Understanding Your Results

This Jewish disease panel is a very useful tool for confirming a disease diagnosis in an affected individual and identifying individuals that are asymptomatic carriers of a defective gene. A knowledge of carrier status for these diseases is especially important for people of Ashkenazi Jewish heritage due to the high frequency of carriers in these populations. If a Jewish couple choose to have children together, it is important that both parents are tested for these ten inherited diseases (along with cystic fibrosis).

Each of these ten diseases are inherited in an autosomal recessive pattern, which means that two defective copies of the disease-associated gene are required before disease symptoms occur. This means that both parents most have at least one defective copy of the same gene. If both parents are carriers of a specific disease-associated gene, there is a 25% chance that their child will inherit two defective copies and suffer from the disease. If one parent is a carrier and the other has two defective copies (and is affected by the disease), the risk for their children increases to 50%.

This knowledge of the risks provides the parents-to-be with the opportunity to test very early for the disease in their child. If the parents are undergoing in vitro fertilization, this test can be conducted preimplantation. Alternatively, the fetus can be screened during the early stages of the pregnancy by amniocentesis, allowing the parents to make the decision to terminate the pregnancy if a severe genetic disease is identified. Some inherited diseases (such as maple syrup urine disease) can be effectively managed if treatment begins before severe organ and tissue damage has occurred. In this situation, knowledge of a child’s disease status very early in life or prenatal, can enable that child to live a relatively normal life if a strict dietary regime is followed.

Bloom Syndrome

Normal A normal result means that the person has tested negative for the 2281del6/ins7 mutation in the BLM gene. This person will not pass a defective BLM gene to the next generation.

Carrier A carrier is an individual who has inherited one defective BLM gene and one normal wild type BLM gene. Carriers have a 50% chance of passing the defective gene to future generations but will not develop the disease themselves. If two carriers have children, there is a 25% chance that their children will be normal, a 50% chance that their children will also be carriers, and a 25% chance that their children will inherit two defective genes and be affected by Bloom syndrome.

Affected An affected individual is one who has inherited two copies of the defective BLM gene, one defective gene from each parent. People who have two defective BLM genes will suffer from the symptoms of Bloom syndrome, including poor growth, frequent infections, sun sensitivity and increased cancer risk at a young age. There is a 100% chance that an affected individual will pass the defective BLM gene to their children.

Canavan Disease

Normal A normal result means that the person has tested negative for the E285A, Y231X, IVS2-2A>G and A305E mutations in the ASPA gene. This person will not pass a defective ASPA gene to the next generation.

Carrier A carrier is an individual who has inherited one defective ASPA gene and one normal wild type ASPA gene. Carriers have a 50% chance of passing the defective gene to future generations but will not develop the disease themselves. If two carriers have children, there is a 25% chance that their children will be normal, a 50% chance that their children will also be carriers, and a 25% chance that their children will inherit two defective genes and be affected by Canavan disease.

Affected An affected individual is one who has inherited two copies of the defective ASPA gene, one defective gene from each parent. Affected individuals may be homozygotes (two identical defective ASPA genes) or compound heterozygotes (two defective ASPA genes with different mutations). People who have two defective ASPA genes will suffer from the symptoms of Canavan disease, including macrocephaly, lack of head control, developmental delays, delayed motor skills and an inability to sit, stand, walk or talk. There is a 100% chance that an affected individual will pass the defective ASPA gene to their children.

Familial Dysautonomia

Normal A normal result means that the person has tested negative for the IVS20+6T>C and R696P mutations in the IKBKAP gene. This person will not pass a defective IKBKAP gene to the next generation.

Carrier A carrier is an individual who has inherited one defective IKBKAP gene and one normal wild type IKBKAP gene. Carriers have a 50% chance of passing the defective gene to future generations but will not develop the disease themselves. If two carriers have children, there is a 25% chance that their children will be normal, a 50% chance that their children will also be carriers, and a 25% chance that their children will inherit two defective genes and be affected by familial dysautonomia.

Affected An affected individual is one who has inherited two copies of the defective IKBKAP gene, one defective gene from each parent. Affected individuals may be homozygotes (two identical defective IKBKAP genes) or compound heterozygotes (two defective IKBKAP genes with different mutations). People who have two defective IKBKAP genes will suffer from the symptoms of familial dysautonomia, including poor muscle tone, feeding problems, infections, difficulty maintaining a stable body temperature and an inability to feel pain. There is a 100% chance that an affected individual will pass the defective IKBKAP gene to their children.

