Jewish Genetic Disease

Diagnosis

Indications for Testing

  • Symptomatic patient
  • Family history of disease

Laboratory Testing

  • Molecular testing for suspected disorder
  • Presence of gene mutations associated with specific disease confirmatory for that disease

Screening

  • Panel testing is recommended for all persons of Ashkenazi Jewish descent who are planning a pregnancy or are currently pregnant
  • Individual disorder testing recommended for the following
    • Ashkenazi Jewish individuals whose partners have been identified as carriers for a specific disorder
      • Detection rate of disease mutations in the non-Ashkenazi population is often much lower than that for Ashkenazi Jews
      • Consider full gene sequencing or enzyme assay for those of non-Ashkenazi descent

Clinical Background

  • The American College of Obstetrics and Gynecology (ACOG) and the American College of Medical Genetics (ACMG) recommend routine preconceptual or prenatal carrier screening for diseases common to individuals of Eastern European (Ashkenazi) descent
    • ACOG 2009 guidelines recommend screening for 4 disorders – Canavan disease, cystic fibrosis, familial dysautonomia and Tay-Sachs disease
      • ACOG states that individuals of Ashkenazi Jewish descent may inquire about the availability of carrier screening for other disorders
    • ACMG 2008 guidelines recommend screening for 9 disorders – Canavan disease, cystic fibrosis, familial dysautonomia, Tay-Sachs disease, Fanconi anemia group C, Niemann-Pick disease type A, Bloom syndrome, mucolipidosis IV and Gaucher disease type 1

Epidemiology

  • Incidence of nine common Ashkenazi Jewish disorders, for which screening is recommended by the ACOG/ACMG guidelines

    Jewish Genetic Diseases

    Disease

    Disease Incidence in Ashkenazim

    Carrier Rate in Ashkenazim

    Canavan disease*

    1/10,000

    1/50

    Cystic fibrosis*1/2,5001/25

    Familial dysautonomia*

    1/3,600

    1/32

    Tay-Sachs disease*

    1/3,000

    1/30

    Fanconi anemia group C*

    1/32,000

    1/89

    Niemann-Pick disease type A**

    1/32,000

    1/90

    Bloom syndrome**

    1/40,000

    1/100

    Mucolipidosis IV**

    1/63,000

    1/127

    Gaucher disease type 1**

    1/900

    1/15

    *Screening recommended by ACOG and ACMG

    **Screening recommended by ACMG

  • Age – usually presents in infancy to early childhood
  • Sex – M:F, equal

Inheritance

  • Autosomal recessive for the nine disorders listed above

Pathophysiology

  • Bloom syndrome (BLM)
    • Deficiency of Bloom helicase
    • BLM leading to mitotic hyper crossover and chromosomal instability
  • Canavan disease
    • Deficiency of aspartoacylase in oligodendrocytes leading to accumulation of N-acetylaspartic acid
  • Cystic fibrosis (CF)
    • Abnormal chloride channel function
  • Familial dysautonomia
    • Depletion of sensory, sympathetic and parasympathetic neurons
    • Compromised myelination and white matter micro-structural integrity
  • Fanconi anemia group C
    • Deficiency of FANCC protein
  • Gaucher disease type 1
    • Deficiency of beta-glucosylceramidase in a lysosomal storage disease
  • Mucolipidosis IV
    • Defective endocytosis of the lysosomal membrane
  • Niemann-Pick disease type A
    • Deficiency of acid sphingomyelinase in lysosomes leading to accumulation of sphingomyelin in cells
  • Tay-Sachs disease
    • Deficiency of hexosaminidase A leading to accumulation of glycosphingolipid ganglioside in lysosomes

Clinical Presentation

  • Bloom syndrome
    • Pre- and postnatal growth deficiency
    • Sun sensitivity
    • Benign and malignant tumors in childhood
    • Male sterility
    • Sparse skin lesions (facial telangiectasias, abnormal pigmentation)
    • Death in early adulthood (usually due to malignancy)
  • Canavan disease
    • Macrocephaly
    • Loss of motor control beginning at 3-5 months
    • Seizures
    • Failure to sit, stand or ambulate
    • Death in childhood/teens
  • Cystic fibrosis
    • Chronic sino-pulmonary disease
    • Gastrointestinal malabsorption/pancreatic insufficiency
    • Obstructive azoospermia
    • Decreased life expectancy
  • Familial dysautonomia
    • Gastrointestinal dysfunction with emesis; abnormal suck and feeding issues
    • Recurrent pneumonia
    • Altered sensitivity to pain and temperature
    • Cardiovascular instability
    • Decreased life expectancy
  • Fanconi anemia group C
    • Short stature
    • Abnormal skin pigmentation
    • Multiple congenital malformations (eyes, ears, heart, thumbs, forearms, kidneys)
    • Developmental delay
    • Progressive bone failure in infancy through childhood
    • Increased risk of malignancy (leukemia)
    • Death in childhood/teens
  • Gaucher disease
    • Variable severity from perinatal lethality to asymptomatic in adulthood
    • Type 1 – bone disease, hepatosplenomegaly, anemia, thrombocytopenia, lung disease
    • Type 2 – central nervous system (CNS) degeneration by age 2 with death by age 4
    • Type 3 – slowly progressive CNS degeneration with death in 20s
  • Mucolipidosis IV
    • Severe psychomotor delay
    • Retinal degeneration and clouding
    • 15% have neurologic degeneration
  • Niemann-Pick type A
    • Hepatosplenomegaly
    • Growth delay, rigidity and hypotonia
    • Developmental delay
    • Death by 3-5 years
  • Tay-Sachs disease
    • Progressive loss of motor skills beginning at 3-6 months
    • Blindness
    • Seizures
    • Death by 4-6 years

