February 2018 Support Group Meeting

Genetic Testing Advancements and Opportunities

within Rare, Undiagnosed, and Genetic Disease
Molly McGinniss MS, LCGC Genetic Counselor and
Senior Market Development Manager, Illumina
(Meeting Feb. 3, 2018),

Meeting Notes
1. Genetic Counselors- Genetic counselors have many roles: Detective, Biology
Teacher, Healthcare professional, Therapist, Science Author, Nurse, Lifelong
student. 30% of genetic counselors fall outside that role and are pushing the
market forward for Whole Genome Sequencing (WGS). They promote research
collaborations with physicians and work with and influence insurance companies.
This is all exciting research.
2. Background on Disease- 3 in 100 (3%) of babies are born with a birth defect,
and up to half of these defects have a genetic component.1 1 in 6 (17%) children
have a developmental disability, such as intellectual disability. 2 1 in 68 (1.5%) of
children have an autism spectrum disorder.3 Autism is quite common.
The majority of defects (~50%) are via an unknown underlying cause. ~25% of
defects are Multifactorial, meaning there are multiple factors like environmental
exposure. It’s like dealing with multiple needles in a haystack. The remainder are
comprised of Chromosomal Conditions (extra or missing chromosomes), Single-
Gene Disorder (one gene causes the condition) and Prenatal Exposure. 1
1. Adapted from Stevenson, RE and Hall, J. Human Malformations and
Related Anomalies, 2nd edition Oxford University Press, Oxford, 2006.
2. Facts About Developmental Disabilities, Center for Disease Control and
Prevention, Centers for Disease Control and Prevention,
http://www.cdc.gov/ncbddd/developmentaldisabilities/facts.html. Updated
July 9, 2015, Accessed November 12, 2015.
3. Facts About ASD, Centers for Disease Control and Prevention, Centers for
Disease Control and Prevention,
 http://www.cdc.gov/ncbddd/autism/facts.html. Updated February 24,
2015, Accessed November 12, 2015.
3. The Diagnostic Odyssey- Conditions are Rare when they affect fewer than
200,000 individuals.1 350 million people worldwide suffer from a rare disease.1
91.5% of rare disease are genetic in origin. Approximately half of those affected
by rare diseases of genetic origin are children.1 The diagnostic odyssey generally
ranges from 5 to 30 years.2 Average years are 7 to 8 and there needs to be an
understanding that there are many diagnoses that aren’t correct. Illumina wants
to shorten this and focus on treatments and other things to help families going
through their diagnostic odyssey.
1. GlobalGenesProject (2017) Rare Diseases: Facts and Statistics
https://globalgenes.org/rare-disease-facts-statistics/
2. Boycott, KM, Vanstone MR, Bulman DE, MacKenzie AE(2013) Rare-disease
genetics in the era of next-generation sequencing: discovery to translation
Nature reviews Genetics 14:681-691 dol: 10.1038/nrg35555
4. The Building Blocks- The breakdown is Human  Cell  Nucleus 
Chromosome  DNA The code for life, DNA is within every cell in the body and
is packaged into chromosomes.1 If you unravel chromosomes, you would see
long codes of DNA. DNA is replicated/transcribed to produce messenger RNA
(mRNA) and then translated into protein. Illumina, in their sequencing
technology, developed a suite of sequencing platforms. Recently, even small
sequence machines have been created to expand and enable sequencing
potential. Illumina focuses on three main clinical areas: Oncology, Rare and
Undiagnosed, and Genomic Sequencing.
1. US National Library of Medicine, Help Me Understand Genetics: Cells and
DNA, https://ghr.nlm.nih.gov/primer/basics.pdf. Published September 19,
2017, Accessed September 20, 2017.
5. Genome and Exome- Genome is the complete set of genes or genetic material
present in a cell or organism and Exome entails the genes that are translated
into proteins (coding DNA). The human genome is composed of 3.2 billion letters
and the exomes comprise 180,000 exons, about 1.5% of our total DNA. 1 From a
genetic testing perspective, it’s a good snapshot but sequences only a little bit of
DNA. The more we do WGS, there are genes outside the coding region that will
be found to be important. We’ll start to see the field grow.
1. US National Library of Medicine, Help Me Understand Genetics: Cells and
DNA, https://ghr.nlm.nih.gov/primer/basics.pdf. Published September 19,
2017, Accessed September 20, 2017.
6. What is a Mutation- A mutation is a permanent change in the DNA. 1 Mutations
make us all different and unique. We are all alike as we are essentially 99.9%
the same.2 Some mutations impact the function of the gene. Only a few affect
functions as most are benign and non-functional.
 1. US National Library of Medicine, Help Me Understand Genetics: Cells and
DNA, https://ghr.nlm.nih.gov/primer/basics.pdf. Published September 19,
2017, Accessed September 20, 2017.
2. National Institute of Health: National Human Genome Research Institute,
https://genome.gov/19016904/faq-about-genetic-and-genome-science/.
Published March 2, 2016, Accessed September 15, 2017.
Types of Mutations-
Autosomal Dominant is when only one parent has a mutation and passes it onto
their child. In thinking of genetic conditions, mutations “just happen”. These are
also referred to as inherited. Examples of Autosomal Dominant diseases are
Alagille syndrome, Shprintzen-Goldberg syndrome, SYNGAP1- Mental Retardation
syndrome, and Dyskinesia, familial, with facial myokymi (ADCY5).
Autosomal Recessive is when both parents have the same mutation and pass it
onto their child. There are essential mutations in both copies of the gene that
don’t work. Examples of Autosomal Recessive diseases are Congenital
Generalized Lipodystrophy, Glutaric Aciduria, NGLY1 (Congenital disorder of
deglycosylation), Congenital Sucrose Isomaltose deficiency, and Spinal Muscular
Atrophy (SMA).
X-linked Recessive is when the mother has a mutation and passes it onto their
