Jewish Genetic Diseases

Diagnosis

Indications for Testing

  • Carrier screening in individuals of Ashkenazi Jewish descent who are planning a pregnancy or are currently pregnant

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) Jewish 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 9 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

    Bloom syndrome**

    1/40,000

    1/100

    Canavan disease*

    1/10,000

    1/50

    Cystic Fibrosis*1/2,5001/25

    Familial dysautonomia*

    1/3,600

    1/32

    Fanconi anemia group C*

    1/32,000

    1/89

    Gaucher disease type 1**

    1/900

    1/15

    Mucolipidosis IV**

    1/63,000

    1/127

    Niemann-Pick disease type A**

    1/32,000

    1/90

    Tay-Sachs disease*

    1/3,000

    1/30

    *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 9 disorders listed above

Pathophysiology

  • Cause of diseases

    Disease

    Pathophysiology

    Bloom syndrome (BLM)

    • Deficiency of member of RecQ helicase protein family
    • Leads to mitotic hyper crossover and chromosomal instability

    Canavan disease

    • Deficiency of aspartoacylase in oligodendrocytes
    • Leads to accumulation of N-acetylaspartic acid

    Cystic fibrosis

    • Abnormal chloride channel function

    Familial dysautonomia

    • Deficiency of IKK complex-associated protein
    • 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-glucocerebrosidase

    Mucolipidosis IV

    • Deficiency of mucolipin-1
    • Defective endocytosis of the lysosomal membrane

    Niemann-Pick disease

    • Deficiency of sphingomyelinase
    • Leads to accumulation of sphingomyelin in cells

    Tay-Sachs disease

    • Deficiency of beta-hexosaminidase A
    • Leads to accumulation of glycosphingolipid ganglioside in lysosomes

Clinical Presentation

  • Symptoms of diseases

    Disease

    Type of disorder/symptoms

    Bloom syndrome

    • Pre- and postnatal growth deficiency
    • Sparse subcutaneous tissue
    • Benign and malignant tumors in childhood
    • Sun sensitivity
    • Telangiectatic hypo- and hyperpigmented skin lesions
    • Male sterility
    • Life expectancy is decreased due to malignancy

    Canavan disease

    • Macrocephaly
    • Loss of motor control beginning at 3–5 months
    • Seizures
    • Failure to sit, stand, or ambulate
    • Death typically occurs in childhood/teens

    Cystic fibrosis

    • Chronic  sinopulmonary disease
    • Gastrointestinal malabsorption/pancreatic insufficiency
    • Obstructive azoospermia
    • Decreased life expectancy

    Familial dysautonomia

    • Gastrointestinal dysfunction with emesis
    • Abnormal suck and feeding issues in infants
    • 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
      • Forearms, thumbs
      • Kidneys
    • Developmental delay
    • Progressive bone marrow failure during first decade of life
      • Hematological malignancies (~20%)
    • Nonhematological malignancies (~30%)
    • Death typically occurs in childhood/teens

    Gaucher disease

    Type 1

    • Bone disease
    • Hepatosplenomegaly
    • Anemia, thrombocytopenia
    • Lung disease
    • No primary central nervous system (CNS) disease

    Type 2

    • CNS degeneration by age 2 years, with a rapidly progressive course, and death by 4 years

    Type 3

    • Slowly progressive CNS degeneration
    • Death in 20s

    Mucolipidosis IV

    • Severe psychomotor delay
    • Retinal degeneration
    • Corneal clouding
    • Neurological state
      • Static until age 30 in most affected individuals
      • Neurological degeneration in ~15%
    • Variable life expectancy

    Niemann-Pick disease type A

    • Hepatosplenomegaly
    • Growth delay, developmental delay
    • Rigidity and hypotonia
    • Death by 3-5 years

    Tay-Sachs disease/variants of HEX A deficiency

    Acute infantile HEX A deficiency – onset 3-6 months of age with rapid progression and life expectancy <4 years

    • Progressive neurodegeneration
    • Hypotonia
    • Decreased attentiveness
    • Increased startle response
    • Cherry-red spot of the macula
    • Seizures
    • Blindness
    • Spasticity
    • Liver disease

