How to choose a Diagnostic test

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CEN4GEN provides many testing options that are applicable in diagnosing or confirming a genetic condition. Furthermore, CEN4GEN offers testing for the identification of pharmacogenomic genetic variants in a patient’s genome which could be important for suggesting appropriate medications, as well as their dosage and toxicity in the treatment of certain medical conditions. The determination of the ideal choice of test for your patient will be dependent on factors like the clinical findings of the patient and why testing should be performed.

Below is a flow chart that will assist you in choosing the different testing options for your patient, which CEN4GEN provides.

Testing flowchart

What are the differences among targeted/custom mutation analysis verses sequencing verses deletion/duplication analysis ?

Targeted, known or custom mutation analysis – By choosing this type of analysis, it refers to the examination of a specific set of common mutations within a gene. You would choose this type of analysis when:

• there is a family history of a specific mutation
• you are looking for the most common mutations in certain ethnicities
• you want to undertake carrier screening

Sequencing analysis – By choosing this type of analysis, it refers to a thorough examination of a gene, and is usually the most commonly requested first-tier test. It must be noted that certain technological limitations and complexities may prevent such sequencing analysis from identifying 100% of mutations within a gene. Nonetheless, this type of analysis is usually the most comprehensive gene analysis that can be undertaken.

Deletion and duplication array analysis – By choosing this type of analysis, it refers to searching for large deletions and duplications to assist in undertaking a more thorough gene analysis, when such were undetected in routine sequencing analysis. It is most commonly used as a second-tier choice, when no mutations (or only 1 mutation in regard to autosomal recessive conditions) are identified by sequencing analysis.

NOTE: Some conditions (such as Duchenne muscular dystrophy) are largely caused by deletions; thus ordering this test would make a better first-tier option.

What are the differences among Single gene verses Multi-Gene panel verses Exome testing verses Whole Genome testing ?

Single-gene tests are best used when there is evidence of a more defined phenotype that corresponds to one condition/gene. You choose these tests to assist in identifying causative mutations and to confirm the suspected diagnosis.

Example: Ordering beta-hemoglobin gene (HBB) analysis for someone who has clinical features with complete blood count or hemoglobin electrophoresis results is consistent with beta-thalassemia and confirmation of causative mutations is desired.

Multi-gene panel tests are best used as an efficient and cost-effective strategy to assist in confining a diagnosis, rather than choosing to sequentially test one gene after the other

Example: Ordering a panel for congenital disorders of glycosylation (including 66 genes) on a patient with suspected clinical features of this type of disorder. Since the phenotypes can overlap, it is more cost effective to analyze many genes at once, instead of the top 3 or 4 as single-gene testing first.

Exome and Whole genome testing.

Exome testing is a comprehensive test and is often used when there are more complex clinical presentations in the patient or when other testing has already shown to be negative. It has an average diagnostic yield of 20-25%, but is more likely to return results of unknown significance than the other two types of testing. To complement exome testing, CEN4GEN also offers its medical whole genome test which is essentially the most comprehensive test that reports what the CEN4GEN exome test does, in addition to genetic predispositions and pharmacogenomic findings that could potentially be useful in the clinical management of the patient.

Example: Patient’s symptom/phenotype does not match any one diagnosis or set of diagnoses so either exome testing or whole genome testing is ordered to try and find the condition and cause (previous testing may have been done but would be negative).

What are the CEN4GEN Medical Exome, as well as Medical Whole Genome Tests ?

What are the Medical Exome and Medical Whole Genome tests ?

Medical Exome testing provides >97% coverage of 22,000 genes of the human genome, with a mean read depth of 100X. Of the ~4600 disease-associated genes analyzed, 3000 have 100% coverage (≥20X) of all exons; which represents twice the number of genes with complete coverage when compared to what other competitors offer, making it the most comprehensive exome sequencing test available worldwide. This is usually the first-tier when ordering exome testing. To further complement the Medical exome test, CEN4GEN also has its Medical Whole genome test which analyzes what the CEN4GEN medical exome test does, in conjunction with reporting any findings that are relevant to genetic predispositions and pharmacogenomic medically actionable variants which could potentially be useful in the clinical management of the patient. If necessary, either the Medical Exome test or Medical Whole genome test can be followed up with a Medical Exome array test which is a comprehensive deletion/duplication analysis of the exome.

What are the ordering options ?

It could be beneficial to perform either the exome testing or whole genome testing on family trios (the patient and usually the patient’s parents), as the additional information is used to help interpret some of the variants seen during analysis. Having additional affected or unaffected family members tested may also help achieve a diagnosis, which is why CEN4GEN has added the option of additional family member testing to any family trio. If additional family members are unavailable, testing of the proband only is also an option.

Variant Interpretation Updates:

As more information from human exome and genome sequencing projects becomes available, and as more research is conducted on previously reported DNA variants, knowledge of variant classification increases. This knowledge can allow variants previously classified as variants of uncertain clinical significance to be reclassified as pathogenic variants or benign polymorphisms. Re-analysis of the patient’s Exome sequencing data can be requested from CEN4GEN.

Other exome services include interpretation only, confirmation testing and interpretation, and exome sequencing without interpretation. Please contact CEN4GEN for more information.