I inherited What???
You and Your Genes:
The Explosive New World
of Genetics
Kara Levine, MS, LCGC
Genetic Counselor,
GeneDx Whole Exome Sequencing Program
Disclosure
In relation to this presentation, I declare
the following real or perceived conflicts
of interest:
 I am employed by GeneDx, a commercial
genetic testing laboratory that performs
whole exome sequencing.
 GeneDx is a wholly owned subsidiary of
BioReference Laboratories, a publicly
traded company.
Overview
 Basics of Inheritance:
 Dominant vs. Recessive Inheritance
 Jewish Genetic Diseases (JGDs)
 Genetic risks faced by Jewish individuals
 Carrier Screening for and Prevention of JGDs
 What is Carrier Screening?
 Past, Present, and Future of Carrier Screening
 Who Should Be Screened for Which Diseases
and When should it be done?
 Options for carriers to have healthy children
 Summary and Resources
Basics of Inheritance
Types of Inheritance
 Autosomal Dominant
 Autosomal Recessive
 Sex-linked/Sex-limited
 X-linked
 Y-linked (Paternal)
 Mitochondrial (Maternal)
 Epigenetic (Imprinting)
 Multifactorial - most diseases
Autosomal Dominant Inheritance
• 50% risk with each pregnancy
• Males and females are equally affected
• Often variable expression with reduced penetrance
Autosomal Recessive Inheritance
• Carriers are
healthy
• If both parents
are carriers…
• 25% risk with
each pregnancy
• Males and
females are
equally affected
Jewish Genetic
Diseases (JGDs)
What are Jewish Genetic Diseases?
 Recessive conditions that have a higher
incidence among Ashkenazi Jews
 Caused by founder effect
Founder Effect
19 Most Common JGDs*
Disorder
Bloom Syndrome
Canavan disease
Cystic Fibrosis
Dihydrolipiamide dehydrogenase
deficiency (LAD)
Familial Dysautonomia
Familial Hyperinsulinism
Fanconi Anemia (C)
Gaucher disease
Glycogen storage disease type 1a
Joubert syndrome
Maple syrup urine disease
Mucolipidosis IV
Nemaline myopathy
Niemann-Pick (A)
Spinal Muscular Atrophy
Tay-Sachs disease (DNA+enzyme)
Usher syndrome 1F
Usher syndrome 3
Walker-Warburg syndrome
Carrier frequency
1/100
1/40
1/25
1/96
1/30
1/66
1/89
1/15
1/71
1/92
1/81
1/122
1/149
1/90
1/41
1/25
1/141
1/107
1/112
Detection Rate
97%
98%
97%
95%
Residual Risk
1/3301
1/1951
1/801
1/1901
99%
88%
99%
95%
99%
>99%
99%
96%
99%
95%
90%
98%
75%
98%
>99%
1/2901
1/543
1/8801
1/281
1/7001
1/9101
1/8001
1/3026
1/14801
1/1781
1/401
1/1201
1/561
1/5301
1/11101
*Currently under evaluation for expansion of the panel
1 in 4
Ashkenazi Jews
is a carrier for
at least one of 19
preventable JGDs
Know Your Family History
 Important to know your family history for all
genetic disease, not just JGDs (i.e. breast
cancer), and review it with a genetic counselor
 Though autosomal recessive conditions are not
typically present in multiple generations, some
JGDs are common enough that it can happen



Example: Gaucher disease (GD)
AJ Carrier frequency: 1/15
Risk to baby (carrier status unknown):
 1/15 * 1/15 * 1/4 = 1/900 = ~0.1%

Risk to baby if one grandparent has GD:
 1 * 1/15 * 1/4 = 1/60 = ~1.7%
JGD Example: Tay-Sachs Disease
 Carrier frequency in Ashkenazi Jews is ~10 times that




of the general population (1/25 vs 1/250)
Caused by deficiency of the lysosomal enzyme betahexosaminidase A (HEXA gene), which leads to a
buildup of toxic GM2 ganglioside in neurons
3 types: infantile, juvenile, &
adult onset
Progressive fatal genetic disorder
Initially healthy infants, with
regression before age 2, leading
to seizures, paralysis, blindness,
and death, often by age 5
Carrier Screening
What is Carrier Screening?
 Examines a (typically) healthy individual’s





DNA for specific known genetic changes
(mutations) which can cause disease in
future children
Does not examine all genes or mutations
Not a diagnostic test or a risk assessment
for the individual being tested
Typically needs to be a blood test
Can be performed at any point in one’s
reproductive life, but best time is
preconception
Turn-around time is usually 4 to 8 weeks
Why Screen for JGDs?