    Juvenile HEX A deficiency – onset between ages 2-10 years

    • Ataxia, incoordination
    • Cognitive decline/vision loss by age 10
    • Optic neuropathy and retinitis pigmentosa may develop

    Adult onset HEX A deficiency – onset in childhood to adulthood, more slowly progressive

    • Clinically variable course
    • Adult onset
      • Muscle wasting, weakness, fasciculations, dysarthria
      • Cognitive dysfunction
      • Psychosis in 40% (often the first manifestation)
    • Chronic
      • Dystonia, choreoathetosis, ataxia, dysarthria
      • Cognitive/verbal skills affected later in the course

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), Common Mutation Panel 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 reported 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, other than those tested on this panel, will not be detected

Diagnostic errors can occur due to rare sequence variations

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

Only the 32 CFTR mutations will be interrogated

Diagnostic errors can occur due to rare sequence variations

 
Hexosaminidase A Percent and Total Hexosaminidase, Plasma or Serum 2008121
Method: Quantitative Fluorometry

Confirm diagnosis of Tay-Sachs disease

Carrier screening in males or nonpregnant females

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 Percent and Total Hexosaminidase in Leukocytes 2008125
Method: Quantitative Fluorometry

Assess Tay-Sachs disease carrier status in women who are pregnant or taking oral contraceptives

Evaluate individuals with inconclusive beta-hexosaminidase A (HEX A) enzyme serum level

   
Tay-Sachs Disease (HEXA) 7 Mutations 0051428
Method: Polymerase Chain Reaction/Primer Extension

Identify causative HEXA gene mutation(s) in individual with abnormal level of HEX A enzyme

Molecular confirmation of common pathogenic and pseudodeficiency gene mutations

Included in a panel of common disorders/mutations for population screening of individuals of Ashkenazi Jewish ancestry (Ashkenazi Jewish Diseases [BLM, ASPA, IKBKAP, FANCC, GBA, MCOLN1, SMPD1, HEXA], Common Mutation Panel)

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

Regulatory region and deep intronic mutations will not be detected

Diagnostic errors can occur due to rare sequence variations

 
Tay-Sachs Disease (HEXA) Sequencing and 7.6kb Deletion 2009298
Method: Polymerase Chain Reaction/Sequencing

Identify causative HEXA gene mutation(s) in individual with abnormal level of HEX A enzyme

Molecular confirmation of pathogenic and pseudodeficiency gene mutations

Clinical sensitivity/specificity – 99%

Analytical sensitivity/specificity – >99%

Regulatory region and deep intronic mutations will not be detected

Large deletions/duplications in HEXA other than the 7.6 kb deletion will not be detected

Diagnostic errors can occur due to rare sequence variations

 
Bloom Syndrome (BLM) 1 Mutation 0051433
Method: Polymerase Chain Reaction/Primer Extension

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

Mutation detected – p.Y736Lfs (c.2207_2212delinsTAGATTC)

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

Mutations other than those tested will not be detected

Diagnostic errors can occur due to rare sequence variations

 
Canavan Disease (ASPA) 4 Mutations 0051453
Method: Polymerase Chain Reaction/Primer Extension

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

Mutations detected – c.433-2A>G, p.Y231X (c.693C>A), p.E285A (c.854A>C), and p.A305E (c.914C>A)

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

Mutations other than those tested will not be detected

Diagnostic errors can occur due to rare sequence variations

 
Fanconi Anemia, Group C (FANCC) 2 Mutations 0051468
Method: Polymerase Chain Reaction/Primer Extension

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

Mutations tested – p.D23Ifs (c.67delG) and c.456+4A>T

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

Mutations other than those tested will not be detected

Diagnostic errors can occur due to rare sequence variations

 
Dysautonomia, Familial (IKBKAP) 2 Mutations 0051463
Method: Polymerase Chain Reaction/Primer Extension

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

Mutations detected – dp.R696P (c.2087G>C) and c.2204+6T>C

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

Mutations other than those tested will not be detected

Diagnostic errors can occur due to rare sequence variations

 
Gaucher Disease (GBA) 8 Mutations 0051438
Method: Polymerase Chain Reaction/Primer Extension

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

Mutations detected – c.115+1G>A, p.L29Afs (c.84dupG), p.N409S (c.1226A>G), c.1263_1319del55, p.V433L (c.1297G>T), p.D448H (c.1342G>C), p.L483P (c.1448T>C), and p.R535H (c.1604G>A)

