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, because of relatively recent population bottlenecks and because of consanguineous marriage (marriage of second cousins or closer). [1] These two phenomena reduce genetic diversity and raise the chance 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, because the phenomenon affects them the most. This has resulted in the discovery of many genetic disorders associated with this ethnic group. [2] The medical genetics of Sephardic Jews and Mizrahi Jews are more complicated, because they are genetically more diverse, and therefore 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 programs have done much, particularly by reducing the instance of Tay–Sachs disease. [5]
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] [ better source needed ] [8] [ better source needed ]
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]
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]
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]
Because of centuries of endogamy, today's 10 million Ashkenazi Jews descend from a population of 350 who lived about 600–800 years ago. [13] [14] That population derived from both Europe and the Middle East. Some evidence shows that the population bottleneck may have allowed deleterious alleles to increase in the population by genetic drift. [15]
This group has therefore been particularly intensively studied, and many mutations have been found to be common in Ashkenazim. [16] Of these diseases, many also occur in other Jewish groups and in non-Jewish populations, although the specific mutation that causes the disease may vary among populations. For example, two mutations in the glucocerebrosidase gene each 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; familial dysautonomia, for example, is almost unknown in other peoples. [5]
| Disease | Subspecialty | Mode of inheritance | Gene | Carrier frequency |
|---|---|---|---|---|
| Favism | Medical genetics | X-linked | G6PD | |
| Bloom syndrome | Medical genetics | Autosomal recessive | BLM | 1/100 |
| Breast cancer and ovarian cancer | Oncology | Autosomal dominant | BRCA1 or BRCA2 | 1/100 and 1/75, respectively |
| Canavan disease | Endocrinology, neurology | Autosomal recessive | ASPA | 1/60 |
| Congenital deafness | Neurology, otorhinolaryngology, audiology | Autosomal recessive | GJB2 or GJB6 | 1/25 |
| Cystic fibrosis | Pulmonology, hepatology | Autosomal recessive | CFTR | 1/25 |
| Haemophilia C | Hematology | Autosomal recessive | F11 | 1/12 |
| Familial dysautonomia | Neurology | Autosomal recessive | IKBKAP | 1/30 |
| Familial hypercholesterolemia | Endocrinology, chemical pathology | Autosomal dominant | LDLR | 1/69 |
| Familial hyperinsulinism | Gastroenterology, endocrinology, pediatrics | Autosomal recessive | ABCC8 | 1/125–1/160 |
| Fanconi anemia C | Hematology | Autosomal recessive | FACC | 1/100 |
| Gaucher disease | Endocrinology, neurology | Autosomal recessive | GBA | 1/7–1/18 |
| Glycogen Storage Disease type 1a | Endocrinology, hematology, immunology | Autosomal recessive | G6PC | 1/71 |
| Mucolipidosis IV | Endocrinology | Autosomal recessive | MCOLN1 | 1/110 |
| Niemann–Pick (type A) | Medical genetics | Autosomal recessive | SMPD1 | 1/90 |
| Nonclassical 21 OHase deficiency | Endocrinology | Autosomal recessive | CPY21 | 1/6 |
| Parkinson's disease | Neurology | Autosomal dominant | LRRK2 | 1/42 [17] |
| Tay–Sachs | Medical genetics | Autosomal recessive | HEXA | 1/25–1/30 |
| Torsion dystonia | Neurology | Autosomal dominant | DYT1 | 1/4000 |
| Usher syndrome | Ophthalmology | Autosomal recessive | PCDH15 | 1/72 |
| Warsaw breakage syndrome | Medical genetics, pediatrics | Autosomal recessive | DDX11 | 1/50 [18] |
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, [19] 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. [20] Since the 1970s, however, proactive genetic testing has been quite effective in eliminating Tay–Sachs from the Ashkenazi Jewish population. [21]
Gaucher's disease, in which lipids accumulate in inappropriate locations, occurs most frequently among Ashkenazi Jews; [22] the mutation is carried by roughly one in every 15 Ashkenazi Jews, compared to one in 100 of the general American population. [23] 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 [24] and Niemann–Pick disease, [25] 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. [26] 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. [27]
Familial dysautonomia (Riley–Day syndrome), which causes vomiting, speech problems, an inability to cry, and false sensory perception, is almost exclusive to Ashkenazi Jews; [28] Ashkenazi Jews are almost 100 times more likely to carry the disease than anyone else. [29]
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:
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, Kurdistan, Turkey, India, and Yemen, with specific genetic disorders found in each regional group, or even in specific subpopulations in these regions. [2]
| Disease | Mode of inheritance | Gene or enzyme | Carrier frequency | Populations | |