High carrier frequency
High morbidity/mortality
Actionable!
Many options available to mutation
carriers
 Cost of testing has come WAY down
 Testing covered by most insurance
companies
 Personalized Medicine/Standard of Care
History of JGD Screening
 Blood Test for HexA enzyme levels to screen for
Tay-Sachs (TSD) carriers (1970s)


Led to a 90% reduction in the birth of babies with
TSD
Still the gold standard with highest detection rate
when combined with mutation analysis
 American College of Obstetricians and
Gynecologists

4 Jewish genetic diseases in 2004
 American College of Medical Genetics

10 Jewish genetic diseases in 2008
 Victor Center

19 Jewish genetic diseases in 2014
JGD Screening Today
 Number of diseases to screen changes rapidly at
this point as the cost of adding new
genes/mutations to these panels is nominal
 Mt. Sinai is currently offering a JGD carrier
screening panel of 38 diseases
 Pan-ethnic panels are also now available, and
screen for gene mutations that are common in
many ethnicities, including Ashkenazi Jewish
 Genetic Information Non-Discrimination Act (GINA)


provides some protections for employment (with >15
employees) and health coverage since 2008
Does not protect against life insurance discrimination
Which JGDs to Screen?
 Old Panel: 19 Genes
 Newer Panels: 38+ Genes (Mt. Sinai)
 Pan-ethnic Panels: >100 genes
 Physicians don’t need to ask ethnicity
 Best option for individuals
with mixed
ancestry or in interfaith relationships
 Usually contain Sefardic Jewish Disorders
 However, not all panels are created
equally…more later from Dr. Finegold
Who should be screened?
 Ashkenazi Jewish adults of reproductive age
(18-45)




Jews of eastern or central European descent
Individuals with some Jewish heritage, even if only
1 Jewish grandparent
Individuals of unknown ancestry
When in doubt, screen!
 Start with screening just one member of couple

if already pregnant, screen both simultaneously
 Screen Jewish partner first if one partner is a
non-Jew; If Jewish partner is a carrier, also
screen/sequence the non-Jewish partner for
that disease
Who is an Ashkenazi Jew?
 Jews of central/eastern European descent:
 95% of the Jews in the United States
Russia, Belarus,
Ukraine, Moldova,
Estonia, Latvia,
Lithuania,
Germany, Poland,
Austria, Hungary,
Romania, Norway,
Sweden, Great
Britain, Ireland,
Northern Ireland,
France, Italy
When should you be screened?
 PRE-CONCEPTION (annual GYN visit)
 The IDEAL time to screen is BEFORE child-
bearing, so couples have all of their
reproductive options available to them
 POST-CONCEPTION (1st OB visit)
 If a woman is already pregnant and has not
been screened, both members of the couple
should be screened simultaneously
 BEFORE EACH SUBSEQUENT PREGNANCY
 Update carrier screening before each
pregnancy, as screening for new diseases may
become available
Where can you be screened?
 Women: OB/GYN or PCP
 Men: PCP
 Magee-Womens Hospital of UPMC


MWH Center for Medical Genetics
(412) 641-4168 or (800) 454-8155
 Allegheny Health Network


Allegheny Perinatal Associates
(412) 359-4186
 JGenesPgh Screenings

Next local Screening: March 31st, 2-6pm at Hillel
 Dor Yeshorim Program


for some orthodox communities
focus is prevention of stigmatization
Reproductive Options for Carriers
 Prenatal diagnosis
 Chorionic villus sampling (10-13 weeks)
 Amniocentesis (After 15 weeks)
 Decision to continue or terminate an affected
pregnancy
 Sperm or egg donation
 In Vitro Fertilization (IVF) with
Preimplantation Genetic Diagnosis (PGD)
 Adoption
Future of JGD Screening
 JGD panels continue to expand
 Pan ethnic panels continue to expand
 Future screening tests are likely to be NextGeneration Sequencing Panels or Whole
Exome Sequencing (WES)
 This technology exists now
 Prices have decreased substantially
 Exome/Genome knowledge advances daily
 Some individuals may ultimately choose these
options to look at their reproductive risks as
well as their own personal health risks (i.e. for
future disease/cancer)
Summary
 JGDs are recessive genetic disorders that can affect
anyone, but children of Jewish individuals are at
higher risk
 Carrier screening is available for 19+ disorders and
should be performed before pregnancy
(preconception) if possible
 Carrier screening is recommended even for
individuals who have only ONE Jewish grandparent,
as well as interfaith couples

If an interfaith couple, the Jewish individual should be
screened first, even if that is the male partner
 Screening should be updated before each
pregnancy since the screening panels are
continuously expanding
Online Resources
 Coming Soon: www.JGenesPgh.org
 YU’s Program for Jewish Genetic Health


Free online educational webinars, etc.
www.myjewishgenetichealth.com
 Jewish Genetic Disease Consortium

http://www.jewishgeneticdiseases.org
 Center for Jewish Genetics

https://www.jewishgenetics.org
 Victor Center


www.victorcenters.org
www.youtube.com/watch?v=uVJflKVMqlg
 CDC Office of Public Health Genomics

www.cdc.gov/genomics/implementation
Additional Resources
 ACOG FAQ about “Preconception Carrier
Screening” for ALL ethnicities:
 www.acog.org/~/media/For Patients/faq179.pdf
 Gene Screen app
for your iPhone
Thank you!