History,Ethnicity, Medicine and History,Ethnicity, Medicine and Genes: Implication of genomics Genes: Implication of genomics for community screening and for community screening and prevention, the case of prevention, the case of Ashkenazi Jewish Populations.Ashkenazi Jewish Populations.•

Why is history important?Why is history important?

• Genomics is a science of populations and Genomics is a science of populations and their diseases. It allows us to understand their diseases. It allows us to understand how disease, history and culture interacthow disease, history and culture interact

• It enables us to design rational screening It enables us to design rational screening and surveillance programsand surveillance programs

• It enables us to target specific populations It enables us to target specific populations and diseases, achieve wide-scale and diseases, achieve wide-scale prevention, and avoid cultural and prevention, and avoid cultural and situational barriers to implementation of situational barriers to implementation of screening and prevention programsscreening and prevention programs

Ideal population for Ideal population for genomic studiesgenomic studies

• Homogenous, genetically isolated Homogenous, genetically isolated over many generationsover many generations

• Traced to known ancestors or specific Traced to known ancestors or specific small ancestral populations small ancestral populations

• Accepts and supports genetic Accepts and supports genetic researchresearch

• Geographic proximity to academic Geographic proximity to academic resourcesresources

Ideal populationsIdeal populations

• IcelandersIcelanders• AmishAmish• French CanadiansFrench Canadians• Ashkenazi JewsAshkenazi Jews

Ashkenazi populations support and welcome Ashkenazi populations support and welcome medical research, live in close proximity to major medical research, live in close proximity to major research centers and a substantial proportion of research centers and a substantial proportion of research scientists are of Ashkenazi origin and a research scientists are of Ashkenazi origin and a part of the communities which they study.part of the communities which they study.

Every ethnic group has its Every ethnic group has its own genetic burdenown genetic burden

• Many of the methods that are now Many of the methods that are now being applied to diverse populations being applied to diverse populations were pioneered in the study of were pioneered in the study of Ashkenazi genetics.Ashkenazi genetics.

• Many advances that intermingle Many advances that intermingle history and medicinehistory and medicine

                                                                Y Chromosome Bears Witness to Story of the Jewish Diaspora

By NICHOLAS WADEMay 9, 2000 With a new technique based on the male or Y chromosome, biologists have traced the diaspora of Jewish populations from the dispersals that began in 586 B.C. to the modern communities of Europe and the Middle East. The analysis provides genetic witness that these communities have, to a remarkable extent, retained their biological identity separate from their host populations, evidence of relatively little intermarriage or conversion into Judaism over the centuries. Another finding, paradoxical but unsurprising, is that by the yardstick of the Y chromosome, the world's Jewish communities closely resemble not only each other but also Palestinians, Syrians and Lebanese, suggesting that all are descended from a common ancestral population that inhabited the Middle East some four thousand years ago.

Gene causes Parkinson's in Ashkenazim

Although Parkinson's disease has not generally been regarded as genetic in origin, researchers at Yeshiva University's Einstein College of Medicine and Beth Israel Medical Center in New York have discovered a single gene that is the "major cause" of Parkinson's in Ashkenazi Jews.

The report appears as "Correspondence" in the January 26 issue of the prestigious New England Journal of Medicine.

      

        

    

                

                           

NEJM, Volume 354:424-425NEJM, Volume 354:424-425 January 26, 2006January 26, 2006

LRRK2 G2019S as a Cause of LRRK2 G2019S as a Cause of Parkinson's Disease in Ashkenazi Parkinson's Disease in Ashkenazi

JewsJews

LRRK2LRRK2 G2019S as a Cause of G2019S as a Cause of Parkinson's Disease in North Parkinson's Disease in North

African ArabsAfrican Arabs  

The Lindex – A Pioneering DatabaseThe Lindex – A Pioneering Database

• Jacob Jay Lindenthal, Ph.D., Dr. PHJacob Jay Lindenthal, Ph.D., Dr. PH, , ProfessorProfessor,,Department of PsychiatryDepartment of Psychiatry, , Director of Director of Public Medical Education,University of Medicine and Public Medical Education,University of Medicine and Dentistry-New Jersey Medical SchoolDentistry-New Jersey Medical School

• focuses on North American Jews and consists of focuses on North American Jews and consists of approximately 2,400 entries derived from over 1000 approximately 2,400 entries derived from over 1000 studies involving 574 diseases and conditions and studies involving 574 diseases and conditions and classified according to the International Classification classified according to the International Classification of Diseases (ICD-9CM). The database allows for of Diseases (ICD-9CM). The database allows for review of each disease via literary form, as well as review of each disease via literary form, as well as permitting manipulation of the data from the studies permitting manipulation of the data from the studies so that investigators can examine relationships among so that investigators can examine relationships among diseases. diseases.