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Ashkenazi Jewish Diseases (BLM, ASPA, IKBKAP, FANCC, GBA, MCOLN1, SMPD1, HEXA) 0051415
Method: Polymerase Chain Reaction/ASPE Bead Array

Carrier screening for Ashkenazi Jewish individuals who are planning a pregnancy or are currently pregnant

Clinical sensitivity is shown after each syndrome tested and varies by disease

Panel includes 28 mutations, two pseudodeficiency alleles and one polymorphism in the following genes

  • BLM – Bloom syndrome; 95%
  • ASPA – Canavan disease; 99%
  • IKBKAP – familial dysautonomia; 99%
  • FANCC – Fanconi anemia group C; 99%
  • GBA – Gaucher disease type 1; 90%
  • MCOLN1 – mucolipidosis IV; 95%
  • SMPD1 – Niemann-Pick disease type A; 95%
  • HEXA – Tay-Sachs disease; 92%

Mutations not included on the panel will not be detected 

Rare diagnostic errors may occur due to primer site mutations

Cystic fibrosis (CF) carrier testing is not included in this panel

Order Cystic Fibrosis (CFTR) 32 Mutations to assess CF carrier status
Cystic Fibrosis (CFTR) 32 Mutations 2001933
Method: Polymerase Chain Reaction/Oligonucleotide Ligation/Fragment Analysis

Determine carrier status for CF

Clinical sensitivity – 94% in Ashkenazi Jewish individuals

Mutations not included on the panel will not be detected

Rare diagnostic errors may occur due to primer site mutations

  
Hexosaminidase A and Total Hexosaminidase, Plasma or Serum 2008121
Method: Fluorometry
 Determine carrier status for Tay-Sachs disease in males, nonpregnant women, and women not taking oral contraceptives

Pregnant women or women using oral contraceptives should not be tested using plasma or serum because of high false-positive rates

If plasma/serum results are inconclusive, perform leukocyte testing
Hexosaminidase A and Total Hexosaminidase in Leukocytes 2008125
Method: Fluorometry

Determine carrier status for Tay-Sachs disease

Recommended  in pregnant women or women taking oral contraceptives

    
Bloom (BLM) 2281del6/ins7 Mutation 0051433
Method: Polymerase Chain Reaction/ASPE Bead Array

Determine carrier status for Ashkenazi Jewish individuals whose partners are carriers for the disorder

Clinical sensitivity – 95% in Ashkenazi Jewish individuals; 55% in other ethnicities

Mutations other than Y231X(C>A), E285A, A305E, 433(-2)A>G and benign polymorphism Y231Y(C>T) will not be detected

Rare diagnostic errors may occur due to primer site mutations

  
Canavan Disease (ASPA) 4 Mutations 0051453
Method: Polymerase Chain Reaction/ASPE Bead Array

Determine carrier status for Ashkenazi Jewish individuals whose partners are carriers for the disorder

Clinical sensitivity – 98% in Ashkenazi Jewish individuals; 55% in other ethnicities 

Mutations other than Y231X(C>A), E285A, A305E, 433(-2)A>G and benign polymorphism Y231Y(C>T) will not be detected

Rare diagnostic errors may occur due to primer site mutations

  
Fanconi Anemia, Group C (FANCC) 2 Mutations 0051468
Method: Polymerase Chain Reaction/ASPE Bead Array

Determine carrier status for Ashkenazi Jewish individuals whose partners are carriers for the disorder

Clinical sensitivity – 99% in Ashkenazi Jewish individuals; unknown in other ethnicities

Mutations other than 322delG and IVS4(+4)A>T will not be detected

Rare diagnostic errors may occur due to primer site mutations

  
Dysautonomia, Familial (IKBKAP) 2 Mutations 0051463
Method: Polymerase Chain Reaction/ASPE Bead Array

Determine carrier status for Ashkenazi Jewish individuals whose partners are carriers for the disorder

