SickKids

Paediatric Laboratory Medicine
Paediatric Laboratory Medicine
print        

Ashkenazi Jewish Screening Panel

Background
Who should be tested?
Testing Methodology
Potential Outcomes Interpretation of Test Results
Cautions
For More Information

Background

The Ashkenazi Jewish screening panel currently consists of testing for seven diseases common in the Ashkenazi Jewish population: Bloom syndrome (BLM), Canavan disease (CVN), Familial dysautonomia (FD), Fanconi anemia group C (FA-C), mucolipidosis type IV (MLP4), Niemann Pick disease type A & B (NP) and Tay-Sachs (TSD) disease. Although these conditions have been reported in individuals of various ethnic backgrounds, these diseases occur most frequently in people of Ashkenazi Jewish ancestry. These conditions present when a child receives two copies of an altered gene, one from each parent. Any person with one copy of an altered gene is a carrier of that disease. Carriers are not affected themselves and will not develop the disease. However, if their partner is also a carrier for the same disease, there is a one in four chance (25%) that their baby will be born with the disease condition. There is a three in four chance (75%) that their baby will not have the disease condition.

Bloom syndrome (BLM) is characterized by short stature, sun-sensitive facial erythema, and immunodeficiency. Individuals with BLM are at increased risk for the development of cancer and diabetes. BLM is an autosomal recessive (AR) condition caused by the lack of RecQ DNA helicase, an enzyme involved in DNA repair. The BLM gene which codes for RecQ DNA helicase located at 15q26.1. One mutation in the BLM gene accounts for 98% of the mutations seen in Ashkenazi Jewish (AJ) individuals affected with BLM.

Patients with Canavan disease (CVN) exhibit progressive mental retardation, atonia of neck muscles, macrocephaly, hyperextension of legs, flexion of arms and blindness. Although survival rates vary, the majority of patients with CVN die in childhood. CVN is an AR disorder caused by a deficiency of the enzyme aspartoacylase, which breaks down N-acetylaspartic acid (NAA). The gene for aspartoacylase (ASPA) has been localized to chromosome 17p13-pter. Four mutations in the ASPA gene account for 98% of the mutations seen in AJ individuals affected with CVN.

Familial dysautonomia (FD) is a progressive degenerative disorder affecting the autonomic and sensory nervous systems. Some common features of FD include a decreased ability to feel pain or temperature sensations, blood pressure and body temperature fluctuations, difficulties feeding and swallowing, gastrointestinal motility problems, developmental delay, recurrent pneumonias and decreased stature. FD is an AR disorder caused by a mutation in the IKBKAP gene, located on chromosome 9 (9q31). Two mutations in the IKBKAP gene account for over 99% of the mutations seen in AJ individuals affected with FD.

Fanconi anemia (FA) is a clinically and genetically heterogeneous condition. Both interfamilial and intrafamilial clinical heterogeneity has been reported. Clinical findings in individuals with FA include: anemia, progressive pancytopenia; abnormal skin pigmentation; short stature; and/or multiple malformations of the skeletal and organ systems. Individuals with FA are at increased risk for leukemias and solid tumours. Fancioni anemia group C (FA-C) is the most common form of FA seen in the AJ population. FA-C is an AR disorder caused by mutations in the FANCC gene, located on chromosome 9 (9q22.3). Two mutations in the FANCC gene account for 99% of the mutations seen in AJ individuals affected with FA-C.

Mucolipidosis IV (MLP4) is a neurodegenerative lysosomal storage disorder characterized by severe psychomotor retardation, ophthalmological abnormalities including corneal clouding, retinal degeneration and strabismus, elevated blood gastrin and iron deficiency. Most patients present at 2-3 years of age and remain in an apparent steady-state for the next 2-3 decades. MLP4 is an AR disorder caused by mutations in the MCOLN1 gene, located on chromosome 19 (19p13.3). Two mutations in the MCOLN1 gene accounrt for 95% of the mutations seen in AJ individuals affected with MLP4.

