TRIO EXOME
Analysis of family pedigrees:
Patient-Father-Grandfather
Patient-Mother-Father
TRIO EXOME ANALYSIS
A powerful approach to identifying causal mutations for inherited diseases or medical conditions
Trio Exome Analysis
Trio exome analysis of family pedigrees (patient-father-mother) based on Next Generation Sequencing (NGS) offers a powerful approach to identify causal mutations for inherited diseases or medical conditions. This analysis can be used to identify variants inherited from the parents causing recessive disease or dominant disease. Furthermore, de novo variants that occur in the patient but are not present in either of the parents can also be detected. Highlights This test serves as a valuable foundation for high-quality genetic counseling by providing important insights into the prognosis and risk of recurrence. It also offers potential cost benefits [1].
- For patients and families, receiving a genetic diagnosis can create opportunities to connect with others who share the same condition, which is often a significant source of support and understanding.
- In certain cases, identifying a specific genetic cause can lead to targeted treatment options—also known as precision medicine—that address the underlying disease mechanism directly [2–6].
FOR PATIENTS:
In a trio exome test, the genes of the patient and their parents (or close family members) are analyzed together. This approach is especially helpful because it looks at all the genes that could be linked to disease, while also making it easier to find the most relevant changes. This means fewer extra tests are needed, which helps reduce time and cost. It also allows medical professionals to check how certain genetic changes are passed down in the family—all in a single test.
Benefit of Trio Exome Analysis
Trio exome sequencing allows simultaneous analysis of all protein-coding regions (exons) in the exome corresponding to approximately 23,000 genes and significantly increases the chances of finding the genetic cause of rare genetic diseases (such as epilepsy and intellectual disability syndromes) in a shorter time compared to genetic testing of small gene panels.
Although the exome accounts for only about 2% of the whole genome, it is estimated that about 85% of all known disease-causing variants are located within the exome.
In family constellations where it is not possible to obtain a sample from both genetic parents or a sister or brother,we can perform a duo exome analysis. A detailed phenotypic description of all affected individuals makes basis for a precise and successful data interpretation. Upgrade to Trio exome
Trio exome is the test that offers the highest chances of identifying the genetic cause of disease. In cases where the treating physician starts with panel test (such as the EPIDASD panel test) and later wants to expand to trio exome, this is offered at a reduced price.
FOR SPECIALISTS: Comparison of the affected patient’s data with those of the parents or any other first grade family members allows us to identify the following SNV/CNV combinations:
- De novo — new in the patient and not present in parents
- Compound heterozygous — two variants (on different alleles) in the same gene in the patient and theparentsareheterozygous carriersof each their variant
- X-linked — In case of a male,the patient is hemizygous, and the mother maybe unaffected or mildly affectedheterozygous carrier
- Homozygous — the patient is homozygous and both parents are heterozygous carriers
- Rare inherited – the patient is heterozygous for a familial disease-causing variant, a variant in an imprinted gene, ora variant in a gene associated with a disease showing incomplete penetrance or variable expressivity
- Parental mosaicism — the patient is heterozygous and one of the parentsis mosaic
GENE LIST & PHENOTYPES
Sample Requirements
Blood (2-5 ml EDTA-blood)
DNA (minimum 3 µg)
Saliva (minimum 2mL)
Test Specifications
Whole exome analysis covering 36.5 Mb of human protein coding regions
Chemistry: Twist Biosystems Human Exome 2.0
Hardware: Illumina Novaseq 6000 Sequencer
Data processing: An in-house bioinformatic pipeline performs variable calling and filtering calling. Based on recent database releases.
Metrics: Average read depth >100-fold. On target coverage,>95% at a >20-fold read depth.
Limitations of the Analysis
The analysis is limited to the protein coding regions and 10bp from the exon-intron boundaries including splice sites. Non-coding regions: 5’-UTR, 3’ UTR, introns, and promoter regions are sparsely analyzed (only known pathogenic variants are reported), and large rearrangements (complex inversions, gene conversions, balanced translocations) as well as single exon deletions or duplications will not be detected. The method is also not appropriate for the analysis of pseudogene regions/duplicated segments or repeat regions. For analysis of the FMR1 gene we recommend our FMR1- Fragile X (CGG) repeat expansion test. Low level mosaicism with an allele fraction less than 20% will not be detected.
Only associations with phenotypes relevant to the indication for choosing the selected panel are reported.
Terms
By ordering an analysis at Amplexa Genetics A/S, the requester confirms to have obtained the necessary informed consent for the performance of the requested analyses and accepts Amplexa Genetics Terms and Conditions. A hard-copy requisition or an e-mail stating the specific study together with the receipt of a sample is considered an order to conduct the analysis.
The results will be ready approximately five weeks after we receive your order. REFERENCES
[1] Oates et al., Incorporating epilepsy genetics into clinical practice: a 360°evaluation. PMID: 29760947.
[2] Brunklauset al., (2020), Biological concepts in human sodium channel epilepsies and their relevance in clinical practice PMID: 32090326.
[3] Bayat et al., (2022), Impact of Genetic Testing on Therapeutic Decision-Making in Childhood-Onset Epilepsies-a Study in a Tertiary Epilepsy Center, PMID: 35723786.
[4] McKnight et al., (2022), Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice, PMID: 36315135.
[5] Beltrán-Corbelliniet al., (2022). Epilepsy Genetics and Precision Medicine in Adults: A New Landscape for Developmental and Epileptic Encephalopathies. PMID: 35250806.
[6] Guerrini et al., (2021). Monogenic Epilepsies - Disease Mechanisms, Clinical Phenotypes, and Targeted Therapies. PMID: 34493617. [7] Balestrini et al., (2023). Steps to Improve Precision Medicine in Epilepsy. PMID: 37755653.
[7] Richards et al., (2015), Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, PMID: 25741868.
[8] Durkieet al., (2024),ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2024. Recommendations ratified by Association for Clinical Genomic Science (ACGS) Quality Subcommittee. (https://www.acgs.uk.com/media/12533/uk-practice-guidelines-for-variant-classification-v12-2024.pdf)
To learn more about how Trio Exome Analysis can assist your patients, please get in touch with one of our experts for more information.
