Medical genetics of Jews

The medical genetics of Jews is the study, screening, and treatment of genetic disorders more common in particular Jewish populations than in the population as a whole.[1] The genetics of Ashkenazi Jews have been particularly well-studied, resulting in the discovery of many genetic disorders associated with this ethnic group. In contrast, the medical genetics of Sephardic Jews and Mizrahi Jews are more complicated, since they are more genetically diverse and consequently no genetic disorders are more common in these groups as a whole; instead, they tend to have the genetic diseases common in their various countries of origin.[1][2] Several organizations, such as Dor Yeshorim,[3] offer screening for Ashkenazi genetic diseases, and these screening programs have had a significant impact, in particular by reducing the number of cases of Tay–Sachs disease.[4]

Genetics of Jewish populations

Different ethnic groups tend to suffer from different rates of hereditary diseases, with some being more common, and some less common. Hereditary diseases, particularly hemophilia, were recognized early in Jewish history, even being described in the Talmud.[5] However, the scientific study of hereditary disease in Jewish populations was initially hindered by scientific racism, which is based on racial supremacism.[6][7]

However, modern studies on the genetics of particular ethnic groups have the tightly defined purpose of avoiding the birth of children with genetic diseases, or identifying people at particular risk of developing a disease in the future.[6] Consequently, the Jewish community has been very supportive of modern genetic testing programs, although this unusually high degree of cooperation has raised concerns that it might lead to the false perception that Jews are more susceptible to genetic diseases than other groups of people.[5]

However, most populations contain hundreds of alleles that could potentially cause disease and most people are heterozygotes for one or two recessive alleles that would be lethal in a homozygote.[8] Although the overall frequency of disease-causing alleles does not vary much between populations, the practice of consanguineous marriage (marriage between second cousins or closer relatives) is common in some Jewish communities, which produces a small increase in the number of children with congenital defects.[9]

According to Daphna Birenbaum Carmeli at the University of Haifa, Jewish populations have been studied more thoroughly than most other human populations because:[10]

The result is a form of ascertainment bias. This has sometimes created an impression that Jews are more susceptible to genetic disease than other populations. Carmeli writes, "Jews are over-represented in human genetic literature, particularly in mutation-related contexts."[10] Another factor that may aid genetic research in this community is that Jewish culture results in excellent medical care, which is coupled to a strong interest in the community's history and demography.[11]

This set of advantages have led to Ashkenazi Jews in particular being used in many genetic studies, not just in the study of genetic diseases. For example, a series of publications on Ashkenazi centenarians established their longevity was strongly inherited and associated with lower rates of age-related diseases.[12] This "healthy aging" phenotype may be due to higher levels of telomerase in these individuals.[13]

Ashkenazi diseases

The most detailed genetic analysis study of Ashkenazi was published in September 2014 by Shai Carmon and his team at Columbia University. The results of the detailed study show that today's 10 million Ashkenazi Jews descend from a population of only 350 individuals who lived about 600-800 years ago. That population derived from both Europe and the Middle East. [14]There is evidence that the population bottleneck may have allowed deleterious alleles to become more prevalent in the population due to genetic drift.[15] As a result, this group has been particularly intensively studied, so many mutations have been identified as common in Ashkenazis.[16] Of these diseases, many also occur in other Jewish groups and in non-Jewish populations, although the specific mutation which causes the disease may vary between populations. For example, two different mutations in the glucocerebrosidase gene causes Gaucher's disease in Ashkenazis, which is their most common genetic disease, but only one of these mutations is found in non-Jewish groups.[4] A few diseases are unique to this group; for example, familial dysautonomia is almost unknown in other populations.[4]

