Jewish Genetic Diseases

  • Diagnosis
  • Algorithms
  • Screening
  • Background
  • Lab Tests
  • References
  • Related Content

Indications for Testing

  • Carrier screening in individuals of Ashkenazi Jewish descent who are planning a pregnancy or are currently pregnant (see Screening section)
  • 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 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

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

Inheritance

  • Autosomal recessive for the 9 disorders listed above

Pathophysiology

Clinical Presentation

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

Ashkenazi Jewish Diseases (BLM, ASPA, IKBKAP, FANCC, GBA, MCOLN1, SMPD1, HEXA), Common Mutation Panel 0051415
Method: Polymerase Chain Reaction/ASPE Bead Array

Limitations

Mutations, other than those tested on this panel, will not be detected

Diagnostic errors can occur due to rare sequence variations

Follow Up

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

Limitations

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

Limitations

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

Follow Up

If plasma/serum results are inconclusive, perform leukocyte testing

Hexosaminidase A Percent and Total Hexosaminidase in Leukocytes 2008125
Method: Quantitative Fluorometry

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

Limitations

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

Limitations

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

Limitations

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

Limitations

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

Limitations

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

Limitations

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

Limitations

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

Limitations

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

Limitations

Mutations other than those tested will not be detected

Rare diagnostic errors can occur due to rare sequence variations

Additional Tests Available

Bloom Syndrome (BLM) 1 Mutation, Fetal 0051434
Method: Polymerase Chain Reaction/Primer Extension

Comments

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

Comments

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

Comments

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

Comments

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

Comments

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

Comments

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

Comments

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

Comments

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

Comments

Preferred test to confirm diagnosis of Tay-Sachs disease

Preferred test for carrier screening in males or nonpregnant females

Bone Marrow Failure Sequencing, 35 Genes 2012222
Method: Massively Parallel Sequencing

Comments

Determine genetic etiology for bone marrow failure and clonal myeloid neoplasms

Confirm a diagnosis of

  • Fanconi anemia
  • Dyskeratosis congenita
  • Diamond-Blackfan anemia
  • Shwachman-Diamond syndrome

Chromosome Analysis - Breakage, Fanconi Anemia, Whole Blood 0097688
Method: Giemsa Band

Comments

Useful for the diagnosis of Fanconi anemia

Not for use in diagnosing ataxia telangiectasia or cell damage due to radiation or chemical exposures

Guidelines

ACOG Committee on Genetics. ACOG Committee Opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent. Obstet Gynecol. 2009; 114(4): 950-3. PubMed

Gross S, Pletcher B, Monaghan K, Professional Practice and Guidelines Committee. Carrier screening in individuals of Ashkenazi Jewish descent. Genet Med. 2008; 10(1): 54-6. PubMed

General References

Kaback M, Desnick R. Hexosaminidase A Deficiency. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Aug 2011; Accessed: Nov 2015]

Matalon R, Michals-Matalon K. Canavan Disease. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Aug 2011; Accessed: Nov 2015]

Pastores G, Hughes D. Gaucher Disease. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Feb 2015; Accessed: Nov 2015]

Sanz M, German J. Bloom's Review. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Mar 2006; Accessed: Nov 2015]

Schiffmann R, Grishchuk Y, Goldin E. Mucolipidosis IV. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Jul 2015; Accessed: Nov 2015]

Shohat M, Hubshman M. Familial Dysautonomia. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews,. Seattle, WA [Last updated Dec 2014; Accessed: Nov 2015]

Wasserstein M, Schuchman E. Acid Sphingomyelinase Deficiency. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Jun 2015; Accessed: Nov 2015]

Medical Reviewers

Last Update: January 2016