The Comprehensive Service Option

1. The genetic testing laboratory will be asked to forward their raw sequence data in an
   electronic format. Each testing laboratory has a different procedure:
   • You may need to complete and/or sign a request form. If so, this form (or the
     hyperlink to the form on the laboratory’s website) will be provided to you.
   • For some laboratories, you may be required to pay a small fee to the testing
     laboratory to cover their costs (e.g. for the flash drive).
   • The electronic sequence may be sent electronically (Internet) or by mail (flash
     drive) to your physician or directly to Dr. Boles. If sent to your physician, his/her
     office will forward the sequence.
2. Dr. Boles will analyze the sequences, with the primary aim of identifying variants that
   might be treatable.
3. Discussion of findings:
   • For Dr. Boles’ private patients, including those seen in any of the Rossignol
     Medical Centers, Dr. Boles will discuss the results with you during a follow-up
     via telemedicine.
   • For the Peer-to-Peer service, Dr. Boles will discuss the results with your physician
     over a telehealth call.
     • You may listen in to this call and ask questions if you are physically
       present in a state that Dr. Boles is licensed to practice, currently CA, AZ, FL,
       NJ, and PA.
     • Later, your physician will discuss with you any options that he/she
       believes are reasonable in you/your child based on an assessment of risks
       and benefits.

Clinical genetics laboratories and the official reports they provide are limited to the standards set
by the American College of Medical Genetics (ACMG). These standards are excellent for
determining which variants are the likely cause of disease in many settings. However, they suffer
from the following limitations:

1. Most laboratories do NOT report findings that MIGHT be disease related, even if there is
   a possible therapy.
2. ACMG standard are designed for monogenic disease, which is disease caused by a
   variant in one gene. Most human disease is polygenic, which means that disease is
   influenced by risk factors consisting of variants in more than one gene.
   • In particular, functional (e.g. pain, fatigue, GI dysmotility, dysautonomia,
     depression) and neuro-developmental (e.g. autism, ADHD) disorders are
     generally thought to be polygenic.
3. Most geneticists and genetic counselors that interpret the sequence data for laboratories
   are trained in a strict allopathic manner, with little to no training in functional medicine.

For all of the above reasons, sequence variants related to disease are likely to be missed by the
laboratory and NOT listed on the reports. A re-analysis of the raw sequence is needed in order to
identify them, and this is what the Comprehensive level of the Service is designed to accomplish.

Some genetics testing laboratories, but not all, will list variants that are of unclear connection
with disease if they believe that they may be disease related. These variants are termed as
Variants of Uncertain Significance (VUS). On the extensive sequence re-analysis as part of the
Comprehensive Service, many additional VUSs will be identified that may or may not be disease
related.
In the Comprehensive Service, each VUS will be considered by Dr. Boles (including discussion
with your physician in the Peer-to-Peer setting) to determine which ones appear to be a good
“fit” for your/your child’s disease. Those variants that are potentially treatable or that inform on
treatment choices are of particular interest and are discussed in detail. The goal is to identify
candidate variants that suggest low-risk therapies which may be of help in treating the disease
and/or improving symptoms.
Every case is different, but our experience to date suggest that one to several such candidate
variants are identified in the average patient. While treatment directed at these candidates is
successful in many patients, in many other patients it is not. Sequence re-analysis is NOT a
guarantee of clinical success.