Fanconi Anemia Group C

Normal A normal result means that the person has tested negative for the IVS4+4A>T and 322delG mutations in the FANCC gene. This person will not pass a defective FANCC gene to the next generation.

Carrier A carrier is an individual who has inherited one defective FANCC gene and one normal wild type FANCC gene. Carriers have a 50% chance of passing the defective gene to future generations but will not develop the disease themselves. If two carriers have children, there is a 25% chance that their children will be normal, a 50% chance that their children will also be carriers, and a 25% chance that their children will inherit two defective genes and be affected by Fanconi anemia group C.

Affected An affected individual is one who has inherited two copies of the defective FANCC gene, one defective gene from each parent. Affected individuals may be homozygotes (two identical defective FANCC genes) or compound heterozygotes (two defective FANCC genes with different mutations). People who have two defective FANCC genes will suffer from the symptoms of Fanconi anemia group C, including physical abnormalities, organ defects, bone marrow failure and an increased risk of certain cancers. There is a 100% chance that an affected individual will pass the defective FANCC gene to their children.

Gaucher Disease

Normal A normal result means that the person has tested negative for the L444P, N370S, 84insG, IVS2+1G>A, V394L, D409H, delta55bp and R496H mutations in the GBA gene. This person will not pass a defective GBA gene to the next generation.

Carrier A carrier is an individual who has inherited one defective GBA gene and one normal wild type GBA gene. Carriers have a 50% chance of passing the defective gene to future generations but will not develop the disease themselves. If two carriers have children, there is a 25% chance that their children will be normal, a 50% chance that their children will also be carriers, and a 25% chance that their children will inherit two defective genes and be affected by Gaucher disease.

Affected An affected individual is one who has inherited two copies of the defective GBA gene, one defective gene from each parent. Affected individuals may be homozygotes (two identical defective GBA genes) or compound heterozygotes (two defective GBA genes with different mutations). People who have two defective GBA genes will suffer from the symptoms of Gaucher disease, including bruising, fatigue, anemia, low blood platelets, and enlargement of the liver and spleen. There is a 100% chance that an affected individual will pass the defective GBA gene to their children.

Glycogen Storage Disease Type IA

Normal A normal result means that the person has tested negative for the R83C and Q347X mutations in the G6PC gene. This person will not pass a defective G6PC gene to the next generation.

Carrier A carrier is an individual who has inherited one defective G6PC gene and one normal wild type G6PC gene. Carriers have a 50% chance of passing the defective gene to future generations but will not develop the disease themselves. If two carriers have children, there is a 25% chance that their children will be normal, a 50% chance that their children will also be carriers, and a 25% chance that their children will inherit two defective genes and be affected by glycogen storage disease type 1A.

Affected An affected individual is one who has inherited two copies of the defective G6PC gene, one defective gene from each parent. Affected individuals may be homozygotes (two identical defective G6PC genes) or compound heterozygotes (two defective G6PC genes with different mutations). People who have two defective G6PC genes will suffer from the organ and tissue damage caused by an accumulation of fat and glycogen in people suffering from glycogen storage disease type IA. There is a 100% chance that an affected individual will pass the defective G6PC gene to their children.

Maple Syrup Urine Disease

Normal A normal result means that the person has tested negative for the Y438N mutation in the BCKDHA gene and the R183P, G278S and E372X mutations in the BCKDHB gene. This person will not pass a defective BCKDHA or BCKDHB gene to the next generation.

Carrier A carrier of maple syrup urine disease type 1A is an individual who has inherited one defective BCKDHA gene and one normal wild type BCKDHA gene. A carrier of maple syrup urine disease type 1B is an individual who has inherited one defective BCKDHB gene and one normal wild type BCKDHB gene. Carriers have a 50% chance of passing the defective gene to future generations but will not develop the disease themselves. If two carriers have children, there is a 25% chance that their children will be normal, a 50% chance that their children will also be carriers, and a 25% chance that their children will inherit two defective genes and be affected by maple syrup urine disease.

Affected An affected individual is one who has inherited two copies of the defective BCKDHA gene (maple syrup urine disease type 1A) or two copies of the defective BCKDHB gene (maple syrup urine disease type 1B). People who have two defective BCKDHA genes or two defective BCKDHB genes will be unable to metabolize certain amino acids (the basic building blocks of proteins) and these build up to toxic levels causing organ and tissue damage. There is a 100% chance that an affected individual will pass the defective gene to their children.

Mucolipidosis Type IV

Normal A normal result means that the person has tested negative for the delta6.4kb and IVS3-2A>G mutations in the MCOLN1 gene. This person will not pass a defective MCOLN1 gene to the next generation.