• Available through the libraryAvailable through the library

Genes, Self and Group IdentityGenes, Self and Group Identity The Human Mosaic

American

Religious Identification

MarriageFamily

Ashkenazi

Jewish

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A species is divided into races when it can be regarded as an essentially discontinuous set of individuals. Jonathan Marks

Some cases are easy

Black Southern African Bantu-speaking population who assert Jewish ancestry:

"Despite their long-term residence in different countries -- most Jewish populations were not significantly different from one another at the genetic level.” (M.F. Hammer, Proc. Nat'l Academy of Science, May 9, 2000)

Who gets to decide who is a member of the group?

DNA Testing to Determine “Native American Identity”

DNA Analysis and the Cultural Affiliation of the Kennewick Man

Genes and HistoryGenes and History

Genetic DiseasesGenetic Diseases

Brief review of HistoryBrief review of History

History LessonHistory Lesson - What happened - What happened in 70 CEin 70 CE

• 2nd Jewish Temple in Jerusalem destroyed in 702nd Jewish Temple in Jerusalem destroyed in 70ADAD

• dispersal +++, to Europe = Ashkenazimdispersal +++, to Europe = Ashkenazim

• to Spain / Portugal = Sephardimto Spain / Portugal = Sephardim

• To other countries of the Middle East - Jews of Arab To other countries of the Middle East - Jews of Arab

landslands

• 2,000 years, mixing of populations between 2,000 years, mixing of populations between

communities – communal recordscommunities – communal records

ebb and flow of populations in each communityebb and flow of populations in each community

Simple genetic markers of Simple genetic markers of populationspopulations

• The Blood Group storyThe Blood Group story

• more complex genetic markers - DNAmore complex genetic markers - DNA

• ‘‘Jewish genetic diseases’Jewish genetic diseases’

• Mitochondrial DNAMitochondrial DNA

What does Tay-Sachs tell What does Tay-Sachs tell us?us?• carried and passed on amongst carried and passed on amongst

Ashkenazi Jews Ashkenazi Jews

• origins in eastern Europeorigins in eastern Europe

• not found amongst native eastern not found amongst native eastern

Europeans or Sephardic populationsEuropeans or Sephardic populations

• must have arisen after Jews moved must have arisen after Jews moved

to Europeto Europe

• Started in Western HungaryStarted in Western Hungary

The Tay-Sachs StoryThe Tay-Sachs Story• in Jews of Polish and Russian originin Jews of Polish and Russian origin

Tay-Sachs carrier frequency is 0.0324 (1 in 31)Tay-Sachs carrier frequency is 0.0324 (1 in 31)• no carriers were found amongst near Eastern Jewsno carriers were found amongst near Eastern Jews

dating these genetic changes to before 1100dating these genetic changes to before 1100when Jewish migration into Poland & Russia occurredwhen Jewish migration into Poland & Russia occurred

• Jews from Austria, Hungary & CzechoslovakiaJews from Austria, Hungary & Czechoslovakiatwice as likely to be Tay-Sachs carrierstwice as likely to be Tay-Sachs carriersthan those with Polish or Russian originthan those with Polish or Russian origin

• indicates a central rather than eastern European originindicates a central rather than eastern European origin• difficult to distinguish the causes and influencesdifficult to distinguish the causes and influences• population bottleneck effects encourage genetic driftpopulation bottleneck effects encourage genetic drift

versus a potential selective advantage.versus a potential selective advantage.

Tay-Sachs

Gaucher’s disease

Niemann-Pick

Dysautonomia

Canavan’s Disease

Bloom’s syndrome,

Fanconi’s Anemia

Factor XI deficiency

Mucolipidosis type IV

Familial breast and

ovarian cancer

Hereditory NonPolyposis

Colon Cancer

and conditions common

in Sephardim:

Familial Mediterranean

Fever, thalassaemia, G6PD

deficiency

‘‘InheritInherit

eded

IllnesIllnes

ss

What happened in eastern What happened in eastern Europe?Europe?

