Genetic Diseases in Jews

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GENETIC DISEASES IN JEWS

The abnormal genes and dna sequences underlying most inherited genetic diseases in Jews have been identified. This progress has helped to understand the nature of these diseases, to increase the prospects for treatment, to facilitate genetic counseling, and to elucidate the population genetics underlying the segregation of these diseases in Jewish communities. Classically, genetic disorders are classified according to their mode of inheritance. Individuals inheriting one abnormal dominant gene or two abnormal recessive genes develop disease. In contrast, individuals who inherit one copy of a recessive gene do not develop disease but are carriers at risk of transmitting the disease. However, progress has revealed further complexities. Diseases formerly attributed to a single abnormal gene are often associated with different or multiple abnormal genes. There is also an imperfect correlation between inheriting an abnormal gene and the clinical features and severity of the resulting disease. Increased recognition of mild forms of classical disease has forced a reevaluation of disease prevalence in Jewish as in other populations. Furthermore, although mutation in identifiable genes is responsible for most genetic diseases, interaction with other genes and with environmental factors often determines disease susceptibility and expression.

Genetic diseases with a high prevalence in Jews are mostly recessive. In general, over 1,000 recessive diseases have been discovered. Most are rare but the prevalence of some of these diseases is increased 100-fold or more in Jewish as in other isolated ethnic groups with predominant inbreeding. This increased prevalence is usually but not invariably confined to individual Jewish ethnic groups ("edot Israel") and not found in Jews in general. Most are severe and often lead to early death. In some diseases genetic analysis has identified the first appearance of an abnormal "founder" gene originating in a small number of individuals within a Jewish group. This creates a genetic bottleneck whereby the prevalence of a recessive genetic disease is maintained at a high level by subsequent inbreeding.

These principles and the practical issues are illustrated by examples of the most common genetic diseases. Ashkenazim are a relatively homogeneous group despite their settlement in different European countries for centuries. The high prevalence of some 20 "Ashkenazi diseases" in this group dates from founder effects and bottlenecks in the era after 75 c.e. and between 1100 and 1400 c.e. The most common of these diseases are the neurodegenerative Tay-Sachs disease and Gaucher type i disease, which has more widespread clinical features. These "lysosomal storage" diseases result from enzyme deficiencies. Familial dysautonomia affects peripheral nerves and predominantly affects certain Ashkenazi groups. The carrier rate in Ashkenazim in Israel of Polish descent is 1 in 18 compared with 1 in 99 in those of non-Polish descent.

Ashkenazi women with a family history of breast cancer are at increased risk of developing this disease, especially of early onset, due to the high (2.5%) prevalence of brca1 and brca2 gene mutations in this population. They also have a high incidence of ovarian cancer of which a large percentage, estimated at up to 41%, are attributable to "founder" mutations in these genes. Approximately 1 in 25 Ashkenazim are carriers for one of these disorders, resulting in the birth of one affected child in approximately every 3,000 Ashkenazi live births for each condition. Screening is essential at least in those with a family history. The gene mutations responsible for other less common diseases with a high prevalence in the Ashkenazi population have also been identified allowing accurate diagnosis in at risk families. Prevention programs have already reduced the number of affected children born to these families by over 90%.

In contrast, genetic analysis in cystic fibrosis is more problematical. This disorder has many clinical features in addition to the characteristic lung and pancreatic involvement. There is a high carrier rate (1 in 23) in Ashkenazi Jews but it is similar in the general northern European population. Over 900 genetic abnormalities have been associated with cystic fibrosis and there is a poor correlation between these abnormalities and disease features and severity.

Sephardi Jews are genetically much more heterogeneous than Ashkenazi Jews and genetic diseases in high prevalence in Sephardi communities reflect their country of origin such as Iraq, Yemen, and Morocco. Some genetic disorders characteristic of the Mediterranean region are relatively common in all Sephardi and in non-Jewish communities, marking constant migration. Genetic screening for the abnormal hemoglobin responsible for thalassemia is well established. Familial Mediterranean fever (fmf) is an intermittent febrile illness, often difficult to diagnose. Five variants of abnormal sequence have been detected in the defective gene associated with fmf which give important insights into disease severity and its occurrence in different communities. However, genetic analysis has not solved the diagnostic problems. See also *Sickness.