Clinical Diagnostic Exome

A significant number of individuals with genetic diseases go
undiagnosed or misdiagnosed because traditional genetic testing approaches are insufficient for complex situations. 

These failures can be due to a number of factors including lack of a known disease gene, phenotypic variability, genetic heterogeneity and joint contribution of multiple genes to complex phenotypes. With the development of next-gen sequencing came the potential to identify genetic variations at base-pair resolution throughout the human genome in a single experiment. With the introduction of the Clinical Diagnostic Exome™, Ambry makes it easy and affordable to use next-gen sequencing to aid in the diagnosis and management of your patients and their families. 

Indications for Clinical Diagnostic Exome™ Include:

  • Discovery of novel mutations and genes associated with Mendelian disorders
    e.g. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome, Ng et al. Nat Genet. 2010 Sep;42(9):790-3
  • Identification of mutations in known disease genes when individuals present with atypical features and/or atypical age at onset 
    e.g. Early diagnosis of Werner’s syndrome using exome-wide sequencing in a single, atypical patient, Raffan et al., Front Endocrin. 2011 Mar;2:1-8
  • Identification of cases where mutations in multiple genes may jointly explain a complex phenotype
    e.g. The concurrent diagnosis of Miller syndrome and Primary Ciliary Dyskinesia in: Exome sequencing identifies the cause of a Mendelian disorder. Ng et al. Nat Genet. 2010 Jan;42(1):30-5

Choosing the Most Appropriate Family Members for Clinical Diagnostic Exome™ Sequencing:

Performing Clinical Diagnostic Exome™ sequencing for multiple members of families increases the likelihood of finding the underlying disease-causing mutation. For simplex cases this involves testing the affected patient along with two unaffected family members, ideally the parents. However, the most ideal testing scenario is to perform full exome sequencing of multiple affected individuals, when available. By testing family trios, we can generally find a more precise answer about a patient’s phenotype within a shorter turn-around time. Other benefits include the application of co-segregation analysis to the majority of the variants identified and de novo mutation confirmation (when testing parents). It is highly recommended that optimal sample submission scenarios and potential yields be discussed with our clinical diagnostic exome team for assistance in identifying optimal family members for submission. 
 

Ambry Performs Free Family Studies for Clinical Diagnostic Exome™ Sequencing:

Ambry approaches exome sequencing analysis within the context of the whole family and encourages sending multiple family members. Free familial studies are performed when it is deemed necessary. Therefore, it is helpful to send samples from multiple 1st degree family members (affected and unaffected) and affected 2nd degree relatives. Co-segregation familial studies for certain candidate mutations may then be performed for the additional family members, if necessary, to help narrow down the final candidate list. 
 
More than 20 genetic counselors and medical directors are available to assist with testing process and results interpretation. 
 

Clinical Diagnostic Exome™ Process:

If the proband has not already undergone microarray analysis with resolution of at least 105K, Ambry recommends performing microarray analysis before exome sequencing to assess for large rearrangements.
 
 
Ambry's robust bioinformatics pipeline removes thousands of variants not likely to be associated with the patient's phenotype.
 

Clinical Diagnostic Exome™ Reporting:

Both printable & online results reporting:
Web browser: All identified variants viewable through web-interface. AVA™ (Ambry Variant Analyzer), Ambry's clinical analysis tool, is applied to each variant identified.
Printable report Candidate mutations undergo interpretation by an ABMG-board certified medical director.
 
 
AVA™ standard analysis tools include:
  • Allele frequency
  • Evolutionary conservation (both amino acid and nucleotide alignments)
  • Previous report of association with human disease via HGMD and OMIM
  • Nature of amino acid change (Grantham score provided)

To learn more, please visit Clinical Diagnostic Exome Requirements.