•not from Adam or Eve•Jews in the pale of Settlement from 1264•since then repeated cycles of growth,

variable population loss and migration•‘ideal environment’ for some genes to

reach high frequency•founder effect, genetic drift + endogamy•strong evolutionary pressures•but perhaps also selective pressures

How did Ashkenazim inherit Tay-How did Ashkenazim inherit Tay-Sachs?Sachs?

What selection pressures What selection pressures may have acted?may have acted?

• genetic driftgenetic drift

• founder effectfounder effect

• selective advantageselective advantage

= random effect

c.f. sickle cell anaemia

c.f. the Pilgrim fathers

Genetic DriftGenetic Drift

• Random fluctuations in the frequency of Random fluctuations in the frequency of the appearance of a gene in a small the appearance of a gene in a small isolated population, presumably owing to isolated population, presumably owing to chance rather than natural selection.chance rather than natural selection.

• The effective size of the Ashkenazi The effective size of the Ashkenazi population has been estimated by Risch et population has been estimated by Risch et al. (1995) to have been as small as several al. (1995) to have been as small as several thousand people about 500 years ago thousand people about 500 years ago

Evidence in Support of a Founder Evidence in Support of a Founder EffectEffect• Jewish religious & cultural practicesJewish religious & cultural practices• marrying within - endogamymarrying within - endogamy• creates multiple genetically isolated population creates multiple genetically isolated population

groupsgroups• does not create genetic diseasesdoes not create genetic diseases• but increases recessive gene concentration and but increases recessive gene concentration and

expression of recessive conditionsexpression of recessive conditions• this is an ideal environment for foundersthis is an ideal environment for founders• multiple isolated settlements, multiple founders, multiple isolated settlements, multiple founders,

many opportunities to concentrate genesmany opportunities to concentrate genes• multiple examples apart from Tay-Sachsmultiple examples apart from Tay-Sachs

What selective pressures might have What selective pressures might have acted?acted?• Ashkenazi Jews subject to cycles of political & social Ashkenazi Jews subject to cycles of political & social

upheavalupheaval

• Matchmaking ethos - scholars married the wealthy and the Matchmaking ethos - scholars married the wealthy and the

eliteelite

• villages were lost in pogroms whilst others were forced to villages were lost in pogroms whilst others were forced to

emigrateemigrate

• subjected to natural selective pressures – oppression.subjected to natural selective pressures – oppression.

• epidemics of plague, TB & starvation over-crowded & epidemics of plague, TB & starvation over-crowded &

confined to ghettosconfined to ghettos

• carrying some gene(s) may confer a survival benefitcarrying some gene(s) may confer a survival benefit

Evidence for Selective Evidence for Selective PressurePressure• Average IQ in Ahskenazic (not Sefardic) Average IQ in Ahskenazic (not Sefardic)

populations is 112 - 115populations is 112 - 115

• Visual Spatial scores are lower and Visual Spatial scores are lower and incidence of myopia higher than incidence of myopia higher than surrounding populationssurrounding populations

• Consistent with 40 generations of narrow Consistent with 40 generations of narrow sense heritability (each 1 point increase n sense heritability (each 1 point increase n IQ of parents leads to a 0.3 point increase IQ of parents leads to a 0.3 point increase in the IQ of children)in the IQ of children)

Balance of EvidenceBalance of Evidence

Selective AdvantageFounder Effect

+ Random Genetic Drift

The origin of Ashkenazis.The origin of Ashkenazis.

Where do Jews fit?Where do Jews fit?

Ashkenazim

Jews of Arab Lands

Genetic Genetic evolutionevolutionary treeary tree

Muslim Kurds

Turks

Kurdish Jews

Iraqi Jews

Armenians

Ashkenazi Jews

Portuguese

North African Jews

Spaniards

Byelorussians

Poles

Russians

LebanesePalestinians

Jordanians

North Africans

Bedouin

Syrians

Genetic Analysis of Genetic Analysis of PopulationsPopulations

• DNA markersDNA markers

• Cohen and Levi genesCohen and Levi genes

• History, Ethnicity and HealthHistory, Ethnicity and Health

Cohanim and their GenesCohanim and their Genes• the priests of the Templethe priests of the Temple

• responsibility to bless the Jewish communityresponsibility to bless the Jewish community

• tradition passed by fathers to sonstradition passed by fathers to sons

• very stringent family / marital rulesvery stringent family / marital rules

• ‘‘Cohen’ families descended from Aaron, the Cohen’ families descended from Aaron, the

High Priest?High Priest?