Niemann disease types A and B (NP) are lysosomal storage disorders resulting from the accumulation of sphingomyelin, cholesterol and other lipids in the cells of affected individuals due to a deficiency of sphingomyelinase activity. Niemann Pick type A (NPA) presents in infancy with organomegaly and rapid neurodegeneration leading to death by ~3 years of age. Niemann Pick type B (NPB) is clinically heterogeneous and individuals can present with multiple findings including hepatosplenomegaly, growth retardation, frequent respiratory infections, fatigue and hematologic abnormalities. Individuals with NPB usually survive into adulthood. DNA testing for three mutations common in the Ashkenazi Jewish population for NPA and one mutation in NPB is performed. NP is an AR disorder caused by mutations in the SMPD1 gene, located on chromosome 11 (11p15.4). Four mutations in the SMPD1 gene account for greater than 95% of the mutations seen in AJ individuals affected with Niemann Pick disease, type A & B.

Tay-Sachs disease (TSD) is characterized by progressive weakness and loss of motor skills beginning between three and six months of age. Over time, signs of progressive neurodegeneration occur, such as seizures, blindness, and paralysis, usually leading to death before the age of four. TSD is caused by a deficiency of the enzyme hexosaminidase-A (Hex-A). Deficiency of the Hex-A enzyme can also be identified by biochemical enzyme tests. TSD is an AR disorder caused by mutations in the HEXA gene, located on chromosome 15 (15q23-q24). Three mutations in the HEXA gene account for more than 99% of the mutations seen in AJ individuals affected with TSD. TSD is also seen at a comparable frequency in other ethnic groups including French Canadians and Cajuns. Two mutations that are seen more frequently in the French Canadian population are also screened for as part of this panel.

Who should be tested?

  • Relatives of individuals affected with BLM, CVN, FD, FA-C, MLP4, NP or TSD
  • Individuals at elevated risk of being carriers of BLM, CVN, FD, FA-C, MLP4, NP or TSD

Testing Methodology

Direct Mutation Analysis: Samples are analyzed using a PCR assay for mutations causing BLM, CVN, FD, FA-C, MLP4, NP and TSD common in the Ashkenazi Jewish population.

Disease Indication

Carrier frequency
in AJ population

Gene
Name

Mutation
cDNA(aa)

Detection
Rate

Bloom Syndrome

~1 in 102

BLM

2281del6/ins7

98%

Canavan Disease

~1 in 57

ASPA

433(-2)A>G
Y231X
E285A
A305E

98%

Familial Dysautonomia

~1 in 30

IKBKAP

R696P
IVS20(+6)T>C

99%

Fanconi Anemia, Group C

~1 in 89

FANCC

322delG
IVS4(+4)A>T

99%

Mucolipidosis IV

~1 in 100

MCOLN1

Δ 6.4kb
IVS3(-2)A>G

 

Niemann Pick Disease
(type A & B)

~1 in 90

SMPD1

L302P
1bp delfsP330
R496L
Δ R608

95%

Tay-Sachs Disease

~1 in 29

HEXA

1278insTATC
IVS12(+1)G>C
G269S
Δ 7.6kb**
IVS9(+1)G>A**
R249W*
R247W*

99%

*non-disease-causing pseudodeficiency alleles. Individuals that have a pseudodeficiency allele are not affected by Tay-Sachs disease, and are not carriers of the disease.
**reported in non-Ashkenazi Jewish chromosomes

Potential Outcomes & Interpretation of Test Results

Reason for referral

Gene Mutations
allele 1 / allele 2

Explanation

carrier testing

none detected / none detected

  • This individual is unlikely to be a carrier of *indicated disease.

carrier testing

mutation detected / none detected

  • This individual is a carrier of *indicated disease and may transmit a mutation to offspring.

*BLM, CVN, FD, FA-C, MLP4, NP, TSD

Cautions

  • Current molecular testing will not detect all possible mutations in these genes. A negative result does not rule out the possibility that the individual carries a rare mutation not included in the assay.
  • Test results should be interpreted in the context of clinical findings, family history, ethnic background and other laboratory data.
  • We strongly recommend that biochemical analysis for Tay-Sachs disease be done on these patients, as it can be a useful complement to molecular testing.
  • The test sensitivity and specificity is different in individuals who are not of Ashkenazi Jewish ancestry.
  • This test was developed and its performance characteristics validated by the Molecular Genetics Laboratory at the Hospital for Sick Children. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. This test is used for clinical purposes.

For More Information: