GENOME ANALYSIS

Commentary:
The decision of whether an individual should pursue genetic testing when he or she presents with unusual variants of a condition or does not respond to the typical treatments is plagued with challenges.  Will the information gained from whole genome sequencing (WGS) or whole exome sequencing (WES) be beneficial clinically? Is the testing affordable?  Is there insurance reimbursement for the testing? Will the clinician treating the patient be able to interpret the results of the testing?  How should the clinician and patient respond to incidental findings?

Consider Mary who  has various renal, cardiac and cerebrovascular manifestations of Fabry disease that have developed despite the typical enzyme replacement therapy.  Her brother also has Fabry disease but has responded to enzyme replacement therapy.  

Briefly, Fabry disease is a lysosomal storage disorder caused by GLA gene mutations.  It is inherited in an X-liked pattern.  As males have only one X chromosome, one altered copy of the GLA gene is sufficient to cause the condition.  However, unlike other X-linked disorders, Fabry disease causes significant medical problems in many females with just one variant of the GLA gene.  More information about Fabry disease can be found here NIH Fabry Disease.
As Mary has been confirmed as being homozygous for a disease causing variant of the GLA gene, she has presumably undergone clinical genome or exome sequencing for Fabry disease. But her lack of response to typical treatment may indicate the presence of other disorders with  renal, cardiac and cerebrovascular manifestations.  As such one option is for Mary to participate in a clinical trial offering full exome analysis at no cost to her and her parents.  However, her ability to participate will depend on the inclusion/exclusion criteria of the trial.  In addition, this trial likely requires the participation of her parents and Mary's ability to enroll in the study will also depend on her parents' willingness to give consent. As a small portion of disease-causing mutations are found in introns, the sequencing offered in this trial may not provide Mary with a comprehensive explanation of her lack of response to traditional therapy.  Another option is for Mary to seek insurance provider approval for full genome analysis. Given, however, that this likely involves a 4 to 6 month negotiation with her insurance carrier, this may not be an option if her condition is deteriorating quickly. Full genome analysis, although decreasing in price, still remains out of reach of many individuals given the $5,000 to $10,000 cost.  Mary may consider direct-to-consumer genome analysis from a commercial lab without the involvement of her health care providers.  Recently, however, the American College of Medicine Genetics Board (ACGM) has issued a statement against this practice due to potentials harms including misinterpretation of test results and lack of necessary follow up ( ACMG statement).  The American Society of Human Genetics (ASHG) has also issued a statement regarding the genetic testing done by laboratories not of high quality whose claims about the testing may be misleading to the consumer (ASHG statement).  Mary will also need to have an in-depth discussion with her provider as to how to handle "incidental" findings during sequencing.  The ACMG has recommended that laboratories search for specific types of mutations for which "preventive measures and/or treatment  are available and disorders in which individuals with pathogenic mutations might be asymptomatic for long periods of time" (ACMG policy statement, see table 1).  
In my opinion, Mary should enroll in the clinical trial if her parents agree as this option provides her with the most information possible with the lowest out-of-pocket cost.  She should have a very detailed discussion with the investigators about the types of conditions, genes and variants that can be expected as per ACMG guidelines.

Conversion of GLA variant to Variant Call Format (VCF):
Per OMIM, the variant of the GLA gene which results in arginine substitution by tryptophan at position 356 of the protein (enzyme) is represented by dbSNP:rs104894827. 

To following screen shot illustrates that the beginning position of the variant relative to position 1 of the X chromosome (on which the GLA gene is located) is position 101398033.  

Exon 7 of the GLA gene contains this variant (as screen in line entitled CCDS).

The VCF format of the rs104894827 variant in a patient who is homozygous for the disease associated variant is represented as follows:

#CHROM POS        ID           REF ALT QUAL FILTER INFO                  FORMAT CB00001

 X     101398033 rs104894827   C   T   25   PASS   NS=1;DP=35;AF=0.5;DB  GT:GQ  1|1:52