Medical genetics of Jews

The medical genetics of Jews have been studied to identify and prevent some rare genetic diseases that, while still rare, are more common than average among people of Jewish descent. There are several autosomal recessive genetic disorders that are more common than average in ethnically Jewish populations, particularly Ashkenazi Jews. This is due to population bottlenecks that occurred relatively recently in the past as well as a practice of consanguineous marriage (marriage of second cousins or closer).[1] These two phenomena lead to a decrease in genetic diversity and a higher likelihood that two parents will carry a mutation in the same gene and pass on both mutations to a child.

The genetics of Ashkenazi Jews have been particularly well-studied, as the phenomenon affects them the most. This has resulted in the discovery of many genetic disorders associated with this ethnic group.[2] 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.[2][3]

Several organizations, such as Dor Yeshorim,[4] 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.[5]

History and purpose

Different ethnic groups tend to have 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.[6] However, the scientific study of hereditary disease in Jewish populations was initially hindered by scientific racism, which was based on racial supremacism.[7][8]

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.[7] Consequently, some members of the Jewish community have been very supportive of modern genetic testing programs; this high level of cooperation has raised concerns that conclusions may lead to stigmatization of the Jewish community.[6]

Genetics of Jewish populations

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.[9] 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) has been common in some Jewish communities, which produces a small increase in the number of children with congenital defects.[1]

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

  • Jewish populations, and particularly the large Ashkenazi Jewish population, are ideal for such research studies, because they exhibit a high degree of endogamy, and at the same time are a large group.
  • Jewish populations are overwhelmingly urban and are concentrated near biomedical centers where such research has been carried out.

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]

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.[11] This "healthy aging" phenotype may be due to higher levels of telomerase in these individuals.[12]

Ashkenazi diseases

Due to their historical endogamy over the centuries, today's 10 million Ashkenazi Jews can trace their ancestry to members of a population of only 350 individuals who lived about 600–800 years ago.[13] That population derived from both Europe and the Middle East. There is evidence that the population bottleneck may have allowed deleterious alleles to become more prevalent in the population due to genetic drift.[14] As a result, this group has been particularly intensively studied, and many mutations have been identified as common in Ashkenazim.[15] 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 cause Gaucher's disease in Ashkenazim, which is that group's most common genetic disease, but only one of these mutations is found in non-Jewish groups.[5] A few diseases are unique to this group; for example, familial dysautonomia is almost unknown in other populations.[5]

Genetic disorders common in Ashkenazi Jews[2]
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[16]
 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 extremely common among Ashkenazi Jews,[17] with lower levels of the disease in some Pennsylvania Dutch, Italian, Irish Catholic, and French Canadian descent, especially those living in the Cajun community of Louisiana and the southeastern Quebec.[18] Since the 1970s, however, proactive genetic testing has been quite effective in eliminating Tay–Sachs from the Ashkenazi Jewish population.[19]

Lipid transport diseases

Gaucher's disease, in which lipids accumulate in inappropriate locations, occurs most frequently among Ashkenazi Jews;[20] the mutation is carried by roughly one in every 15 Ashkenazi Jews, compared to one in 100 of the general American population.[21] Gaucher's disease can cause brain damage and seizures, but these effects are not usually present in the form manifested among Ashkenazi Jews; while those affected 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[22] and Niemann–Pick disease,[23] 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.[24] 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.[25]

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;[26] Ashkenazi Jews are almost 100 times more likely to carry the disease than anyone else.[27]

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 has been verified, including:

Sephardi and Mizrahi diseases

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.[2]

Genetic disorders common in Sephardic Jews[2]
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 All MENA (Middle Eastern and North African countries).
 Glycogen storage disease III Autosomal recessive AGL 1/35 Morocco, North Africa
 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 (Oriental) Jews[2]
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, but heterozygous carriers also can show clinical manifestations. MEFV 1/5–1/7 Iraq, Iran, Armenia, North African Jews, Ashkenazi[46]
 Glucose-6-phosphate dehydrogenase deficiency X-linked G6PD 1/4 Iraq, esp. Kurdistan, Syria and all MENA countries. Female heterozygotes can also show clinical symptoms due to lyonization (X-inactivation) especially during pregnancy.[47]
 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.[48] Identifying carriers and counseling couples on reproductive options have had a large impact on the incidence of the disease, with a decrease from 40 to 50 per year worldwide to only four or five per year.[5] 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.[3] In the US, these screening programs have been widely accepted by the Ashkenazi community, and have greatly reduced the frequency of the disorders.[49]

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 disease, Canavan disease, cystic fibrosis, and familial dysautonomia as part of routine obstetrical care.[50]

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.[51] 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.[51] 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 disease.[4]

See also

References
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