High-quality reporting is a key essential for building a partnership of trust
CENTOGENE's philosophy is more than just producing technical data. The extensive interpretation of clinical data delivered with our comprehensive medical reports includes differential diagnostic approaches as well as a detailed interpretation of key findings.
Sequencing analysis has become a valuable approach for diagnostics of rare diseases. The increasing numbers of analyzed genes makes a clear, consistent and reproducible classification system mandatory.
What are the basics in our reporting?
- Clinical anamnesis evaluation
- Detailed method description
- Clear results of identified variants following international best-practice guidelines (CMGS / ACMG)
- Comprehensive medical interpretation with differential diagnostic approaches if applicable
- References to publications supporting the medical and scientific results
- Recommendations for follow-up analyses for specific diseases
Classify variants to improve the understanding of their pathogenicity
ACMG guidelines define five classes regarding a Mendelian variant: pathogenic, likely pathogenic, uncertain significance, likely benign and benign (class 1–5). For some cases, disease-associated variants are reported (class 6) if current medical literature supports an increased disease risk. Frequency of the variant, in silico predictions, conservation and published data with clinical information, segregation data or functional analyses among others, have all to be evaluated to classify the variants to the best of the available knowledge at the time of reporting. As knowledge on variant frequencies dramatically increases year by year, reevaluation of variants is an important step in improving our understanding of disease pathogenicity.
To strengthen this decisive topic CENTOGENE has created CentoMD®, a publicly available mutation database that includes detailed clinical information, frequency, geographic origin, etc. The depth of available information in CentoMD® allows in many cases a pathogenic/likely pathogenic or benign/ likely benign classification exclusively based in CentoMD® data.
Thorough uniform and comprehensive classification of variants based on a highly qualified and standardized curation workflow are hallmarks for the reporting at CENTOGENE. Such an approach guarantees you the best classification and basis for clinical interpretation of newly identified variants, and also ensures that changes in variant classification will be communicated by reclassification reports.
Reporting of identified variants
In the final step, all identified variants along with their annotations have to undergo a medical validation regarding their possible relevance to the provided clinical symptoms and/or suspected diagnosis of the patient.
For all NGS panels analyzed by Illumina, ION torrent or NGS454, all identified variants are classified according to our standardized system.
Classes 1–6 are assigned based on publicly available databases according to a standard protocol. Available databases for previously reported variants are checked (HGMD, LOVD, UMD, etc.). If the variant has not been reported to date, classification relies on data regarding the nature and frequency of the variant (ExAC browser, exome sequencing project, 1000 Genomes and dbSNP), in silico predictions (SIFT, Polyphen, MutationTaster–ALAMUT program suite) and finally all available information regarding the zygosity and segregation of the identified variant in the patient’s family.
Whole exome sequencing (WES) and whole genome sequencing (WGS)
By WES analysis the protein-coding region of the human genome (exome; ~1%) is analyzed. This also includes those genes without any known involvement in human disease. In these cases filtering of the identified variants is performed using the above-mentioned workflow including all available information in public databases such as Online Mendelian Inheritance in Man (OMIM) and HGMD®, gene specific databases, publications (PubMed) and genotype-phenotype databases such as CentoMD®.
Based on the standard guidelines and due to the diagnostic setting, only detected variants in genes with well-defined causation for human diseases are reported. From these, all relevant variants related to the phenotype of the patient are mentioned in the report. Pathogenicity of the variant(s) is discussed in light of the clinical information provided. Taking into account the clinical picture of the patient and family history of the disorder further diagnostic steps are recommended. Disease-associated polymorphisms with well-established clinical significance for the individual disease phenotype(s) are also reported.
WGS is the most comprehensive method for analyzing the genome. In addition, enrichment artifacts and coverage issues are not a problem. It allows the interrogation of single-nucleotide variants (SNVs), INDELs, structural variants (SVs) and copy number variants (CNVs) in both the ~1% part of the genome that encodes protein sequences and the ~99% of remaining non-coding sequences. Reporting procedure of the WGS findings is similar to WES.
Dual genetic diagnosis is possible with WES and WGS. In these cases, two pathogenic or likely pathogenic genetic variants are associated with either non-overlapping clinical presentations or contributing to one major phenotype. In some occasions, it is necessary to discuss the case (before reporting) with the ordering clinician.
Incidental or secondary findings
If requested by the clinician we also provide information on variants in genes not associated with the patient’s disease or symptoms but with medically actionable information available (incidental or secondary findings). We report variants in 59 selected genes according to the recommendations of the ACMG (6).
Contact your medical expert
For any questions or comments, do not hesitate to contact us anytime or get in touch with one of our experts.
- Aida Bertoli-Avella, PhD, Vice Director Routine Genetic Testing
- Nahid Nahavandi, PhD, Senior Vice Director Genetic Reporting
- Karen Wessel, PhD, Vice Director Genetic Reporting
- Oliver Brandau, PhD, MD, Director Syndromic and Predictive Genetics
Latest scientific articles
A study was conducted using whole exome sequencing (WES) to identify underlying pathogenic variants, or likely pathogenic variants, in 1,000 diagnostic cases from 54 different countries. Patients selected displayed a wide variety in the number, nature and severity of symptoms. Clinical information given by the requesting physicians was translated to HPO terms and WES was performed on patient samples according to standardized settings.
The work was performed by a group of laboratory geneticists and bioinformaticians, and discussed with clinical geneticists, industry and patients’ representatives, and other stakeholders in the field of human genetics. The statements that were written during the elaboration of the guidelines are presented here.
During the last few months we have observed for the first time since the introduction of the first massive parallel sequencers in 2007, that the cost of sequencing a human genome has not changed significantly.