaffected) or any other index-relative constellations. A detailed phenotypic description of all affected individuals is the basis for a precise and successful data interpretation.
In the evaluation process, our experienced team investigates all variants according to the latest scientific knowledge. For variants in genes that are not yet clearly associated
with the suspected phenotype of the patient, we predict the potential contribution by extensive additional literature research. If we find supporting evidence that a yet undescribed variant contributes to the patient’s phenotype, this variant will be described in our medical report.
Comparing the data of the affected patient with that of the unaffected parents allows us to identify the following SNV/CNV combinations
- De novo – new in index, not present in parents
- Homozygous – homozygous in index, heterozygous in both parents
- Compound heterozygous – two or more variants in same gene in index on different alleles, each parent is heterozygous carrier of one variant
- X-linked – male patient is hemizygous, mother is heterozygous
- Loss of heterozygosity – index is homozygous, one parent heterozygous, other parent wildtype
- Parental mosaicism – index is heterozygous, one parent has a genetic mosaicism
Our unique analysis strategy considers often overlooked issues, such as mildly affected parents.
Standard trio exome diagnostics rely on the assumption that both parents are not affected. This filtering ignores that some parents are for example only mildly affected and would result in negative findings. We compensate for these situations with a unique analysis strategy that allows us to solve cases where the phenotype is caused by variants with
- reduced penetrance
- variable expressivity
- imprinting effects
Further, we always evaluate variants in the mitochondrial genome.
CeGaT‘s Premium Service
CNV analysis, VUS re-evaluation, and personal consultation included. We at CeGaT aim 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 certain phenotype, but also copy number variants. Genetic testing without a screening for deletions and duplications hence is incomplete and may result in incorrect medical reports.
Our CNV analysis in combination with our customized enrichment increases the diagnostic yield substantially.
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. Additionally, we validate our analysis using MLPA or qPCR, once we find deletions or duplications that are associated with the patient’s phenotype. The deletion/duplication analysis contributes to CeGaT’s high-quality medical reports to provide you with all major analysis options available.
CeGaT’s analysis strategy enables us to call CNV/SNV combinations in order to provide even more detailed and important information.
Further, we always determine and describe the quality of the CNV analysis within our medical report. We recommend to ship fresh EDTA blood for highest sensitivity of CVN calling.
CNV analysis principle
We use reference samples to create a model of the expected coverage that represents wet-lab biases as well as inter-sample variation (blue). CNV calling is performed by computing the sample’s normalized coverage profile (red) and its deviation against the expected coverage. Genomic regions are called as a copy number variant 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 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 (“probably pathogenic” / “pathogenic”) or benign (“probably 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 clinical picture of the patient and a revised medical report is issued, without extra fees.
The re-evaluation is very relevant for the care and treatment of patients and family members.
Personal medical consultation
CeGaT offers medical counseling along the entire process. We assist in choosing the diagnostic strategy, discuss the results, and provide follow-up suggestions.
Fast results
Our turnaround time is approximately 4-6 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 and deliver the medical report in 2-3 weeks. This service is free of charge.
Trusted in-house analysis
All steps of the diagnostic process, from sample receipt to delivery of the medical report, are performed by us in-house. This includes the bioinformatic processing of the sequencing data on servers located in our facility. No data and no samples ever leave CeGaT, guaranteeing data quality and security.
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 ques.tions related to your patient. This may include recommen.dations of the most suitable genetic testing or help with the interpretation and consequences of our medical report. Please contact us at sales@cegat.de anytime.
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 sales@cegat.de.
How long does the test take?
Our turnaround time is approximately 4-6 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 and deliver the medical report within 2-3 weeks. 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 reques.ted 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 if both unaffected parents are included in the analysis. Nevertheless, we also established a reliable exome pipeline, far cases where one parent is unavailable or similarly affected as the index. The inclusion of further family members is also possible. If you are unsure which approach is the most suitable for your patient, please contact us at sales@cegat.de.
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. Thus, it is mandatory that the patient’s physician orders a genetic test at CeGaT. After data evaluation, the medical report will be sent to the treating physician, as we need like to ensure that the patient receives proper genetic counseling.
Is whole genome sequencing a more comprehensive approach for patients with a complex phenotype?
CeGaT Exome Xtra outperforms WGS in current diagnostic use in several features. The lower coverage of WGS does not permit reliable diagnostics. CeGaT Exome Xtra also includes all known pathogenic and likely pathogenic non-coding regions. Please find detailed technical information at cegat.com/betterthanWGS.
Can CeGaT Exome Xtra 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 will be 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 are unsolved by classical trio analysis.
What if a case cannot be solved?
CeGaT Exome Xtra 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.