Genetic disorders common in Ashkenazi Jews[1]
Disease Mode of inheritance Gene Carrier frequency
 Favism X-linked G6PD
 Bloom syndrome Autosomal recessive BLM 1/100
 Breast cancer and ovarian cancer Autosomal dominant BRCA1 or BRCA2 1/100 and 1/75, respectively
 Canavan disease Autosomal recessive ASPA 1/60
 Congenital deafness Autosomal recessive GJB2 or GJB6 1/25
 Cystic fibrosis Autosomal recessive CFTR 1/25
 Haemophilia C Autosomal recessive F11 1/12
 Familial dysautonomia Autosomal recessive IKBKAP 1/30
 Familial hypercholesterolemia Autosomal dominant LDLR 1/69
 Familial hyperinsulinism Autosomal recessive ABCC8 1/125–1/160
 Fanconi anemia C Autosomal recessive FACC 1/100
 Gaucher disease Autosomal recessive GBA 1/7–1/18
 Glycogen Storage Disease type 1a Autosomal recessive G6PC 1/71
 Mucolipidosis IV Autosomal recessive MCOLN1 1/110
 Niemann–Pick (type A) Autosomal recessive SMPD1 1/90
 Nonclassical 21 OHase deficiency Autosomal recessive CPY21 1/6
 Parkinson's disease Autosomal dominant LRRK2 1/42[17]
 Tay–Sachs Autosomal recessive HEXA 1/25–1/30
 Torsion dystonia Autosomal dominant DYT1 1/4000
 Usher syndrome Autosomal recessive PCDH15 1/72

Tay–Sachs disease

Tay–Sachs disease, which can present as a fatal illness of children that causes mental deterioration prior to death, was historically more prevalent among Ashkenazi Jews,[18] although high levels of the disease are also found in some Pennsylvania Dutch, southern Louisiana Cajun, and eastern Quebec French Canadian populations.[19] Since the 1970s, however, proactive genetic testing has been quite effective in eliminating Tay–Sachs from the Ashkenazi Jewish population.[20]

Lipid transport diseases

Gaucher's disease, in which lipids accumulate in inappropriate locations, occurs most frequently among Ashkenazi Jews;[21] the mutation is carried by roughly one in every 15 Ashkenazi Jews, compared to one in 100 of the general American population.[22] Gaucher's disease can cause brain damage and seizures, but these effects are not usually present in the form manifested among Ashkenazi Jews; while sufferers still bruise easily, and it can still potentially rupture the spleen, it generally has only a minor impact on life expectancy.

Ashkenazi Jews are also highly affected by other lysosomal storage diseases, particularly in the form of lipid storage disorders. Compared to other ethnic groups, they more frequently act as carriers of mucolipidosis[23] and Niemann–Pick disease,[24] the latter of which can prove fatal.

The occurrence of several lysosomal storage disorders in the same population suggests the alleles responsible might have conferred some selective advantage in the past.[25] This would be similar to the hemoglobin allele which is responsible for sickle-cell disease, but solely in people with two copies; those with just one copy of the allele have a sickle cell trait and gain partial immunity to malaria as a result. This effect is called heterozygote advantage.[26]

Some of these disorders may have become common in this population due to selection for high levels of intelligence (see Ashkenazi intelligence).[27][28] However, other research suggests no difference is found between the frequency of this group of diseases and other genetic diseases in Ashkenazis, which is evidence against any specific selectivity towards lysosomal disorders.[29]

Familial dysautonomia

Familial dysautonomia (Riley–Day syndrome), which causes vomiting, speech problems, an inability to cry, and false sensory perception, is almost exclusive to Ashkenazi Jews;[30] Ashkenazi Jews are almost 100 times more likely to carry the disease than anyone else.[31]

Other Ashkenazi diseases and disorders

Diseases inherited in an autosomal recessive pattern often occur in endogamous populations. Among Ashkenazi Jews, a higher incidence of specific genetic disorders and hereditary diseases have been verified, including:

Non-Ashkenazi disorders

In contrast to the Ashkenazi population, Sephardic and Mizrahi Jews are much more divergent groups, with ancestors from Spain, Portugal, Morocco, Tunisia, Algeria, Italy, Libya, the Balkans, Iran, Iraq, India, and Yemen, with specific genetic disorders found in each regional group, or even in specific subpopulations in these regions.[1]