• Y-borne traditionY-borne tradition

Cohanim and their GenesCohanim and their Genes

• Goldstein & Bradman, UCL LondonGoldstein & Bradman, UCL London

• gathered DNA samples from priests - ‘the Cohanim’gathered DNA samples from priests - ‘the Cohanim’

• genetic markers indicate a common genetic origingenetic markers indicate a common genetic origin

• regardless of which post-Temple community group regardless of which post-Temple community group

but approaches 100% in some communitiesbut approaches 100% in some communities

• consistent with descent from one ancestral Y consistent with descent from one ancestral Y

chromosomechromosome

Levite GenesLevite Genes• Levites (c.f. Levy) = assistants to the priestsLevites (c.f. Levy) = assistants to the priests

• similarly passed father to sonsimilarly passed father to son

• more heterogeneous, more mixedmore heterogeneous, more mixed

• less strict religious gate-keepingless strict religious gate-keeping

• common Ashkenazi patterncommon Ashkenazi pattern

• Mr.Levy@eastern Europe.shtetl.comMr.Levy@eastern Europe.shtetl.com

is ancestor for >50% Ashkenazi Levitesis ancestor for >50% Ashkenazi Levites

• Mitochondrial DNA suggests Levites stem from 4 Mitochondrial DNA suggests Levites stem from 4

unique women on the maternal side (?unique women on the maternal side (?

European, ?Middle Eastern)European, ?Middle Eastern)

SummarySummary• Jews are heteroJews are heterogenegeneous, but not randomous, but not random

• more in common than people realisemore in common than people realise

• documented history reflected in their genesdocumented history reflected in their genes

• a large & complex a large & complex extendedextended family family

• no single ‘no single ‘Jewish’Jewish’ gene gene

• Relevant to understanding and impacting genetic Relevant to understanding and impacting genetic

illnessillness

Mendelian Disorders in Ashkenazi

Bloom SyndromeCanavan DiseaseCystic FibrosisFactor XI DeficiencyFamilial Dysautonomia (Riley-Day syndrome)Fanconi AnemiaGaucher DiseaseMucolipidosis IVNiemann-Pick DiseaseNon-Classical Adrenal HyperplasiaNonsyndromic Hearing LossTay-Sachs DiseaseTorsion Dystonia

Cancer Predisposition GenesCancer Predisposition Genes Breast Cancer (BRCA1 and BRCA2) Familial Colon Cancer

Clinical Issues and Clinical Issues and ScreeningScreening

Prevalence of BRCA Mutations Prevalence of BRCA Mutations and and CancereCancere

Only 5Only 5--10% of all breast and ovarian 10% of all breast and ovarian cancer are attributable to cancer are attributable to germlinegermlinemutationsmutationsHowever, 7% of breast and 10% of However, 7% of breast and 10% of ovarian cancers are hereditaryovarian cancers are hereditaryOnly 10Only 10--16% of these are associated with 16% of these are associated with other genetic causes(Liother genetic causes(Li--FraumeniFraumeni, Cowden , Cowden etc)etc)Much higher in the J ewish Ashkenazi Much higher in the J ewish Ashkenazi population population –– 2.5% carry the BRCA 2.5% carry the BRCA mutations.mutations.

Jewish AshkenaziJewish AshkenaziOne in 10 women with breast cancerOne in 10 women with breast cancerForty % of women with ovarian cancerForty % of women with ovarian cancerLife time breast cancer risk for those with Life time breast cancer risk for those with mutationmutation–– 85%85%Life time risk of ovarian cancer Life time risk of ovarian cancer –– 4040--50% 50% for BRCA I and 20% for BRCA I Ifor BRCA I and 20% for BRCA I IParity may increase risk; risk increases Parity may increase risk; risk increases with agewith ageUse of oral contraceptives may decrease Use of oral contraceptives may decrease riskrisk

