Jewish Genetic Health and a Glimpse into the Future Susan Gross, MD Professor, Albert Einstein College of Medicine

www.yu.edu/genetichealth

Our vision: nobody in the Jewish community facing a genetic health issue should be deprived of proper care due to financial barriers, lack of awareness, or difficulty in navigating the healthcare system To address those needs, we provide affordable and accessible genetic testing services for all, we organize and speak at educational symposia for the lay community and its leadership, and we serve as a Jewish professional resource network and support center. GENETIC TESTING EDUCATION SUPPORT www.yu.edu/genetichealth

Recent Programs For the Community and its Leadership To Tell or Not to Tell: Issues Related to Family Health and Genetics (Keter Torah, Teaneck) Cancer Risk in the Jewish population- Is it in Our Genes? (Temple Shaarey Tefilah, Westchester) Genetics on Campus (OU’s Jewish Learning Initiative on Campus) Dealing with Genetic Health Issues in the Community, Before and After They Arise (Rebbetzin Esther Rosenblatt Yarchei Kallah for Rebbetzins) Campus screening events at YU/Stern and Einstein--and soon at Columbia and YU We see that the lay public and its leaders are interested in exploring health and related social issues that arise in the Jewish community. Among our many talks we have given, here are a few highlights: Last week, we did a panel discussion in conjunction with YUConnects about disclosure of genetic conditions when it comes to shidduchim We recently gave a talk about how common hereditary breast and ovarian cancer is in the Ashkenazi population, and encouraged people to think about their family and personal histories We spoke about the importance of carrier screening with the OU’s JLIC educators-young couples who serve as Torah educators and mentors on college campuses around the country And we spoke at the Yarchei Kallah for Rebbetzins about their role in guiding families in their community through genetic health issues Aside from these lectures, we held carrier screening events at YU, Stern and Einstein and we have a screen this week at Columbia and are planning for another screen at YU after Pesach

Overview Basics of genetics and inheritance Jewish Genetic Diseases and carrier screening Options for carrier couples The future Q & A

Basics of genetics and inheritance

DNA Sequence Diversity in a single species - Humans DNA Sequence Diversity is <0.1% Majority of diversity among individuals with only modest differences between geographical populations

Genetic “Typos” or Mutations A few of these differences represent ‘Disease-Causing Mutations’ Most minor changes reflect normal human variation

Jewish Genetic Diseases and carrier screening

Genetic Disorders within the Jewish Community Diseases Specific to certain Jewish Groups Tay-Sachs, Familial Dysautonomia (Ashkenazi) Lanzmann thrombasthenia (Iraqi) Glycogen Storage Disease III (Moroccan) Diseases with Mutations Shared Among Jewish Groups Factor XI deficiency (Ashkenazi, Iraqi) BRCA1 (Ashkenazi, Iraqi, Moroccan)

decrease, migration, or isolation Founder Effect A high frequency of a specific gene mutation in a population founded by a small ancestral group Original population Marked population decrease, migration, or isolation Generations later

Timing of Mutations in Jewish Populations Ostrer H. Nat Rev Genet. 2001

Recessive Ashkenazi Jewish Genetic Diseases Someone who is AFFECTED has no working copies of the specific gene A carrier of a recessive genetic disease has one working copy, and one not-working copy of a particular gene. Carriers are healthy. Being a carrier is significant because for a couple where both partners are carriers of the same condition, there is a chance that they can have an affected child. carrier Being a carrier is quite common. Everyone is a carrier for 5-10 recessive conditions 1 in 4 ashkenazi jews is a carrier for one of the conditions currently tested for.

Carrier All of these conditions are inherited in a recessive manner, and the screening programs are aimed at identifying carriers of mutations in the various disease genes. A mutation, or pathogenic alteration or change in a gene’s DNA sequence, affects the creation of a protein. For recessive traits, a carrier is a person with one copy of a gene that has been altered by such a mutation. Carriers of mutations in (Jewish Genetic Disease) genes are not symptomatic because they have a second, intact copy of the gene that is sufficient for normal cell function.

Affected When both copies of a (Jewish) genetic disease gene have been altered by mutations, the gene can no longer do its job in creating a sufficient amount of a vital protein. As a result, the person will be affected with the condition. 

50% chance of passing along the mutation Carrier All of these conditions are inherited in a recessive manner, and the screening programs are aimed at identifying carriers of mutations in the various disease genes. A mutation, or pathogenic alteration or change in a gene’s DNA sequence, affects the creation of a protein. For recessive traits, a carrier is a person with one copy of a gene that has been altered by such a mutation. Carriers of mutations in (Jewish Genetic Disease) genes are not symptomatic because they have a second, intact copy of the gene that is sufficient for normal cell function. 50% chance of passing along the mutation during each pregnancy

“Not in Our Family” These mutations can easily pass from generation through generation, with the family (and their health care providers) unaware that they are at risk to have a child with the disease. Until one family member who is a carrier…..