Genetic disorders common in Sephardic and Mizrahi Jews[1]
Disease Mode of inheritance Gene or enzyme Carrier frequency Populations
 Oculocutaneous albinism Autosomal recessive TYR 1/30 Morocco
 Ataxia telangiectasia Autosomal recessive ATM 1/80 Morocco, Tunisia
 Creutzfeldt–Jakob disease Autosomal dominant PRNP 1/24,000 Libya
 Cerebrotendinous xanthomatosis Autosomal recessive CYP27A1 1/70 Morocco
 Cystinuria Autosomal recessive SLC7A9 1/25 Libya
 Familial Mediterranean fever Autosomal recessive MEFV 1/5–7 Libya, Morocco, Tunisia
 Glycogen storage disease III Autosomal recessive AGL 1/35 Morocco
 Limb girdle muscular dystrophy Autosomal recessive DYSF 1/10 Libya
 Tay–Sachs Autosomal recessive HEXA 1/110 Morocco
 11-β-hydroxylase deficiency Autosomal recessive CYP11B1 1/30–1/128 Morocco
Genetic disorders common in Mizrahi Jews[1]
Disease Mode of inheritance Gene or enzyme Carrier frequency Populations
 Beta-thalassemia Autosomal recessive HBB 1/6 Iran, Iraq, Kurdistan
 Factor VII deficiency Autosomal recessive F7 1/40 Iran
 Familial Mediterranean fever Autosomal recessive MEFV 1/5–1/7 Iraq, Iran, Armenia, North African Jews, Ashkenazi
 Glucose-6-phosphate dehydrogenase deficiency X-linked G6PD 1/4 Iraq, esp. Kurdistan
 Inclusion body myopathy Autosomal recessive GNE 1/12 Iran
 Metachromatic leukodystrophy Autosomal recessive ARSA 1/50 Yemen
 Oculopharyngeal muscular dystrophy Autosomal, recessive or dominant PABPN1 1/7 Bukhara
 Phenylketonuria Autosomal recessive PAH 1/35 Yemen

Genetic testing in Jewish populations

One of the first genetic testing programs to identify heterozygote carriers of a genetic disorder was a program aimed at eliminating Tay–Sachs disease. This program began in 1970, and over one million people have now been screened for the mutation.[47] Identifying carriers and counseling couples on reproductive options have had a large impact on the incidence of the disease, with a decrease from 40–50 per year worldwide to only four or five per year.[4] Screening programs now test for several genetic disorders in Jews, although these focus on the Ashkenazi Jews, since other Jewish groups cannot be given a single set of tests for a common set of disorders.[2] In the USA, these screening programs have been widely accepted by the Ashkenazi community, and have greatly reduced the frequency of the disorders.[48]

Prenatal testing for several genetic diseases is offered as commercial panels for Ashkenazi couples by both CIGNA and Quest Diagnostics. The CIGNA panel is available for testing for parental/preconception screening or following chorionic villus sampling or amniocentesis and tests for Bloom syndrome, Canavan disease, cystic fibrosis, familial dysautonomia, Fanconi anemia, Gaucher disease, mucolipidosis IV, Neimann-Pick disease type A, Tay-Sachs disease, and torsion dystonia. The Quest panel is for parental/preconception testing and tests for Bloom syndrome, Canavan disease, cystic fibrosis, familial dysautonomia, Fanconi anemia group C, Gaucher disease, Neimann-Pick disease types A and B and Tay-Sachs disease.

The official recommendations of the American College of Obstetricians and Gynecologists is that Ashkenazi individuals be offered screening for Tay Sachs, Canavan, cystic fibrosis, and familial dysautonomia as part of routine obstetrical care.[49]

In the orthodox community, an organization called Dor Yeshorim carries out anonymous genetic screening of couples before marriage to reduce the risk of children with genetic diseases being born.[50] The program educates young people on medical genetics and screens school-aged children for any disease genes. These results are then entered into an anonymous database, identified only by a unique ID number given to the person who was tested. If two people are considering getting married, they call the organization and tell them their ID numbers. The organization then tells them if they are genetically compatible. It is not divulged if one member is a carrier, so as to protect the carrier and his or her family from stigmatization.[50] However, this program has been criticized for exerting social pressure on people to be tested, and for screening for a broad range of recessive genes, including disorders such as Gaucher's disease.[3]