Approach to a woman with BRCAApproach to a woman with BRCA

11 Do nothingDo nothing

2 2 SurveillanceSurveillance

3 3 ChemopreventionChemoprevention

44 Prophylactic mastectomyProphylactic mastectomy

55 Prophylactic Prophylactic oophorectomyoophorectomy

Founder MutationsFounder Mutations

Ashkenazi 6174 Ashkenazi 6174 delTdelT BRCA2BRCA2

Icelandic 999del5 Icelandic 999del5 BRCA2BRCA2

Dutch deletion in Dutch deletion in BRCA1BRCA1 in 27%in 27%

Spain: Sephardic Jews have common Spain: Sephardic Jews have common origin with Ashkenazim, butorigin with Ashkenazim, but……

SpanishSpanish BRCA1 BRCA1 330A>G (Galician)330A>G (Galician)

Ashkenazi Ashkenazi BRCABRCA Founder Founder MutationsMutations

2.5% overall population frequency2.5% overall population frequency Very few other familyVery few other family--specific mutationsspecific mutations 10.3% in 1,008 unselected breast cancer 10.3% in 1,008 unselected breast cancer

casescases 4.2% 185delAG, 2.5% 5382insC (4.2% 185delAG, 2.5% 5382insC (BRCA1BRCA1)) 3.7% 6174delT 3.7% 6174delT BRCA2BRCA2 Half from lowHalf from low--incidence families incidence families

Some concern that report is epidemiologically unsound, likely toSome concern that report is epidemiologically unsound, likely to result result in in penetrancepenetrance figures that are too highfigures that are too high

(M(M--C.King, Science 302; 2003)C.King, Science 302; 2003)

Ashkenazi Founder Ashkenazi Founder MutationsMutations

185delAG, 5382insC in 185delAG, 5382insC in BRCA1 BRCA1 and and 6174delT in 6174delT in BRCA2BRCA2, found in 1 in 40 , found in 1 in 40 Ashkenazi individualsAshkenazi individuals

Approximately 20% breast cancer Approximately 20% breast cancer accounted for by these mutationsaccounted for by these mutations

StruewingStruewing NEJM 336, 1997NEJM 336, 1997

5318 Jewish individuals; 120 founder 5318 Jewish individuals; 120 founder mutation carriersmutation carriers

By age 70y, estimated breast cancer risk By age 70y, estimated breast cancer risk 56%(4056%(40--73)73)

Ovarian cancer risk 16%; prostate Ovarian cancer risk 16%; prostate cancer risk 16%, no increase in cancer risk 16%, no increase in colorectal cancer riskcolorectal cancer risk

Similar risks for both Similar risks for both BRCA1 BRCA1 and and BRCA2BRCA2

Population Genetics due to Population Genetics due to mutations in mutations in BRCA1BRCA1 and and BRCA2BRCA2

Population genetics is the study of allele Population genetics is the study of allele frequencies in populations. frequencies in populations.

Breast cancer is very common. It has a strong Breast cancer is very common. It has a strong genetic component, affecting 1 in 10 women at genetic component, affecting 1 in 10 women at some point in her life. some point in her life.

Certain alleles are more common among certain Certain alleles are more common among certain ethnic groups.ethnic groups.–– BRCA1BRCA1 breast cancer affects 1 in 800 women in breast cancer affects 1 in 800 women in

the U.S. population. the U.S. population. –– However, among Jewish women of eastern However, among Jewish women of eastern

European descent, the risk increases to 1 in 100 European descent, the risk increases to 1 in 100 womenwomen**

Population Genetics (Cont.)Population Genetics (Cont.)

Other populationOther population--based epidemiological based epidemiological studies confirmed the high prevalence of the studies confirmed the high prevalence of the cancercancer--predisposing predisposing BRCA1BRCA1 allele among allele among Jewish women.Jewish women.

–– In general U.S. population, abnormal In general U.S. population, abnormal BRCA1BRCA1 genes account for about 4% of all genes account for about 4% of all breast cancer and 12% of all ovarian breast cancer and 12% of all ovarian cancers.cancers.

–– Among the Jewish women in the U.S., Among the Jewish women in the U.S., BRCA1 BRCA1 accounts for 16% of all breast accounts for 16% of all breast cancers and 39% of all ovarian cancer.cancers and 39% of all ovarian cancer.