Recessive Inheritance Father Mother Carrier Unaffected …meets another carrier and has an affected child. In this classic example of autosomal recessive inheritance, each parent has a 50% chance of passing along their mutation. This in turn leads to a 25% chance to have a child without any mutations, and a 50% chance to have a child who is a healthy carrier like the parents. For every pregnancy this couple conceives there is a 25% chance that the child will be born with both gene copies altered and therefore affected with the disorder. Affected Child

What are Jewish Genetic Diseases? (And Why?) “Jewish Genetic Disease” is a misnomer Carrier testing for Tay-Sachs began in the 1970s We now test for many more disease than just Tay-Sachs disease Specifically Ashkenazi Jewish Testing is necessary in every generation since carriers are healthy no simple way to remove mutations from the gene pool Currently the ACOG recommends that 4 genetic conditions are screened for in the Ashkenazi Jewish population The ACMG recommends that 9 genetic conditions are screened for in the Ashkenazi Jewish population Testing for founder mutations which are ethnicity specific. ?

1/127 1/4 > 90%

Why, When, Where, and How to Screen? To build healthy families! When? As early as possible Well before a pregnancy and before subsequent pregnancies. Where? Closed testing: Dor Yeshorim Open testing: doctors’ offices, genetics practices, community screenings, our PJGH How? Informed consent, blood draw, laboratory tests, results, and counseling

What if you are identified to be a carrier of one of these diseases? Carriers—do not have signs or symptoms of the condition in question Not a stigma (1 in 4 are carriers) Talk to a genetic counselor Tell your family members Discussion with your potential spouse 1 in 100 couples are “carrier couples” Genetic Carrier

Options if both partners are carriers 1- Disqualification before dating 2- Breaking up the engagement (divorce?) 3- Not having children 4- Adoption 5- Donor sperm/egg 6- Taking a chance--Prenatal testing of the fetus (termination?) 7- Giving birth to the affected child 8- Pre-implantation genetic diagnosis

Options for carrier couples

Prenatal Diagnosis Prenatal testing to identify an affected child CVS/Amniocentesis In-Vitro Fertilization with Preimplantation Genetic Diagnosis

Testing and Counseling For Jewish Genetic Diseases - Sue Gross, M.D. Preimplantation Diagnosis For couples who are aware of their carrier status prior to pregnancy, pre-implantation genetic diagnosis (PGD) is possible for many Jewish genetic disesases. The specific mutations must be characterized. Generally PGD reduces a couple's chances of having an affected child from 25% to less than 5%. Amnio or CVS are commonly offered as a backup to PGD because of these residual risks. Therefore amniocentesis or CVS is often recommended for couples who have conceived through IVF with PGD. For at-risk Jewish couples who would not have a pregnancy termination, this option offers the opportunity to conceive a biological child with a much lower risk of having the disease. Jewish law, (Halacha), does seem to be consistent with using these reproductive techniques. Courtesy of Montefiore's Institute of Reproductive Medicine and Health Embryology Laboratory

Even if you are not a “carrier couple”… Not a guarantee that you will have a healthy child Residual risk Other diseases Genetic compatibility for these diseases does not guarantee marital compatibility in all of the other realms Over time, new diseases are being added. You need to update your testing. Now that we’ve spent a bit of time talking about AJ carrier screening and some issues related to it- I do want to bring up a few things that I know you’re not going to like- once you go through whichever genetic screening process you choose- that does not mean that you are free and clear and will absolutely have healthy children. Don’t get me wrong- MOST babies are born healthy- and I want you to remember that- because I’m not trying to scare you with these statistics- but 3-5% of babies are born with birth defects- includes physical birth defects and MR. even if you are tested for 18 conditions now- in 2 years from now– that number might be up to 20, or 25. Initially they were only testing for tay sachs- then 4 conditions- then 9, then 16, now 18. that number will continue to rise over time. and having normal carrier screening- does not ensure you will have a healthy child. I work in genetics so I do end up seeing a slightly skewed view of the world. I will remind you that MOST babies are born healthy- but there are those who aren’t. and everyone says it’s not going to be mine. But there are children born with various rare conditions or with medical issues, and none of us are immune to that.

The future

Our most exciting undertaking has been the development of our online educational series, GeneSights. Each GeneSights webinar will focus on a different condition that seems to have a genetic link to the Ashkenazi population. Here is a sneak peek of our advertisement for GeneSights, which will be featured in all the major Jewish newspapers in a few weeks. We plan to launch this series with our introduction to genetics and hereditary breast and ovarian cancer modules. Genesights lectures are developed by experts in the given fields and are meant to be watched by the lay public. Since we understand that we are all busy and going to lectures is not necessarily on the top of most people’s ‘to-do’ lists, we think that this webinar -style series will meet the needs of the community—who wants to learn, but needs to do it on their own time. We are very excited about the launch of GeneSights, and we hope you will be seeing more of it in the weeks to come.

For further thought… Other categories of Jewish Genetic Diseases (other types of inheritance; other types of diseases) New genetic technology Slippery slope (e.g., new PGD applications)

Questions?