See also

Related:

References

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  2. 1 2 Talia Bloch (August 21, 2009). "Sephardi Jews lack screening programs for their genetic diseases". Haaretz.
  3. 1 2 Gina Kolata (December 7, 1993). "Nightmare or the Dream Of a New Era in Genetics?". New York Times.
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  5. 1 2 Levin M (1999). "Screening Jews and genes: a consideration of the ethics of genetic screening within the Jewish community: challenges and responses". Genet. Test. 3 (2): 207–13. doi:10.1089/gte.1999.3.207. PMID 10464669.
  6. 1 2 Abel 2001, p. 7
  7. ↑ Bachrach S (July 2004). "In the name of public health—Nazi racial hygiene". N. Engl. J. Med. 351 (5): 417–20. doi:10.1056/NEJMp048136. PMID 15282346.
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  9. ↑ Paul DB, Spencer HG (December 2008). Keller, Evelyn Fox, ed. ""It's Ok, We're Not Cousins by Blood": The Cousin Marriage Controversy in Historical Perspective". PLoS Biol. 6 (12): 2627–30. doi:10.1371/journal.pbio.0060320. PMC 2605922. PMID 19108607.
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  13. ↑ Atzmon G, Cho M, Cawthon RM, et al. (November 2009). "Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians". Proc. Natl. Acad. Sci. U.S.A. 107 Suppl 1 (suppl_1): 1710–7. doi:10.1073/pnas.0906191106. PMC 2868292. PMID 19915151.
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  16. ↑ Nicholas Wade (March 4, 2003). "Diseases Common in Ashkenazim May Be Random". New York Times.
  17. ↑ Orr-Urtreger A, Shifrin C, Rozovski U, et al. (October 2007). "The LRRK2 G2019S mutation in Ashkenazi Jews with Parkinson disease: is there a gender effect?". Neurology 69 (16): 1595–602. doi:10.1212/01.wnl.0000277637.33328.d8. PMID 17938369.
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  21. ↑ Diaz GA, Gelb BD, Risch N, et al. (2000). "Gaucher disease: the origins of the Ashkenazi Jewish N370S and 84GG acid beta-glucosidase mutations". Am. J. Hum. Genet. 66 (6): 1821–32. doi:10.1086/302946. PMC 1378046. PMID 10777718.'
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  23. ↑ "Mount Sinai – Center for Jewish Genetic Diseases – Department of Human Genetics".
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  26. ↑ Harpending H, Cochran G (March 2006). "Genetic diversity and genetic burden in humans". Infect. Genet. Evol. 6 (2): 154–62. doi:10.1016/j.meegid.2005.04.002. PMID 16246638.
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  30. ↑ Ashkenazi Disorders: Mendelian – Familial dysautonomia: from The Chicago Center for Jewish Genetic Disorders
  31. ↑ about one in 30 Ashkenazi Jews carry the disease, compared to 1 in 3000 of the general population
  32. ↑ Ashkenazi Jews and Colorectal Cancer: from The Chicago Center for Jewish Genetic Disorders
  33. ↑ Ashkenazi Disorders: Mendelian – Non-Classical Adrenal Hyperplasia
  34. ↑ Shalimar, A.; Sharaf, I.; Farah Wahida, I.; Ruszymah, B. H. (2007). "Congenital insensitivity to pain with anhydrosis in a Malaysian family: A genetic analysis" (PDF). Journal of Orthopaedic Surgery (Hong Kong) 15 (3): 357–360. PMID 18162686. Type III is familial dysautonomia or Riley–Day syndrome. It is multisystemic and affects mainly Ashkenazi Jews.
  35. ↑ "Large multicenter study suggests new genetic markers for Crohn's disease: Results shed light on special genetic vulnerabilities of Ashkenazi Jews"