Estimated Risk in BRCA Mutation Estimated Risk in BRCA Mutation Carriers – by Age 70Carriers – by Age 70

Breast Breast CancerCancer

36 – 36 – 85%85%

1/9 in general 1/9 in general populationpopulation

Ovarian Ovarian CancerCancer

10 – 10 – 44%44%

1/70 in general 1/70 in general populationpopulation

Prostate Prostate CancerCancer

8 – 16%8 – 16% 3/100 in general 3/100 in general populationpopulation

Males with BRCA MutationMales with BRCA Mutation

• Risk of breast cancer – 10%Risk of breast cancer – 10%

• BRCA II – increases prostate cancer riskBRCA II – increases prostate cancer risk

• May increase risk of colon cancerMay increase risk of colon cancer

• Hereditary non-polyposis colon cancer Hereditary non-polyposis colon cancer gene is also higher in the Ashkenazi gene is also higher in the Ashkenazi populationpopulation

• Can pass BRCA without being affected –Can pass BRCA without being affected –skip generationsskip generations

• Some correlation of BRCA with Fanconi Some correlation of BRCA with Fanconi anemiaanemia

Latvian PopulationLatvian Population

BRCA1 founders 4154delA and BRCA1 founders 4154delA and 5382insC5382insC

Found in 80% of Found in 80% of BRCA1 BRCA1 mutations mutations detecteddetected

Detected in 25% of breast cancer Detected in 25% of breast cancer cases diagnosed below 48y. agecases diagnosed below 48y. age

Non-Jewish Populatons Non-Jewish Populatons with BRCAwith BRCA

*Reducing the Risk of Breast *Reducing the Risk of Breast and Ovarian Cancers In High and Ovarian Cancers In High Risk PopulationsRisk Populations Increased Surveillance for Breast CancerIncreased Surveillance for Breast Cancer

–– Monthly breast selfMonthly breast self--exams starting between ages 18exams starting between ages 18--2121

–– Annual or semiannual clinical breast exams starting between Annual or semiannual clinical breast exams starting between ages 25ages 25--3535

–– Annual mammography starting between ages 25Annual mammography starting between ages 25--35.35.

Increased Surveillance for Ovarian CancerIncreased Surveillance for Ovarian Cancer

–– Annual or semiannual Annual or semiannual transvaginal ultrasound (TVU)transvaginal ultrasound (TVU) starting starting between ages 25between ages 25--3535

Preventive Drug Therapies for Breast CancerPreventive Drug Therapies for Breast Cancer

–– Preventive drug therapies may be implemented along with Preventive drug therapies may be implemented along with increased surveillance. Specifically, Tamoxifen has been proven increased surveillance. Specifically, Tamoxifen has been proven to cut in half the risk for women with to cut in half the risk for women with BRCABRCA mutations.mutations.

Cont. Cont.

Preventive Drug Therapies for Ovarian CancerPreventive Drug Therapies for Ovarian Cancer–– Oral contraceptives can reduce the chances of ovarian cancer in Oral contraceptives can reduce the chances of ovarian cancer in

women with women with BRCA BRCA mutations. mutations. –– Research has shown a risk reduction of up to 60 % in women Research has shown a risk reduction of up to 60 % in women

with with BRCA BRCA mutations who took oral contraceptives.mutations who took oral contraceptives.

Prophylactic MastectomyProphylactic Mastectomy–– reduce breast cancer risk by greater than 90 % in women with a reduce breast cancer risk by greater than 90 % in women with a

BRCA BRCA mutation or a family history of the disease.mutation or a family history of the disease.

Prophylactic OophorectomyProphylactic Oophorectomy–– reduce ovarian cancer risk by 96 % in women with a reduce ovarian cancer risk by 96 % in women with a BRCA BRCA

mutation. It is generally recommended after 35 years of age or mutation. It is generally recommended after 35 years of age or after childbearing is completed.after childbearing is completed.

Testing entire populationsTesting entire populations

TSD carrier testingTSD carrier testing Carrier frequency in the Ashkenazi (Eastern Carrier frequency in the Ashkenazi (Eastern

European) Jewish population estimated to be 1 in European) Jewish population estimated to be 1 in 25.25.

Various estimates of the carrier frequency in the Various estimates of the carrier frequency in the general population - between 1 in 167 and 1 in general population - between 1 in 167 and 1 in 400.400.

Biochemical carrier testing on leucocytes and Biochemical carrier testing on leucocytes and serum to detect reduced Hex A activity.serum to detect reduced Hex A activity.