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

Mutations other than those tested will not be detected

Diagnostic errors can occur due to rare sequence variations

 
Mucolipidosis, Type IV (MCOLN1) 2 Mutations 0051448
Method: Polymerase Chain Reaction/Primer Extension

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

Mutations detected –g.511_6493del and c.406-2A>G

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

Mutations other than those tested will not be detected

Diagnostic errors can occur due to rare sequence variations

 
Niemann-Pick, Type A (SMPD1) 4 Mutations 0051458
Method: Polymerase Chain Reaction/Primer Extension

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

Mutations detected – p.L304P (c.911T>C), p.F333Sfs (c.996delC), p.R498L (c.1493G>T), and p.R610del (c.1829_1831delGCC)

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

Mutations other than those tested will not be detected

Rare diagnostic errors can occur due rare sequence variations

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Bloom Syndrome (BLM) 1 Mutation, Fetal 0051434
Method: Polymerase Chain Reaction/Primer Extension

Mutation detected – p.Y736Lfs (c.2207_2212delinsTAGATTC)

Diagnostic errors can occur due to rare sequence variations

Canavan Disease (ASPA) 4 Mutations, Fetal 0051454
Method: Polymerase Chain Reaction/Primer Extension

Time-sensitive test

Mutations detected – c.433-2A>G, p.Y231X (c.693C>A), p.E285A (c.854A>C), p.A305E (c.914C>A)

Diagnostic errors can occur due to rare sequence variations

Fanconi Anemia, Group C (FANCC) 2 Mutations, Fetal 0051469
Method: Polymerase Chain Reaction/Primer Extension

Time-sensitive test

Mutations detected –  p.D23Ifs (c.67delG) and c.456+4A>T

Diagnostic errors can occur due to rare sequence variations

Dysautonomia, Familial (IKBKAP) 2 Mutations, Fetal 0051464
Method: Polymerase Chain Reaction/Primer Extension

Time-sensitive test

Mutations detected – p.R696P (c.2087G>C) and c.2204+6T>C

Diagnostic errors can occur due to rare sequence variations

Gaucher Disease (GBA) 8 Mutations, Fetal 0051439
Method: Polymerase Chain Reaction/Primer Extension

Time-sensitive test

Mutations detected – c.115+1G>A, p.L29Afs (c.84dupG), p.N409S (c.1226A>G), c.1263_1319del55, p.V433L (c.1297G>T), p.D448H (c.1342G>C), p.L483P (c.1448T>C), and p.R535H (c.1604G>A)

Diagnostic errors can occur due to rare sequence variations

Mucolipidosis, Type IV (MCOLN1) 2 Mutations, Fetal 0051449
Method: Polymerase Chain Reaction/Primer Extension

Time-sensitive test

Mutations detected – g.511_6493del and c.406-2A>G

Diagnostic errors can occur due to rare sequence variations

Niemann-Pick, Type A (SMPD1) 4 Mutations, Fetal 0051459
Method: Polymerase Chain Reaction/Primer Extension

Time-sensitive test

Mutations detected –  L304P, p.F333Sfs, p.R498L, p.R610del

Diagnostic errors can occur due to rare sequence variations

Tay-Sachs Disease (HEXA) 7 Mutations, Fetal 0051429
Method: Polymerase Chain Reaction/Primer Extension

Molecular diagnosis of common pathogenic mutations and pseudodeficiency alleles in prenatal samples when the targeted mutations have been confirmed in the parents

Mutations detected – four severe [7.6kb del, c.1073+1G>A, p.Y427lfs (c.1274_1277dupTATC), c.1421+1G>C], one mild [p.G269S (c805G>A)], and two pseudodeficiency alleles [(p.R247W (c.739C>T) and p.R249W (c.745C>T)]

Diagnostic errors can occur due to rare sequence variations

Hexosaminidase A Percent and Total Hexosaminidase in Plasma with Reflex to Hexosaminidase A Percent and Total Hexosaminidase in Leukocytes 2008129
Method: Quantitative Fluorometry

Preferred test to confirm diagnosis of Tay-Sachs disease

Preferred test for carrier screening in males or nonpregnant females