Jewish Genetic Disease

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

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

The American College of Medical Genetics (ACMG) recommends routine preconceptual or prenatal carrier screening for nine different diseases common to individuals of Eastern European (Ashkenazi) descent. These disorders include Bloom syndrome, Canavan disease, cystic fibrosis, familial dysautonomia, Fanconi anemia group C, Gaucher disease, mucolipidosis IV, Niemann-Pick disease type A, and Tay-Sachs disease.

Epidemiology

Incidence of eight common Ashkenazi Jewish disorders

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
Familial dysautonomia	1/3,600	1/32
Fanconi anemia group C	1/32,000	1/89
Gaucher disease	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

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

Inheritance

Autosomal recessive for eight 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
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
- 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
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

Tests generally appear in the order most useful for common clinical situations

Test name: Ashkenazi Jewish Diseases (BLM, ASPA, IKBKAP, FANCC, GBA, MCOLN1, SMPD1, HEXA)

ARUP #: 0051415

Methodology: Polymerase Chain Reaction/ASPE Bead Array

Use:

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; 90%
MCOLN1 - mucolipidosis IV; 95%
SMPD1 - Niemann-Pick disease type A; 95%
HEXA - Tay-Sachs disease; 92%

Limitations:

Mutations not included on the panel will not be detected

Rare diagnostic errors may occur due to primer site mutations

Follow-up:

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

Order cystic fibrosis (CFTR) 32 mutations to assess CF carrier status

Test name: Cystic Fibrosis (CFTR) 32 Mutations

ARUP #: 2001933

Methodology: Polymerase Chain Reaction/Oligonucleotide Ligation/Fragment Analysis

Use:

Determine carrier status for CF

Clinical sensitivity - 94% in Ashkenazi Jewish individuals

Limitations:

Mutations not included on the panel will not be detected

Rare diagnostic errors may occur due to primer site mutations

Test name: Bloom (BLM) 2281del6/ins7 Mutation

ARUP #: 0051433

Methodology: Polymerase Chain Reaction/ASPE Bead Array

Use:

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

Limitations:

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

Test name: Canavan Disease (ASPA) 4 Mutations

ARUP #: 0051453

Methodology: Polymerase Chain Reaction/ASPE Bead Array

Use:

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

Limitations:

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

Test name: Fanconi Anemia, Group C (FANCC) 2 Mutations

ARUP #: 0051468

Methodology: Polymerase Chain Reaction/ASPE Bead Array

Use:

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

Limitations:

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

Rare diagnostic errors may occur due to primer site mutations

Test name: Dysautonomia, Familial (IKBKAP) 2 Mutations

ARUP #: 0051463

Methodology: Polymerase Chain Reaction/ASPE Bead Array

Use:

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

Limitations:

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

Rare diagnostic errors may occur due to primer site mutations

Test name: Gaucher (GBA) 8 Mutations

ARUP #: 0051438

Methodology: Polymerase Chain Reaction/ASPE Bead Array

Use:

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

Limitations:

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

Test name: Mucolipidosis, Type IV (MCOLN1) 2 Mutations

ARUP #: 0051448

Methodology: Polymerase Chain Reaction/ASPE Bead Array

Use:

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

Limitations:

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

Rare diagnostic errors may occur due to primer site mutations

Test name: Niemann-Pick, Type A (SMPD1) 4 Mutations

ARUP #: 0051458

Methodology: Polymerase Chain Reaction/ASPE Bead Array

Use:

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

Limitations:

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

Rare diagnostic errors may occur due to primer site mutations

Test name: Tay-Sachs (HEXA) 7 Mutations

ARUP #: 0051428

Methodology: Polymerase Chain Reaction/ASPE Bead Array

Use:

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

Limitations:

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

Test name: Bloom (BLM) 2281del6/ins7 Mutation, Fetal

ARUP #: 0051434

Methodology: Polymerase Chain Reaction/ASPE Bead Array

Comments:

Mutations detected - 2281del6/ins7

Rare diagnostic errors may occur due to primer site mutations

Test name: Canavan (ASPA) 4 Mutations, Fetal

ARUP #: 0051454

Methodology: Polymerase Chain Reaction/ASPE Bead Array

Comments:

Time-sensitive test

Mutations detected - Y231X(C>A), E285A, A305E, 433(-2)A>G ; benign polymorphism Y231Y(C>T)

Test name: Fanconi Anemia, Group C (FANCC) 2 Mutations, Fetal

ARUP #: 0051469

Methodology: Polymerase Chain Reaction/ASPE Bead Array

Comments:

Time-sensitive test

Mutations detected - 322delG and IVS4(+4)A>T

Test name: Dysautonomia, Familial (IKBKAP) 2 Mutations, Fetal

ARUP #: 0051464

Methodology: Polymerase Chain Reaction/ASPE Bead Array

Comments:

Time-sensitive test

Mutations detected - R696P and IVS20(+6)T>C

Test name: Gaucher (GBA) 8 Mutations, Fetal

ARUP #: 0051439

Methodology: Polymerase Chain Reaction/ASPE Bead Array

Comments:

Time-sensitive test

Mutations detected - 84G>GG, IVS2(+1)G>A, N370S, del55bp, V394L, D409H, L444P, R496H

Test name: Mucolipidosis, Type IV (MCOLN1) 2 Mutations, Fetal

ARUP #: 0051449

Methodology: Polymerase Chain Reaction/ASPE Bead Array

Comments:

Time-sensitive test

Mutations detected - del6.4kb and IVS3(-2)A>G

Test name: Niemann-Pick, Type A (SMPD1) 4 Mutations, Fetal

ARUP #: 0051459

Methodology: Polymerase Chain Reaction/ASPE Bead Array

Comments:

Time-sensitive test

Mutations detected - L302P, 1bp del fsP330, R496L, R608del

Test name: Tay-Sachs (HEXA) 7 Mutations, Fetal

ARUP #: 0051429

Methodology: Polymerase Chain Reaction/ASPE Bead Array

Comments:

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)

Test name: Hexosaminidase A & Total, Serum

ARUP #: 0095269

Methodology: Quantitative Heat Inactivation/Fluorometry, Automated

Comments:

Test name: Hexosaminidase A & Total, Leukocytes

ARUP #: 0092471

Methodology: Heat Inactivation/Fluorometry, Semiautomated

Comments:

Guidelines

General

Comprehensive Review: November 2011
Last Update: November 2011

Acute Lymphoblastic Leukemia

Central Nervous System Tumors

Developmental Delay (DD) or Intellectual Disability (ID) Testing

Glaucoma (Primary Congenital)

Seizure Disorders