Clinical Exome | Actia | MedGenome

What is Clinical Exome?

Clinical Exome is a DNA test that can identify the molecular basis of a genetic disorder in individuals with a genetically heterogeneous disease and/or an atypical presentation of a genetic disorder. The test covers genes that are know to be disease associated and curated from databases such as OMIM, HGMD and ClinVar.

What genetic test to choose? How to choose the right genetic test?

Indications for prescribing Clinical Exome testing

  • In cases where Clinical findings or family history is suggestive of an underlying genetic etiology
  • To screen for genetically heterogeneous diseases
  • To detect an undiagnosed genetic disease (diagnostic odyssey) in a patient
  • To facilitate medical intervention and/or treatment
  • To confirm the suspected genetic diagnosis
  • To guide reproductive planning and assessment of recurrence risk
  • To determine a prognosis (based on family history)

Clinically relevant for a range of disorders across

  • Rare Diseases
  • Inherited Cancers
  • Neurology
  • Cardiology
  • Endocrinology
  • Nephrology
  • ENT
  • Others

MedGenome Clinical Exome Version 4

  1. The new Clinical Exome (Ver. 4) is more refined to proved more focused and in-depth coverage of known disease causing genes
  2. This is a customed focused exome curated in-house by experts at MedGenome and covers 6670 genes encompassing both nuclear and mitochondrial genes
  3. The new exome provides better coverage of disease associated genes including coding variants, splice variants, reported deep intronic variants and CNV
  4. Clinical Exome (Ver. 4) provides very high diagnostic utility at a low cost compared to whole exome sequencing

What are the key features of Clinical Exome?

  • Enhanced coverage of disease associated genes with strong, moderate or supporting evidence in literature and databases: 4,468 genes from OMIM (19 Oct-2019 update), 2,937 genes from ClinVar (Sep-2019 update), 4,860 genes from HGMD (version. 2019.2), 3,931 genes from Orphanet (Sep-2019 update),  4,217 genes from HPO (Sep-2019 update) and ACMG (59 genes; incidental finding)
  • Coverage of known pathogenic/likely pathogenic mutations: Professional HGMD (184,632), High confident pathogenic variants from ClinVar (70,703) and In-house reported novel variants (10,120) from 50,000+ clinical reports
  • Coverage of deep intronic and promoter pathogenic mutations based on HGMD (2,170) and ClinVar (13,037)
  • Improved CNV detection: Additional probes in the intronic regions in 668 genes previously reported in publications and in-house clinical reports for the Mendelian disorders
  • Probes designed based on multiple gene models
  • Coverage of mitochondrial genome (37 genes)
  • Phenotype based analysis, using Varminer, a MedGenome developed proprietary tool
  • Latest analysis pipeline using GRCh38.p13 assembly: validated on NA12878 reference sample and clinical samples
  • Proficiency: Requisite quality control steps throughout the workflow from the laboratory sample processing till the interpretation ensures consistency, validity and accuracy of results

Improved coverage

The Clinical Exome (Ver. 4) has been designed not only to include variants in coding region, but also known pathogenic noncoding mutations (HGMD, ClinVar) and enhanced coverage for the detection of copy number variants. In genetically heterogeneous diseases, the additional disease associated genes with moderate evidence increases the potential for better diagnosis.

Improved Coverage

Representative metrics of the coverage of disease associated genes in MedGenome Clinical Exome (Ver.4)

Better disease association

“Clinical Exome (Ver.4)” Panel is enriched for disease associated genes (with strong
evidence) and genes with limited but emerging evidence from OMIM, Orphanet and other
sources.

Focused Design for Deeper Coverage Of Disease Variants:

Approximately 184,076 + 70,268 coding variants and 2123 + 12693 noncoding variants from HGMD
and ClinVar respectively are covered with a minimum of 10x coverage.

How does MedGenome Clinical Exome (Ver. 4) compare with
other exomes

Clinical Exome (Ver. 4) shows better coverage of the disease annotation sources compared to other
exomes, increasing the likelihood of identifying the disease-causing variant. Percent coverage of databases
(intersect of baited regions with the databases) is shown in the table below.

Coverage across selected annotation sources (Percentage of databases targeted)

Clinical Exome (Ver.4) validation has been done as per global standard

  • The sensitivity and precision of the variant calling was determined based on the NA12878 (a reference
    standard with truth genotypes).
  • The analytical sensitivity is >99% for SNPs and 93% for indels
  • Repeatability, reproducibility, sensitivity and specificity were tested and were on par with global
    standards (99% for SNVs and >80% for CNVs)
  • CAP (College of American Pathologists) Proficiency Testing score of 100%

Validation in positive cases with known mutations

  • 41 samples with known pathogenic variants in the nuclear genes were validated end to end including
    analysis and interpretation
  • Variant position and zygosity of the 49 pathogenic variants corresponding to 40 genes were concordant
  • The 49 pathogenic variants consisted of :
    1. 29 SNV (Missense/Nonsense/splice variants )
    2. 11 Indels (7 deletion, 4 insertion)
    3. 9 CNV (7 deletions, 2 duplications)
  • The copy number variants (deletions and duplications) corroborated in the positive samples
  • Similarly ~99.8% concordance of mitochondrial gene variants in 40 samples

Limitations

  • All Clinical Exome orders include Del/Dup analysis of phenotypically significant genes. Single exon deletions or duplications are not routinely detected by this assay, however may occasionally be identified. Deletions and duplications are reported at the exon level. Breakpoint locations are not analyzed
  • Although next generation sequencing technologies and our bioinformatics analysis significantly reduce the contribution of pseudogene sequences or other highly-homologous sequences, these may still occasionally interfere with the technical ability of the assay to identify pathogenic variant alleles in both sequencing and deletion/duplication analyses
  • Due to the inherent limitation of the assay technology translocations, repeat expansions, gross chromosomal rearrangements and methylation cannot be assessed

MedGenome Clinical Exome V4 test details

 Clinical Exome (MedGenome)
Panel size~30 Mb
Number of genes6670 genes
Panel coverage80-100x
Coverage at >20x≥97% with 20x coverage
Annotation sourceClinVar, HGMD, Ensembl, OMIM, RefSeq, and literature
Clinical exomeSingleTrioCarrier testing
SampleProbandParents and probandCouples
Sample requirements Whole blood or extracted DNA of good quality Whole blood or extracted DNA of good quality Whole blood or extracted DNA of good quality
TAT28 working days28 working days28 working days
Segregation StudiesOn request in the parents by Sanger sequencingThis is done as part of the analysisOn request in the affected/unaffected family members by Sanger sequencing

Reporting of Results

The clinical and sequenced data is systematically evaluated and reviewed by an experienced analyst and a clinical geneticist. The results are reported based on the recommendations of the American College of Medical Genetics (2015). We ensure the best available support for your patients and families via:

  • Latest technologies
  • Helpful customer service
  • Clear interpretation of results
  • Counseling sessions with our Genetic Counselors

FREE GENETIC COUNSELING

MedGenome offers all your patients FREE pre- and post-test genetic counselling with our expert, certified genetic counsellors. This genetic counseling will enable patients to:

  • Make an informed decision
  • Understand risk if any
  • Discuss the implications of the result
  • Connect them to resources or support groups

Brochures

Clinical Exome

Blog

Spina bifida is part of a group of birth defects called neural tube defects.

Patient Stories

Genetic testing provides hope for couple with family history of hearing loss

Talk to our Genetic experts for free today or reach out to us

Our certified genetic specialists are available to discuss your queries

Test Menu

Genetic Counselling

Microsites

Collaterals

Contact Us