EPIDASD

How can the EPIDASD test benefit a patient?

Most treatments for neurological disorders are designed for the "average patient" as a one-size-fits-all-approach, which may be successful for some patients but not for others.

Precision medicine, sometimes known as "personalized medicine" is an innovative approach to tailoring disease prevention and treatment that takes into account differences in people's genes, environments, and lifestyles. The goal of precision medicine is to target the right treatments to the right patients at the right time.

Studies of clinician-reported outcomes in patients with epilepsy suggest that the use of genetic testing to guide the clinical decision-making, in average improve the patient outcome or at least prevent worsening the epilepsy and save health care money [2-3].

With the EPIDASD panel test a total of 1740 genes are examined, with the primary purpose of identifying the underlaying cause(s) of the neurological disease verifying the clinical diagnosis, supporting the genetic counselling, predicting the future outcome and ultimately offering the patient a personalized or at time best possible treatment as early as possible.

What type of patients is this test ideal for?

Although all patient with epilepsy may benefit from genetic testing, screening with the EPIDASD panel will be of greatest value to patients with syndromic epilepsy, patients with early-onset epilepsy (before the age of 10 years), and/or patients with a family history of epilepsy, neurological deficit, an autism spectrum disorder, and/or intellectual disability [2-3].

THE ANALYSIS

EPIDASD

Epilepsy, Intellectual Disability and Autism Spectrum Disorders. The most common neurological and neuropsychological diseases.

In total, 1740 genes associated with Epilepsy, Intellectual Disability, or Autism Spectrum Disorders are analyzed in the EPIDASD panel. Data is extracted as a virtual panel from human exome data, and an in-house bioinformatic pipeline performs variant calling and filtering.

Rare or low-frequency variants (SNVs and CNVs) are evaluated according to the ACMG guidelines [6], the ACGS guidelines as well as individual estimates. In the evaluation are database searches in the Human Gene Mutation Database (HGMD), ClinVar, DECIPHER, the Genome Aggregation Database (gnomAD, release 4.0.0), and dbSNP (155)

Synonymous variants in autosomal dominant genes which have been observed with a allele frequency higher than 1% or observed in homo-/hemizygous state in the gnomAD database are not reported. Predictions on protein level are obtained from dbNSFP Functional Predictions and Cores 3.0 database, REVEL functional prediction, and CADD score 1.6.

Predictions on transcriptional level variants are submitted to bioinformatics software tools e.g. NNSplice, GeneSplicer, MaxEntScan and PWN.

Sample Requirements

• Blood (2-5 ml EDTA-blood)
• DNA (minimum 3 µg)
• Saliva (minimum 2mL)

Test Specifications

The test is performed as data extract (virtual targeted panel) from whole exome data. Chemistry: Twist Biosystems Human Core Exome Hardware: Illumina Novaseq 6000 Sequencer Data processing: An in-house bioinformatic pipeline performs variable calling and filtering calling Metrics: Average read depth >100-fold. On target coverage,>97% 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.

[6] 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

References

[1] Brunklaus et al., (2020), Biological concepts in human sodium channel epilepsies and their relevance in clinical practice PMID: 32090326.

[2] 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.

[3] McKnight et al., (2022), Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice, PMID: 36315135.

[4] Cirnigliaro et al. (2023), The contributions of rare inherited and polygenic risk to ASD in multiplex families, PMID: 37506195.

[5] Rylaarsdam & Guemez-Gamboa A, (2019), Genetic Causes and Modifiers of Autism Spectrum Disorder, PMID: 31481879.

[6] 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