child. This is somewhat a common inheritance problem that affects males more
than girls. Reason is because males only have one X chromosome, therefore the
mutation in code is read. Examples of X-linked diseases are Duchenne Muscular
Dystrophy (DMD) and Microvillis Inclusion Disease. There is exciting research
being conducted on potential therapies for DMD. One type of investigational
therapy is “exon skipping” which allows the DNA translation process to “skip”
over a specific part of DNA that contains a mutation. This DMD does a lot of
genetic testing and were able to develop medication that allows individual to skip
that protein. This allows the important protein to be made, just not completely.
Clinical trials are underway to evaluate the effectiveness of this therapy.
7. Comparison of Genetic Testing-
Whole Genome Sequencing is when you are testing the entire human genome.
This has largely been enabled to faster and cheaper sequencing technologies.
Whole Exome Sequencing is when you are testing the exons: the DNA
responsible for coding proteins. This is the first time we’re able to do hypothesis
for re-testing- this lets us look at the exome. Some insurance companies cover it.
Targeted sequencing is when you are testing a subset of genes that are clinically
important. Target sequencing or gene panels allows us to test 40 genes to test
for intellectual disability. This doesn’t necessarily uncover anything. It is
generally covered by insurance.
Single Gene Testing is when you are testing a single gene of interest.
8. Pros and Cons of Genetic Testing- Some families on a diagnostic odyssey are
trying to gather all the answers they can. Testing is not for everyone and need to
assess the pros and cons. In regards to the Pros: Can confirm a diagnosis, can
determine medical recommendations and further testing, Can predict if other
family members may be at risk, Can reduce anxiety and uncertainty, and Can
inform family planning. The power of having an answer can be important. In
regards to Cons: Can increase anxiety about having a genetic condition and its
prognosis, Can cause fear of social stigma, Cannot always find the answer for
the problem, and Lowers self-esteem and may promote negative self-image.
9. Examples of Positive Outcomes from Sequencing Earlier- A local physician, Dr.
Stephen Kingsmore drove the method of doing rapid genome sequencing. (Most
labs might do sequencing, but filtering and interpreting the results takes weeks.
Each day is valuable when presenting with life-threatening symptoms.) Dr.
Kingsmore was determined to make it quicker and targeted newborns in the
NICU.
Baby E’s Story1: Born on New Year’s Eve, Baby E had fluctuating blood sugar and
seizures. Current drugs were ineffective. Got the family in for rapid genome
sequencing, the blood of parents and baby were sent to the lab. The lab filtered
the sequencing to 500 genes in 26 hours. They found the needle in the haystack,
a mutation in the SCN2A gene that neither parent had. The official diagnosis was
Ohtahara Syndrome. Through the sequencing, they found out that the seizure
medicine being used does not work on that particular gene. Sequencing and
diagnosis led to improved medical management. Doctors administered a new
medication. Baby E was released at 5 months with seizures under control.
Baby S’s Story2: This story appeared in TIME magazine in September. Baby S
began to spasm within hours of her birth. She had multiple convulsions within
her first night, refusal to eat. The neurologist predicted she would not survive.
Whole Genome Sequencing was implemented. The DNA is isolated and loaded
onto a Sequencer. Results were completed in 3-4 days. Doctors determined the
underlying genetic cause and also that her brain was developed normally. The
current treatment had a negative impact on Baby S. With sequencing, Baby S got
improved medical management and quality of life. Doctors administered a rarely
used anti-seizure medication which resulted in Baby S becoming more alert and
her seizures stopping.
1. Beil, L. On A Fast Track: Can rapid genome sequencing at birth help save
lives? Genome Web site, http://genomemag.com/on-a-fast-
track/#.V8BoXPkrJD8. Published June 29, 2015. Accessed August 26,
2016.
2. Park A. Genetic Testing is Providing New Hope for Babies Born with
Mysterious Ailments. Time Magazine. http://time.com/4951200/genetic-
testing-providing-hope-babies-ailments/. Published September 21, 2017.
10. Genetic Sequencing Progress- Showing economic value of diagnosing early
shows value to help push sequencing forward. It is necessary to do physician
training to get them more comfortable with sequencing. The body of knowledge
that is out there is getting better all of the time. We want people to become
refined in their interpretation of sequencing results. It is important to request a
list of all variants interpreted. We are still in uncharted times. Now isn’t always
perfect, but will continue to get better.
11. Rare Parent Highlight- Dr. Matthew Might had a computer science background
and new nothing about rare disease until his 4 year old son got genetic testing
and was diagnosed with N-glycanase deficiency, or NGLY1 deficiency. His son
was the first known case and so Matt set out to find other families and cases.
Within 24 hrs, his search went viral and 9 other families came forth. With his
skills in data modeling, Matt identified two FDA-approved compounds that
seemed like they could help. After 3 days on one particular compound, his son
started crying tears making him the first child with the disease to ever cry. Dr.
Might has since co-founded a company that conducts personalized drug screens
for genetic epilepsy.1
1. DeBellis A. Matthew Might, Ph.D. – 2017 Rare Impact Award Honoree,
NORD Web site, https://rarediseases.org/matthew-might-ph-d-2017-rare-
impact-award-honoree/. Published March 15, 2017.