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* DisorderCarrier frequencyDetection RateResidual Risk Bloom Syndrome 1/10097%1/3301 Canavan disease 1/4098%1/1951 Cystic Fibrosis 1/2597%1/801 Dihydrolipiamide dehydrogenase deficiency (LAD) 1/9695%1/1901 Familial Dysautonomia 1/3099%1/2901 Familial Hyperinsulinism 1/6688%1/543 Fanconi Anemia (C) 1/8999%1/8801 Gaucher disease 1/1595%1/281 Glycogen storage disease type 1a 1/7199%1/7001 Joubert syndrome 1/92>99%1/9101 Maple syrup urine disease 1/8199%1/8001 Mucolipidosis IV 1/12296%1/3026 Nemaline myopathy 1/14999%1/14801 Niemann-Pick (A) 1/9095%1/1781 Spinal Muscular Atrophy 1/41 90% 1/401 Tay-Sachs disease (DNA+enzyme) 1/2598%1/1201 Usher syndrome 1F 1/14175%1/561 Usher syndrome 3 1/10798%1/5301 Walker-Warburg syndrome 1/112>99%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  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 frequency in Ashkenazi Jews is ~10 times that of the general population (1/25 vs 1/250)  Caused by deficiency of the lysosomal enzyme beta- hexosaminidase A (HEXA gene), which leads to a buildup of toxic GM2 ganglioside in neurons

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) or (800)  Allegheny Health Network  Allegheny Perinatal Associates  (412)  JGenesPgh Screenings  Next local Screening: March 31 st, 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 Next- Generation 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:  YU’s Program for Jewish Genetic Health  Free online educational webinars, etc.   Jewish Genetic Disease Consortium   Center for Jewish Genetics   Victor Center    CDC Office of Public Health Genomics 

Additional Resources  ACOG FAQ about “Preconception Carrier Screening” for ALL ethnicities:  Patients/faq179.pdf Patients/faq179.pdf  Gene Screen app for your iPhone

Thank you!