Carrier A carrier is an individual who has inherited one defective MCOLN1 gene and one normal wild type MCOLN1 gene. Carriers have a 50% chance of passing the defective gene to future generations but will not develop the disease themselves. If two carriers have children, there is a 25% chance that their children will be normal, a 50% chance that their children will also be carriers, and a 25% chance that their children will inherit two defective genes and be affected by mucolipidosis type IV.

Affected An affected individual is one who has inherited two copies of the defective MCOLN1 gene, one defective gene from each parent. Affected individuals may be homozygotes (two identical defective MCOLN1 genes) or compound heterozygotes (two defective MCOLN1 genes with different mutations). People who have two defective MCOLN1 genes will suffer from the symptoms of mucolipidosis type IV, including severe developmental delay and progressive vision problems. There is a 100% chance that an affected individual will pass the defective MCOLN1 gene to their children.

Niemann-Pick Disease Type A and B

Normal A normal result means that the person has tested negative for the R496L, L302P, fsp330 and delta608 mutations in the SMPD1 gene. This person will not pass a defective SMPD1 gene to the next generation.

Carrier A carrier is an individual who has inherited one defective SMPD1 gene and one normal wild type SMPD1 gene. Carriers have a 50% chance of passing the defective gene to future generations but will not develop the disease themselves. If two carriers have children, there is a 25% chance that their children will be normal, a 50% chance that their children will also be carriers, and a 25% chance that their children will inherit two defective genes and be affected by Niemann-Pick disease.

Affected An affected individual is one who has inherited two copies of the defective SMPD1 gene, one defective gene from each parent. The less severe type B version of Niemann-Pick disease occurs if both defective copies carry the delta608 mutation. The other three mutations (R496L, L302P and fsp330) cause Niemann-Pick disease type A. Individuals affected by type A disease may be homozygotes (two identical defective SMPD1 genes) or compound heterozygotes (two defective SMPD1 genes with different mutations). People who have two defective SMPD1 genes will have an accumulation of fat in cells, resulting in cell death, which impairs the function of tissues and organs, including the brain, lungs, spleen and liver. There is a 100% chance that an affected individual will pass the defective SMPD1 gene to their children.

Tay-Sachs Disease

Normal A normal result means that the person has tested negative for the 1278insTATC, IVS12+1G>C, IVS9+1G>A, delta7.6kb and G269S mutations in the HEXA gene. This person will not pass a defective HEXA gene to the next generation.

Carrier A carrier is an individual who has inherited one defective HEXA gene and one normal wild type HEXA gene. Carriers have a 50% chance of passing the defective gene to future generations but will not develop the disease themselves. If two carriers have children, there is a 25% chance that their children will be normal, a 50% chance that their children will also be carriers, and a 25% chance that their children will inherit two defective genes and be affected by Tay-Sachs disease.

Affected An affected individual is one who has inherited two copies of the defective HEXA gene, one defective gene from each parent. The severe, infantile Tay-Sachs disease occurs if both copies of the HEXA gene carry one (or more) of the four null mutations (1278insTATC, IVS12+1G>C, IVS9+1G>A and delta7.6kb). Individuals can inherit two identical mutations (homozygotes) or two different null mutations (compound heterozygotes). These null mutations prevent the production of any functional beta-hexosaminidase A and individuals will suffer from early-onset, rapid neurodegeneration and death at a young age.

If both copies of the HEXA gene have the G269S mutation (homozygote) or one copy has the G269S mutation and one copy has a null mutation (compound heterozygote), the less severe, adult-onset form of Tay-Sachs disease is more likely to occur. The G269S mutation still allows some residual beta-hexosaminidase A activity, (approximately 15% of normal), and affected individuals show a variety of symptoms with a later-onset and slower progression of disease.

Pseudodeficiency Mutations The last two mutations (R249W and R247W) in the Jewish disease panel are called pseudodeficiency mutations. These two mutations do not cause any reduction in functional beta-hexosaminidase A and do not cause any disease symptoms. They are included in this panel, as they show reduced activity against the artificial substrate used during beta-hexosaminidase A enzyme assays (a common diagnostic tool for Tay-Sachs disease). However, these alleles do not show reduced activity against the natural substrate (GM2 ganglioside). Individuals who carry one or more of these mutations are not at increased risk of Tay-Sachs disease. Although they can still pass these mutations to the next generation, it will not increase the risk of Tay-Sachs disease in their children.

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