  36. ↑ Weissmann, A.; Linn, S.; Weltfriend, S.; Friedman-Birnbaum, R. (2000). "Epidemiological study of classic Kaposi's sarcoma: A retrospective review of 125 cases from Northern Israel". Journal of the European Academy of Dermatology and Venereology 14 (2): 91–95. doi:10.1046/j.1468-3083.2000.00022.x. PMID 10972092.
  37. ↑ Ashkenazi Jewish Diseases: Tufts Medical Center
  38. ↑ Ashkenazi Disorders: Mendelian – Mucolipidosis IV: from The Chicago Center for Jewish Genetic Disorders
  39. ↑ Ashkenazi Disorders: Mendelian – Nonsyndromic Hearing Loss and Deafness, DFNB1 (Connexin 26): from The Chicago Center for Jewish Genetic Disorders
  40. ↑ Bonifati, V. (2006). "Parkinson's Disease: The LRRK2-G2019S mutation: Opening a novel era in Parkinson's disease genetics". European Journal of Human Genetics 14 (10): 1061–1062. doi:10.1038/sj.ejhg.5201695. PMID 16835587.
  41. ↑ Lesage, S.; Patin, E.; Condroyer, C.; Leutenegger, A. L.; Lohmann, E.; Giladi, N.; Bar-Shira, A.; Belarbi, S.; et al. (2010). "Parkinson's disease-related LRRK2 G2019S mutation results from independent mutational events in humans". Human Molecular Genetics 19 (10): 1998–2004. doi:10.1093/hmg/ddq081. PMID 20197411.
  42. ↑ Zimprich, A.; Biskup, S.; Leitner, P.; Lichtner, P.; Farrer, M.; Lincoln, S.; Kachergus, J.; Hulihan, M.; et al. (2004). "Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology". Neuron 44 (4): 601–607. doi:10.1016/j.neuron.2004.11.005. PMID 15541309. We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8)...
  43. ↑ Klein J, Sato A (September 2000). "The HLA system. Second of two parts". The New England Journal of Medicine 343 (11): 782–786. doi:10.1056/NEJM200009143431106. PMID 10984567.
  44. ↑ http://www.haaretz.com/israel-news/.premium-1.560128
  45. ↑ Glycogen Storage Disease Type Ia Mutation Analysis (Ashkenazi Jewish)"
  46. ↑ Ahn, J. K.; Lev, D.; Leshinsky-Silver, E.; Ginzberg, M.; Lerman-Sagie, T. (15 June 2003). "A new autosomal recessive syndrome with Zellweger-like manifestations". American Journal of Medical Genetics 119A (3): 352–355. doi:10.1002/ajmg.a.20124. PMID 12784304. A son and daughter of consanguineous Ashkenazi Jewish parents presented with phenotypic features that are typically seen in Zellweger syndrome...
  47. ↑ Kaback MM (December 2000). "Population-based genetic screening for reproductive counseling: the Tay–Sachs disease model". Eur. J. Pediatr. 159 (Suppl 3): S192–5. doi:10.1007/PL00014401. PMID 11216898.
  48. ↑ Kronn D, Jansen V, Ostrer H (April 1998). "Carrier screening for cystic fibrosis, Gaucher disease, and Tay–Sachs disease in the Ashkenazi Jewish population: the first 1000 cases at New York University Medical Center, New York, NY". Arch. Intern. Med. 158 (7): 777–81. doi:10.1001/archinte.158.7.777. PMID 9554684.
  49. ↑ ACOG committee on genetics (October 2009). "ACOG Committee Opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent". Obstet. Gynecol. 114 (4): 950–3. doi:10.1097/AOG.0b013e3181bd12f4. PMID 19888064.
  50. 1 2 Ekstein J, Katzenstein H (2001). "The Dor Yeshorim story: community-based carrier screening for Tay-Sachs disease". Adv. Genet. Advances in Genetics 44: 297–310. doi:10.1016/S0065-2660(01)44087-9. ISBN 978-0-12-017644-1. PMID 11596991.

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