Normal range: 62-79%. Carrier range: 35-61%Normal range: 62-79%. Carrier range: 35-61%

Occasionally results are inconclusive and Occasionally results are inconclusive and retesting is required.retesting is required.

Psychosocial implications Psychosocial implications No major adverse psychosocial effects have been found in the No major adverse psychosocial effects have been found in the

community but yes in some populations. Depends on how the community but yes in some populations. Depends on how the screening is done.screening is done.

Carriers experience short term shock and anxiety after receiving Carriers experience short term shock and anxiety after receiving resultresult

Most stressful for couples where already pregnant (a very Most stressful for couples where already pregnant (a very common situation!)common situation!)

Carriers do Carriers do notnot, on the whole, feel stigmatised, even if tested , on the whole, feel stigmatised, even if tested during adolescence.during adolescence.

Carriers’ choice of marriage partner is rarely affected (except in Carriers’ choice of marriage partner is rarely affected (except in the Strictly-Orthodox community). A big issue for shidduchimthe Strictly-Orthodox community). A big issue for shidduchim

Dor Yesharim programDor Yesharim program

Current issuesCurrent issues Community education – no systematic basis Community education – no systematic basis

for this. On-going problems with trying to for this. On-going problems with trying to ensure that people get the info they need at ensure that people get the info they need at the right time for screening.the right time for screening.

Financial burden on families who have Tay Financial burden on families who have Tay Sachs testing through the Dor Yesharim Sachs testing through the Dor Yesharim system.system.

Requires community acceptance and Requires community acceptance and rabbinic approvalrabbinic approval

Current issues cont…Current issues cont…

Gaucher’s disease (1 in 15) – treatment availableGaucher’s disease (1 in 15) – treatment available• Familial Dysautonomia (1 in 30)Familial Dysautonomia (1 in 30)• Canavans disease (1 in 40)Canavans disease (1 in 40)• ‘‘Jewish’ CF mutations (1 in 30)Jewish’ CF mutations (1 in 30)

Other “Jewish” DiseasesOther “Jewish” Diseases::• Torsion Dystomia/ Tourette’s SyndromeTorsion Dystomia/ Tourette’s Syndrome• Mucolipidosis IV (1 in 50)Mucolipidosis IV (1 in 50)• Fanconi Anaemia (1 in 80)Fanconi Anaemia (1 in 80)• Niemann-Pick (1 in 80)Niemann-Pick (1 in 80)• Blooms syndrome (1 in 100)Blooms syndrome (1 in 100)

• Higher in Jews:Higher in Jews:• Crohn’s diseaseCrohn’s disease• SchizophreniaSchizophrenia• Down Syndrome – older mothers in the Orthodox communityDown Syndrome – older mothers in the Orthodox community

Other genetic diseases

????????????????????????????????????????????????????????????• Should everyone be tested?Should everyone be tested?

• StigmatizationStigmatization

• Impact on community image and marital Impact on community image and marital practicespractices

• AbortionAbortion

• CounselingCounseling

• Do we screen if we do not know how to treatDo we screen if we do not know how to treat

• Community EducationCommunity Education

Human Genome ProjectHuman Genome Project

• Initiated 1990 Initiated 1990

• Completion originally planned for 2005Completion originally planned for 2005

• Anticipate completion prior to deadlineAnticipate completion prior to deadline

• ResultsResults– Complete sequencing of the Human Complete sequencing of the Human

GenomeGenome– New branch of science and medicine - New branch of science and medicine -

GenomicsGenomics

http://images.google.com/imgres?imgurl=http://www.humanbecoming.org/images/symbol.gif&imgrefurl=http://www.humanbecoming.org/&h=257&w=240&sz=22&tbnid=YcOfzojVincJ:&tbnh=106&tbnw=99&start=1&prev=/images%3Fq%3Dsymbol%26hl%3Den%26lr%3D%26ie%3DUTF-8

What Is a Genome?What Is a Genome?What Is a Genome?What Is a Genome?