|---|---|---|---|---|---|
| Oculocutaneous albinism | Ophthalmology, dermatology | Autosomal recessive | TYR | 1/30 | Morocco |
| Ataxia–telangiectasia | Neurology, medical genetics | Autosomal recessive | ATM | 1/80 | Morocco, Tunisia |
| Creutzfeldt–Jakob disease | Neurology | Autosomal dominant | PRNP | 1/24,000 | Libya |
| Cerebrotendinous xanthomatosis | Medical genetics, endocrinology | Autosomal recessive | CYP27A1 | 1/70 | Morocco |
| Cystinuria | Endocrinology | Autosomal recessive | SLC7A9 | 1/25 | Libya |
| Familial Mediterranean fever | Rheumatology, immunology | Autosomal recessive | MEFV | 1/5–7 | All MENA (Middle Eastern and North African countries). |
| Glycogen storage disease III | Endocrinology | Autosomal recessive | AGL | 1/35 | Morocco, North Africa |
| Limb girdle muscular dystrophy | Neurology | Autosomal recessive | DYSF | 1/10 | Libya |
| Tay–Sachs disease | Neurology | Autosomal recessive | HEXA | 1/110 | Morocco |
| 11-β-hydroxylase deficiency | Endocrinology | Autosomal recessive | CYP11B1 | 1/30–1/128 | Morocco |
| Disease | Mode of inheritance | Gene or enzyme | Carrier frequency | Populations | |
|---|---|---|---|---|---|
| Beta-thalassemia | Hematology | Autosomal recessive | HBB | 1/6 | Iran, Kurdistan, Syria |
| Factor VII deficiency | Hematology, medical genetics | Autosomal recessive | F7 | 1/40 | Iran |
| Familial Mediterranean fever | Rheumatology, immunology | Autosomal recessive, but heterozygous carriers also can show clinical manifestations. | MEFV | 1/5–1/7 | Iran, Kurdistan, Armenia, Azerbaijan, North African Jews, Ashkenazi [49] |
| Glucose-6-phosphate dehydrogenase deficiency | Medical genetics | X-linked | G6PD | 1/4 | Iran, esp. Kurdistan, Syria and all MENA countries. Female heterozygotes can also show clinical symptoms due to lyonization (X-inactivation) especially during pregnancy. [50] |
| Inclusion body myopathy | Neurology | Autosomal recessive | GNE | 1/12 | Iran |
| Metachromatic leukodystrophy | Endocrinology, neurology | Autosomal recessive | ARSA | 1/50 | Yemen |
| Oculopharyngeal muscular dystrophy | Neurology | Autosomal, recessive or dominant | PABPN1 | 1/7 | Bukhara |
| Phenylketonuria | Medical genetics, pediatrics, dietetics | Autosomal recessive | PAH | 1/35 | Yemen |
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. [51] 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. [52]
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. [53]
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. [54] 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. [54] 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]
Hebrew University Professor Raphael Falk published a criticism of studies identifying genetic disorders as being the result of hereditary endogamy. [55]
Dr. Sherry Brandt-Rauf of the University of Illinois and Sheila Rothman of Columbia University co-authored a critique of the methodologies as well as condemning those who worked on the eugenic studies which attributed genetic disorders to religious demographics in paper which explored the ramifications of such concepts entering the workplace stating, "such linkages 'exaggerate genetic differences among ethnic groups' and may result in 'health disparities' in groups not targeted for screening. [56] There has been a tendency to consider Tay-Sachs an exclusively "Jewish" genetic disorder and, as a result of this bias, non-Jewish children with Tay-Sachs may not initially have their disease properly diagnosed and non-Jewish heterozygous carriers may not be aware that they still could carry one of its genetic variants. In a peer-reviewed medical study, a team of researchers from 23andMe, one of whom (Noura Abul-Husn) is an Associate Professor of Medicine and Genetics at the Icahn School of Medicine at Mount Sinai, criticized guidelines and policies that restrict Tay-Sachs genetic screening to Jews, French Canadians, and Cajuns. [57] This team found that 59.4 percent of their data pool of 22,681 participants who carry one Tay-Sachs-causing variant on one side of their pair of relevant chromosomes "did not self-report [a] qualifying ethnicity" (one of the three aforementioned populations). [57] They also found that 51.3 percent of participants who carry one Ashkenazi-associated pathogenic variant for 15 different diseases had less than 20 percent Ashkenazi autosomal admixture as calculated by 23andMe. They concluded that restrictive testing "leads to the under detection of heterozygotes and associated reproductive risk" of having a child with a serious disease. [57]
Tay–Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord. The most common form is infantile Tay–Sachs disease, which becomes apparent around the age of three to six months of age, with the baby losing the ability to turn over, sit, or crawl. This is then followed by seizures, hearing loss, and inability to move, with death usually occurring by the age of three to five. Less commonly, the disease may occur later in childhood, adolescence, or adulthood. These forms tend to be less severe, but the juvenile form typically results in death by age 15.