Clinical sensitivity – 99% in Ashkenazi Jewish individuals; unknown in other ethnicities

Mutations other than R696P and IVS20(+6)T>C will not be detected

Rare diagnostic errors may occur due to primer site mutations

  
Gaucher (GBA) 8 Mutations 0051438
Method: Polymerase Chain Reaction/ASPE Bead Array

Determine carrier status for Ashkenazi Jewish individuals whose partners are carriers for the disorder

Clinical sensitivity – 90% in Ashkenazi Jewish individuals; at least 55% in other ethnicities

Mutations other than 84G>GG, IVS2(+1)G>A, N370S, del55bp, V394L, D409H, L444P, R496H will not be detected

  
Mucolipidosis, Type IV (MCOLN1) 2 Mutations 0051448
Method: Polymerase Chain Reaction/ASPE Bead Array

Determine carrier status for Ashkenazi Jewish individuals whose partners are carriers for the disorder

Clinical sensitivity – 95% in Ashkenazi Jewish individuals; unknown in other ethnicities

Mutations other than del6.4kb and IVS3(-2)A>G will not be detected

Rare diagnostic errors may occur due to primer site mutations

  
Niemann-Pick, Type A (SMPD1) 4 Mutations 0051458
Method: Polymerase Chain Reaction/ASPE Bead Array

Determine carrier status for Ashkenazi Jewish individuals whose partners are carriers for the disorder

Clinical sensitivity – 99% in Ashkenazi Jewish individuals; unknown in other ethnicities

Mutations other than L302P, 1bp del fsP330, R496L, R608del will not be detected

Rare diagnostic errors may occur due to primer site mutations

  
Tay-Sachs (HEXA) 7 Mutations 0051428
Method: Polymerase Chain Reaction/ASPE Bead Array

Determine carrier status for Ashkenazi Jewish individuals whose partners are carriers for the disorder

Clinical sensitivity – 94% in Ashkenazi Jewish individuals; unknown in other ethnicities

HEXA enzymatic activity assay has greater sensitivity than targeted mutation analysis for diagnosis of symptomatic individuals and carrier screening

Mutations other than del7.6kb, R247W, R249W, G269S, IVS9(+1)G>A, 1278insTATC, IVS12(+1)G>C will not be detected

Rare diagnostic errors may occur due to primer site mutations

  
Additional Tests Available
 
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Bloom (BLM) 2281del6/ins7 Mutation, Fetal 0051434
Method: Polymerase Chain Reaction/ASPE Bead Array

Mutations detected – 2281del6/ins7

Rare diagnostic errors may occur due to primer site mutations
Canavan (ASPA) 4 Mutations, Fetal 0051454
Method: Polymerase Chain Reaction/ASPE Bead Array

Time-sensitive test

Mutations detected – Y231X(C>A), E285A, A305E, 433(-2)A>G ; benign polymorphism Y231Y(C>T)
Fanconi Anemia, Group C (FANCC) 2 Mutations, Fetal 0051469
Method: Polymerase Chain Reaction/ASPE Bead Array

Time-sensitive test

Mutations detected – 322delG and IVS4(+4)A>T
Dysautonomia, Familial (IKBKAP) 2 Mutations, Fetal 0051464
Method: Polymerase Chain Reaction/ASPE Bead Array

Time-sensitive test

Mutations detected – R696P and IVS20(+6)T>C
Gaucher (GBA) 8 Mutations, Fetal 0051439
Method: Polymerase Chain Reaction/ASPE Bead Array

Time-sensitive test

Mutations detected – 84G>GG, IVS2(+1)G>A, N370S, del55bp, V394L, D409H, L444P, R496H
Mucolipidosis, Type IV (MCOLN1) 2 Mutations, Fetal 0051449
Method: Polymerase Chain Reaction/ASPE Bead Array

Time-sensitive test

Mutations detected – del6.4kb and IVS3(-2)A>G
Niemann-Pick, Type A (SMPD1) 4 Mutations, Fetal 0051459
Method: Polymerase Chain Reaction/ASPE Bead Array

Time-sensitive test

Mutations detected – L302P, 1bp del fsP330, R496L, R608del
Tay-Sachs (HEXA) 7 Mutations, Fetal 0051429
Method: Polymerase Chain Reaction/ASPE Bead Array

Mutations detected – four severe (Delta7.6kb, IVS9(+1)G>A, 1278insTATC, IVS12(+1)G>C), one mild (G269S), and two pseudodeficiency alleles (R247W and R249W)
Hexosaminidase A and Total Hexosaminidase in Plasma with Reflex to Hexosaminidase A and Total Hexosaminidase in Leukocytes 2008129
Method: Fluorometry

Carrier screening for Tay-Sachs disease in pregnant women and women taking oral contraceptives

If plasma/serum results are inconclusive, leukocyte testing is added