• Genome: All of the DNA for an Genome: All of the DNA for an organismorganism

• Human GenomeHuman Genome– Nucleus: 3.2 billion base pairs Nucleus: 3.2 billion base pairs

packaged into chromosomes packaged into chromosomes – Mitochondrion: 16,600 base pairs Mitochondrion: 16,600 base pairs

packaged in one circular packaged in one circular chromosomechromosome

• Genome: All of the DNA for an Genome: All of the DNA for an organismorganism

• Human GenomeHuman Genome– Nucleus: 3.2 billion base pairs Nucleus: 3.2 billion base pairs

packaged into chromosomes packaged into chromosomes – Mitochondrion: 16,600 base pairs Mitochondrion: 16,600 base pairs

packaged in one circular packaged in one circular chromosomechromosome

Promise of thePromise of theHuman Genome ProjectHuman Genome ProjectPromise of thePromise of theHuman Genome ProjectHuman Genome Project

• Improved diagnosis and Improved diagnosis and treatment through the treatment through the application of genetic application of genetic information and technologiesinformation and technologies– Predictive medicinePredictive medicine– Individualized medical careIndividualized medical care– Population screeningPopulation screening

• Improved diagnosis and Improved diagnosis and treatment through the treatment through the application of genetic application of genetic information and technologiesinformation and technologies– Predictive medicinePredictive medicine– Individualized medical careIndividualized medical care– Population screeningPopulation screening

The Promise of Genomic The Promise of Genomic MedicineMedicineThe Promise of Genomic The Promise of Genomic MedicineMedicine

•Predictive rather than reactivePredictive rather than reactive

•Preventive rather than Preventive rather than responding only after acute responding only after acute presentationpresentation

•Screening of populations, sub-Screening of populations, sub-populations and individualspopulations and individuals

•PharmacogenomicsPharmacogenomics

•Predictive rather than reactivePredictive rather than reactive

•Preventive rather than Preventive rather than responding only after acute responding only after acute presentationpresentation

•Screening of populations, sub-Screening of populations, sub-populations and individualspopulations and individuals

•PharmacogenomicsPharmacogenomics

What’s So Different About Genetic What’s So Different About Genetic Testing for Cancer?Testing for Cancer?• PredictivePredictive

– UncertaintyUncertainty• Will the condition develop?Will the condition develop?

• When?When?

• How severe?How severe?

• Will interventions make a difference? – untestedWill interventions make a difference? – untested

• Direct implications for family membersDirect implications for family members– ““If you test positive for a gene then maybe If you test positive for a gene then maybe

that’s going to have a ripple effect that’s going to have a ripple effect throughout the whole genetic tree.”throughout the whole genetic tree.”

• Ethical, legal and social issuesEthical, legal and social issues

Public Interest in Genetic Public Interest in Genetic TestingTesting

• High, even among those at low riskHigh, even among those at low risk

• 2 surveys of women in general 2 surveys of women in general populationpopulation– 82-90% interested in testing for genetic 82-90% interested in testing for genetic

susceptibility to breast cancersusceptibility to breast cancer

Andrykowski 1997, Chaliki 1995Andrykowski 1997, Chaliki 1995

Motivation for Genetic Motivation for Genetic Susceptibility TestingSusceptibility Testing• Desire to reduce uncertainty about Desire to reduce uncertainty about

riskrisk• To learn about risk for offspringTo learn about risk for offspring• To learn about other associated risksTo learn about other associated risks• To explore further surveillance / To explore further surveillance /

treatment optionstreatment options• To make child-bearing and marital To make child-bearing and marital

decisionsdecisions• To participate in researchTo participate in research

• RisksRisks– Positive test resultPositive test result

• AnxietyAnxiety• DepressionDepression• GuiltGuilt• Family issuesFamily issues• Insurance/job discriminationInsurance/job discrimination• ConfidentialityConfidentiality• Impact on shidduchimImpact on shidduchim

– Negative test resultNegative test result• Survivor guiltSurvivor guilt• ComplacencyComplacency

– Uncertain test resultUncertain test result

Role of Discussion of Risks, Role of Discussion of Risks, Benefits and Limitations of Genetic Benefits and Limitations of Genetic TestingTesting

Future DirectionsFuture Directions

• Better Surveillance OptionsBetter Surveillance Options• Better Understanding of Better Understanding of

Transmission PatternsTransmission Patterns• Delineating how BRCA interacts with Delineating how BRCA interacts with

other tumor suppressive genesother tumor suppressive genes• ChemopreventionChemoprevention• Rational Design of Community Wide Rational Design of Community Wide

Screening ProgramsScreening Programs

““Never make Never make predictionspredictions…especially about …especially about the future.”the future.”

Samuel Samuel Goldwyn Sr.Goldwyn Sr.

Hollywood Hollywood producerproducer