Dor Yeshorim also called Committee for Prevention of Jewish Genetic Diseases, is a nonprofit organization that offers genetic screening to members of the Jewish community worldwide. Its objective is to minimize, and eventually eliminate, the incidence of genetic disorders common to Jewish people, such as Tay–Sachs disease. Dor Yeshorim is based in Brooklyn, New York, but has offices in Israel and various other countries.
Gaucher's disease or Gaucher disease (GD) is a genetic disorder in which glucocerebroside accumulates in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low blood platelet count and enlargement of the liver and spleen, and is caused by a hereditary deficiency of the enzyme glucocerebrosidase, which acts on glucocerebroside. When the enzyme is defective, glucocerebroside accumulates, particularly in white blood cells and especially in macrophages. Glucocerebroside can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow.
Lysosomal storage diseases are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective due to a mutation, the large molecules accumulate within the cell, eventually killing it.
Familial dysautonomia (FD), also known as Riley–Day syndrome, is a rare, progressive, recessive genetic disorder of the autonomic nervous system that affects the development and survival of sensory, sympathetic, and some parasympathetic neurons in the autonomic and sensory nervous system.
Sandhoff disease is a lysosomal genetic, lipid storage disorder caused by the inherited deficiency to create functional beta-hexosaminidases A and B. These catabolic enzymes are needed to degrade the neuronal membrane components, ganglioside GM2, its derivative GA2, the glycolipid globoside in visceral tissues, and some oligosaccharides. Accumulation of these metabolites leads to a progressive destruction of the central nervous system and eventually to death. The rare autosomal recessive neurodegenerative disorder is clinically almost indistinguishable from Tay–Sachs disease, another genetic disorder that disrupts beta-hexosaminidases A and S. There are three subsets of Sandhoff disease based on when first symptoms appear: classic infantile, juvenile and adult late onset.
GM2-gangliosidosis, AB variant is a rare, autosomal recessive metabolic disorder that causes progressive destruction of nerve cells in the brain and spinal cord. It has a similar pathology to Sandhoff disease and Tay–Sachs disease. The three diseases are classified together as the GM2 gangliosidoses, because each disease represents a distinct molecular point of failure in the activation of the same enzyme, beta-hexosaminidase. AB variant is caused by a failure in the gene that makes an enzyme cofactor for beta-hexosaminidase, called the GM2 activator.
IKBKAP is a human gene encoding the IKAP protein, which is ubiquitously expressed at varying levels in all tissue types, including brain cells. The IKAP protein is thought to participate as a sub-unit in the assembly of a six-protein putative human holo-Elongator complex, which allows for transcriptional elongation by RNA polymerase II. Further evidence has implicated the IKAP protein as being critical in neuronal development, and directs that decreased expression of IKAP in certain cell types is the molecular basis for the severe, neurodevelopmental disorder familial dysautonomia. Other pathways that have been connected to IKAP protein function in a variety of organisms include tRNA modification, cell motility, and cytosolic stress signalling. Homologs of the IKBKAP gene have been identified in multiple other Eukaryotic model organisms. Notable homologs include Elp1 in yeast, Ikbkap in mice, and D-elp1 in fruit flies. The fruit fly homolog (D-elp1) has RNA-dependent RNA polymerase activity and is involved in RNA interference.
Sphingolipidoses are a class of lipid storage disorders or degenerative storage disorders caused by deficiency of an enzyme that is required for the catabolism of lipids that contain ceramide, also relating to sphingolipid metabolism. The main members of this group are Niemann–Pick disease, Fabry disease, Krabbe disease, Gaucher disease, Tay–Sachs disease and metachromatic leukodystrophy. They are generally inherited in an autosomal recessive fashion, but notably Fabry disease is X-linked recessive. Taken together, sphingolipidoses have an incidence of approximately 1 in 10,000, but substantially more in certain populations such as Ashkenazi Jews. Enzyme replacement therapy is available to treat mainly Fabry disease and Gaucher disease, and people with these types of sphingolipidoses may live well into adulthood. The other types are generally fatal by age 1 to 5 years for infantile forms, but progression may be mild for juvenile- or adult-onset forms.
