Clinical Information

Certain genetic diseases are more common in individuals of Ashkenazi Jewish heritage (Jewish individuals of Eastern European ancestry) compared to the non-Jewish population. The majority of these conditions are inherited in an autosomal recessive manner. This group of diseases includes Gaucher, Tay-Sachs, familial dysautonomia, Canavan, mucolipidosis IV, Niemann-Pick Type A and B, FANCC-related Fanconi anemia, and Bloom syndrome. While these conditions are observed outside of the Ashkenazi Jewish population, they occur at a lower frequency. It is estimated that an individual of Ashkenazi Jewish ancestry has a 20% to 25% chance of being a carrier of 1 of these diseases.

Gaucher Disease:

Gaucher disease is a relatively rare lysosomal storage disorder resulting from a deficiency of acid beta-glucocerebrosidase. Mutations in the beta-glucocerebrosidase gene, GBA, cause the clinical manifestations of Gaucher disease. There are 3 major types of Gaucher disease: nonneuropathic (type 1), acute neuropathic (type 2), and subacute neuropathic (type 3). Type 1 accounts for over 95% of all cases of Gaucher disease and is the presentation commonly found among Ashkenazi Jewish patients. Type 1 disease does not involve nervous system dysfunction; patients display anemia, low blood platelet levels, massively enlarged livers and spleens, lung infiltration, and extensive skeletal disease. There is a broad spectrum of disease in type 1, with some patients exhibiting severe symptoms and others very mild disease. Types 2 and 3 are associated with neurological disease of variable onset and progression, though type 2 tends to be more severe. Eight common GBA mutations, including the N370S mutation most commonly found in the Ashkenazi Jewish population, are included in this test: delta55bp, V394L, N370S, IVS2+1G->A, 84G->GG, R496H, L444P, and D409H.

Tay-Sachs:

Tay-Sachs disease is caused by an absence of hexosaminidase (HexA) enzyme activity, which results in the accumulation of the sphingolipid GM2 ganglioside. Mutations in the HEXA gene cause the clinical manifestations of Tay-Sachs disease (TSD). The most common form of TSD becomes apparent in infancy when mild motor weakness is noted along with impaired visual acuity and the presence of a "startle response." Other manifestations of this condition include progressive neurodegeneration, seizures, and blindness, leading to total incapacitation and death. This panel tests for the 3 common mutations in the Ashkenazi Jewish population: 1278insTATC, G269S, and IVS12+1G->C. Also included in this assay are the mutations IVS9+1G->A and delta7.6kb mutations along with the R247W and R249W polymorphisms associated with pseudodeficiency.

Familial Dysautonomia:

Familial dysautonomia affects sensory, parasympathetic, and sympathetic neurons. Patients experience gastrointestinal dysfunction, pneumonia, vomiting episodes, altered sensitivity to pain and temperature, and cardiovascular problems. Progressive neuronal degeneration continues throughout the lifespan. Mutations in the IKBKAP gene cause the clinical manifestations of familial dysautonomia. Two mutations in the IKBKAP gene are common in the Ashkenazi Jewish population: IVS20(+6)T->C and R696P.

Canavan Disease:

Canavan disease is a severe leukodystrophy resulting from a deficiency of the enzyme aspartoacylase. Mutations in the ASPA gene cause the clinical manifestations of Canavan disease. The deficiency of aspartoacylase leads to spongy degeneration of the brain, and the disease is characterized by delayed development beginning at age 3 to 6 months, head lag, macrocephaly, and hypotonia. Death usually occurs in the first decade of life. Four ASPA mutations are included in this test: 433(-2)A->G, A305E, E285A, and Y231X.

Mucolipidosis IV:

Mucolipidosis IV is a lysosomal storage disease characterized by mental retardation, hypotonia, corneal clouding, and retinal degeneration. Mutations in the MCOLN1 gene are responsible for the clinical manifestations of mucolipidosis IV. Two mutations in the MCOLN1 gene account for the majority of mutations in the Ashkenazi Jewish population: IVS3(-2)A->G and delta6.4kb.

Niemann-Pick Disease Types A and B:

Niemann-Pick disease (types A and B) is a lysosomal storage disease caused by a deficiency of the enzyme acid sphingomyelinase. The clinical presentation of type A disease is characterized by jaundice, progressive loss of motor skills, feeding difficulties, learning disabilities, and hepatosplenomegaly. Death usually occurs by age 3. Type B disease is milder, though variable in its clinical presentation. Most individuals with type B do not have neurologic involvement and survive to adulthood. Mutations in the SMPD1 gene are known to cause Niemann-Pick disease types A and B. There are 3 common mutations causing Niemann-Pick type A in the Ashkenazi Jewish population: L302P, R496L, and fsP330. The deltaR608 mutation accounts for approximately 90% of the type B mutant alleles in individuals from the Maghreb region of North Africa and 100% of the mutation alleles in Gran Canaria Island.

Fanconi Anemia:

Fanconi anemia is an aplastic anemia that leads to bone marrow failure and myelodysplasia or acute myelogenous leukemia. Physical findings include short stature; upper limb, lower limb, and skeletal malformations; and abnormalities of the eyes and genitourinary tract. Mutations in several genes have been associated with Fanconi anemia, although 1 mutation, IVS4(+4)A->T, in the FANCC gene is common in the Ashkenazi Jewish population. A second mutation, 322delG, is over represented in FANCC patients of Northern European ancestry.

Bloom Syndrome:

Bloom syndrome is characterized by short stature, sun sensitivity, susceptibility to infections, and a predisposition to cancer. Mutations in the BLM gene lead to genetic instability (increased chromosomal breakage and sister chromatid exchange) and cause the clinical manifestations of Bloom syndrome. The protein encoded by the BLM gene is a helicase involved in maintaining DNA integrity. There is a common mutation in the Ashkenazi Jewish population: 2281delATCTGAinsTAGATTC (2281del6/ins7).

Because of the high sensitivity of carrier testing in the Ashkenazi Jewish population, the American College of Medical Genetics and Genomics (ACMG) recommends that carrier screening for cystic fibrosis, Canavan, Tay-Sachs, familial dysautonomia, Niemann-Pick type A, Fanconi anemia (FANCC), Bloom syndrome, mucolipidosis IV, and Gaucher disease be offered to individuals of Ashkenazi Jewish ancestry. The mutation detection rates and carrier frequencies for the diseases included in this panel are listed below. Of note, testing for cystic fibrosis is not included in this panel. If testing for this disorder is desired, please see details and ordering information under CFP / Cystic Fibrosis Mutation Analysis, 106-Mutation Panel.

The Ashkenazi Jewish panel is useful for identifying carriers of these 8 conditions in an at-risk population. Because the diseases included in the panel are inherited in an autosomal recessive manner, the presence of a family history is not a prerequisite for testing consideration. The identification of disease-causing mutations allows for carrier testing of at-risk family members and prenatal diagnosis for pregnancies in which both parents are known carriers. Refer to Carrier Testing for Tay-Sachs Disease and Other GM2 Gangliosidosis Variants: Supplementing Traditional Biochemical Testing with Molecular Methods, Mayo Medical Laboratories Communique 2004 Jul;29(7) for more information regarding diagnostic strategy.

Of note, approximately 1 in 25 individuals of Ashkenazi Jewish ancestry are also carriers of cystic fibrosis (CF). Therefore, the American College of Medical Genetics also recommends that carrier screening for CF be offered to individuals of Ashkenazi Jewish ancestry who are pregnant or considering pregnancy. Carrier screening for CF is available by ordering CFP / Cystic Fibrosis Mutation Analysis, 106-Mutation Panel.