Test ID: AJPWO
Ashkenazi Jewish Mutation Analysis Panel Without Cystic Fibrosis (CF)

Carrier screening in individuals of Ashkenazi Jewish ancestry for Bloom syndrome, Canavan disease, FANCC-related Fanconi anemia, familial dysautonomia, Gaucher disease, mucolipidosis IV, Niemann-Pick disease types A and B, and Tay-Sachs disease

Panel includes the following disorders Bloom syndrome, Canavan disease, FANCC related Fanconi anemia, familial dysautonomia, Gaucher disease, mucolipidosis IV, Niemann-Pick disease types A and B, and Tay-Sachs disease. Specific detection rates for the Ashkenazi Jewish population are provided. (ACD/yellow-top tube only)

When this test is ordered, hexosaminidase A and total, white blood cells will always be performed at an additional charge.

See Tay-Sachs Disease Carrier Testing Protocol in Special Instructions

• Molecular Genetics-Biochemical Disorders Patient Information Sheet
• Informed Consent for Genetic Testing
• Tay-Sachs Disease Carrier Testing Protocol

AJPWO/88887: Polymerase chain reaction (PCR) analysis is used to test for mutations associated with 8 disorders prevalent in the Ashkenazi Jewish population.
(PCR is utilized pursuant to a license agreement with Roche Molecular Systems, Inc.)
23425: Heat Inactivation, Fluorometric, Semiautomated

Specimen must arrive within 72 hours of draw.

Specimen Type: Whole blood

Container/Tube:

Preferred: Yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 2 full tubes

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tubes.

Additional Information: A patient education brochure (Supply T561) is available upon request.

Forms:

1. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (Supply T576) is available in Special Instructions.

2. Molecular Genetics-Biochemical Disorders Patient Information Sheet (Supply T527) in Special Instructions

3. If not ordering electronically, submit a Molecular Genetics Request Form (Supply T245) with the specimen.

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 CFPB 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 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 CFPB/9497 Cystic Fibrosis Mutation Analysis, 106-Mutation Panel.

An interpretive report will be provided.

An interpretive report will be provided.

This assay will not detect all of the mutations that cause these 8 diseases. Therefore, the absence of a detectable mutation(s) does not rule out the possibility that an individual is a carrier of or affected with 1 or more of the listed diseases.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.

In rare cases, DNA alterations of undetermined significance may be identified.

A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.

Gross SJ, Pletcher BA, Monaghan KG: Carrier screening individuals of Ashkenazi Jewish descent. Genet Med 2008:10(1):54-56

A laboratory-developed multiplex PCR-based assay is used to detect the following mutations: 84G->GG, IVS2(+1)G->A, N370S, delta55bp, V394L, D409H, L444P, and R496H mutations in the GBA gene (Gaucher disease); delta7.6kb, R247W, R249W, G269S IVS9(+1)G->A, 1278insTATC, and IVS12(+1)G->C mutations in the HEXA gene (Tay-Sachs disease); 433(-2)A->G, E285A, Y231X (C->A & C->T), and A305E mutations in the ASPA gene (Canavan disease); R696P and IVS20(+6)T->C mutations in the IKBKAP gene (familial dysautonomia); 2281del6/ins7 mutation in the BLM gene (Bloom syndrome); 322delG and IVS4(+4)A->T mutations in the FANCC gene (Fanconi anemia); L302P, fsP330, R496L, and deltaR608 mutations in the SMPD1 gene (Niemann-Pick disease types A and B); and delta6.4kb and IVS3(-2)A->G mutations in the MCOLN1 gene (mucolipidosis type IV). (Fulton R, McDade R, Smith P, et al: Advanced multiplexed analysis with the FlowMetrix system. Clin Chem 1997;43:1749-1756; Ye F, Li MS, Taylor JD, et al: Fluorescent microsphere-based readout technology for multiplexed human single nucleotide polymorphism analysis and bacterial identification. Hum Mutat 2001 Apr;17[4]:305-316)

Tuesday; 10 a.m.

81200  ASPA aspartoacylase (eg, Cnavan disease) gene analysis, common variants (eg, E285A, Y231X)

81330  SMPD1 (sphingomyelin phosphodiesterase 1, acid sysosomal) (eg, Niemann-Pick disease, Type A) gene analysis, common variants (eg, R496L, L302P, fsP330)

81290  MCOLN1 (mucolipin 1) (eg. Mucolipidosis, type IV) gene analysis, common variants (eg, IVS3-2A>G, del6.4kb)

81260  IKBKAP (inhibitor of kappa light polypeptide gene enhance in B-cells, kinase complex-associated protein) (eg. Familial dysautonomia) gene analysis common variants (eg, 2507_6T>C, R696P

81255  HEXA (hexosaminidase A (alpha polypeptide) (eg. Tay-Sachs disease) gene analysis, common variants (eg, 1278insTATC, 1421+1G>C, G269S)

81251  GBA (glucosidase, beta acid) (eg. Gaucher disease) gene analysis, common variants (eg, N370S, 84GG, L444P, IVS2+1G>A)

81242  FANCC (Fanconi anemia, complementation group C) (eg, Fanconi anemia, type C) gene analysi, common variant (eg IVS4+4A>T)

81209  BLM (Bloom syndrome, Rec! helicase-like) (eg, Bloom syndrome) gene analysis, 2281 del6ins7 variant