The GM2 gangliosidoses are a group of three related genetic disorders that result from a deficiency of the enzyme beta-hexosaminidase. This enzyme catalyzes the biodegradation of fatty acid derivatives known as gangliosides. The diseases are better known by their individual names: Tay–Sachs disease, AB variant, and Sandhoff disease.
Mucolipidosis type IV is an autosomal recessive lysosomal storage disorder. Individuals with the disorder have many symptoms including delayed psychomotor development and various ocular aberrations. The disorder is caused by mutations in the MCOLN1 gene, which encodes a non-selective cation channel, mucolipin1. These mutations disrupt cellular functions and lead to a neurodevelopmental disorder through an unknown mechanism. Researchers dispute the physiological role of the protein product and which ion it transports.
In medical genetics, compound heterozygosity is the condition of having two or more heterogeneous recessive alleles at a particular locus that can cause genetic disease in a heterozygous state; that is, an organism is a compound heterozygote when it has two recessive alleles for the same gene, but with those two alleles being different from each other. Compound heterozygosity reflects the diversity of the mutation base for many autosomal recessive genetic disorders; mutations in most disease-causing genes have arisen many times. This means that many cases of disease arise in individuals who have two unrelated alleles, who technically are heterozygotes, but both the alleles are defective.
Reproductive compensation was originally a theory to explain why recessive genetic disorders may persist in a population. It was proposed in 1967 as an explanation for the maintenance of Rh negative blood groups. Reproductive compensation refers to the tendency of parents, seeking a given family size, to replace offspring that are lost to genetic disorders. It may also refer to the effects of increased maternal or parental investment in caring for disadvantaged offspring, seeking to compensate for genetic disadvantage. It is a theory that suggests that behavioral as well as physiological factors may play a role in the level of recessive genetic disorders in a population.
A pseudodeficiency allele or pseudodeficiency mutation is a mutation that alters the protein product or changes the gene's expression, but without causing disease. For example, in the lysosomal storage diseases, patients with a pseudodeficiency allele show greatly reduced enzyme activity, yet they remain clinically healthy.
The Program for Jewish Genetic Health is a centralized resource for the Jewish community, addressing all health concerns related to the medical genetics of the Jewish people. The Program's stated mission is to protect the health of the current Jewish community and its future generations. Launched in 2011, the Program for Jewish Genetic Health integrates the social mission they Montefiore Health System with the clinical services, genetic education, and biomedical advances of its medical school, the Albert Einstein College of Medicine.
For preventing Tay–Sachs disease, three main approaches have been used to prevent or reduce the incidence of Tay–Sachs disease in those who are at high risk:
The history of Tay–Sachs disease started with the development and acceptance of the evolution theory of disease in the 1860s and 1870s, the possibility that science could explain and even prevent or cure illness prompted medical doctors to undertake more precise description and diagnosis of disease. Waren Tay and Bernard Sachs, two physicians of the late 19th century described the progression of the disease precisely and provided differential diagnostic criteria to distinguish it from other neurological disorders with similar symptoms.
Advances in knowledge about Tay–Sachs disease have stimulated debate about the proper scope of genetic testing, and the accuracy of characterizing diseases as specific to one ethnicity. Jewish communities have been in the forefront of genetic screening and counseling for this disease.
A hereditary cancer syndrome is a genetic disorder in which inherited genetic mutations in one or more genes predispose the affected individuals to the development of cancer and may also cause early onset of these cancers. Hereditary cancer syndromes often show not only a high lifetime risk of developing cancer, but also the development of multiple independent primary tumors.
Genetic studies on Arabs refers to the analyses of the genetics of ethnic Arab people in the Middle East and North Africa. Arabs are genetically diverse as a result of their intermarriage and mixing with indigenous people of the pre-Islamic Middle East and North Africa following the Arab and Islamic expansion. Genetic ancestry components related to the Arabian Peninsula display an increasing frequency pattern from west to east over North Africa. A similar frequency pattern exist across northeastern Africa with decreasing genetic affinities to groups of the Arabian Peninsula along the Nile river valley across Sudan and the more they go south. This genetic cline of admixture is dated to the time of Arab expansion and immigration to North Africa (Maghreb) and northeast Africa.
Type III is familial dysautonomia or Riley–Day syndrome. It is multisystemic and affects mainly Ashkenazi Jews.
We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8)...
A son and daughter of consanguineous Ashkenazi Jewish parents presented with phenotypic features that are typically seen in Zellweger syndrome...
