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Individuals of Ashkenazi Jewish descent are at an increased risk for certain autosomal recessive genetic disorders. These disorders include cystic fibrosis, Canavan disease, familial dysautonomia, Tay-Sachs disease, Fanconi anemia, Niemann-Pick disease, Bloom syndrome, mucolipidosis type IV, and Gaucher disease, among others. , , It is estimated that one in every four or five individuals of Ashkenazi Jewish descent is a carrier for one of these conditions. Due to the increased incidence of these diseases in this population (see the table in the Ashkenazi Jewish Genetic Diseases Test Fact Sheet), routine preconception or prenatal expanded carrier screening is recommended. , Laboratory testing may entail a gene panel for multiple disorders, single-disorder genetic testing, or other testing (eg, hexosaminidase enzyme assays for Tay-Sachs disease), depending on the needs of the patient. , ,
Quick Answers for Clinicians
Individuals of Ashkenazi Jewish descent may carry pathogenic variants for Bloom syndrome, Canavan disease, cystic fibrosis, familial dysautonomia, familial hyperinsulinism, Fanconi anemia C, Gaucher disease, glycogen storage disease type 1A, Joubert syndrome type 2, maple syrup urine disease type 1B, mucolipidosis IV, Niemann-Pick disease type A, and Tay-Sachs disease, among other disorders. Guidelines recommend offering expanded carrier testing for disorders with a carrier frequency of 1 in 100 or greater that have a significant negative impact on quality of life (among other criteria) to individuals of Ashkenazi Jewish descent who are pregnant or plan to become pregnant. ,
Genetic testing for Tay-Sachs disease is appropriate as part of an expanded carrier screening panel for individuals of Ashkenazi Jewish descent. Hexosaminidase A (HexA) testing (serum or leukocyte) may be used for individuals of all ethnic backgrounds. , False-positive results may occur in serum enzyme testing in women who are pregnant or taking oral contraceptives; in these patient populations, leukocyte testing must be performed.
Indications for Testing
Laboratory testing for Ashkenazi Jewish genetic diseases is used for expanded carrier screening in individuals of Ashkenazi Jewish descent who are planning a pregnancy or are currently pregnant , and for disorder-specific testing in the following circumstances:
- Screening in relatives of individuals with an identified pathogenic variant , ,
- Diagnosis in individuals of Ashkenazi Jewish descent with suggestive symptoms , ,
- Screening in individuals of non-Ashkenazi Jewish descent who are reproductive partners of individuals with an identified pathogenic variant , ,
Laboratory Testing
Screening
Expanded Carrier Screening for Individuals of Ashkenazi Jewish Descent
Due to their increased risk for specific disorders, individuals with one or more grandparents of Ashkenazi Jewish descent should be offered expanded carrier screening. , The American College of Medical Genetics (ACMG) recommends offering expanded carrier screening for nine diseases ; the American College of Obstetricians and Gynecologists (ACOG) recommends testing for the same nine and considering testing for five additional diseases. Testing before pregnancy is recommended to enable individuals to make appropriate reproductive decisions. ,
Diseases Recommended for Carrier Screening by ACOG and ACMG | |||
|---|---|---|---|
| Disease (Gene) | Incidence | Carrier Frequency | Symptoms and Characteristics |
| Bloom syndrome (BLM) | 1/40,000 | 1/100 | Pre- and postnatal growth deficiency; skin lesions that appear at 1-2 yrs of age; benign and malignant tumors in childhood; telangiectatic hypo- and hyperpigmented skin lesions; male sterility; decreased life expectancy due to malignancy |
| Canavan disease (ASPA) | 1/10,000 | 1/40-1/82 | Macrocephaly; loss of motor control beginning at 3-5 mos of age; failure to sit, stand, or ambulate; survival usually until childhood or teenage yrs |
| Cystic fibrosis (CFTR) | See Cystic Fibrosis topic | ||
| Familial dysautonomia (IKBKAP) | 1/3,600 | 1/36 | Delayed motor milestones in infants and progressive deterioration of gait throughout life; gastrointestinal dysfunction with emesis; altered sensitivity to pain and temperature; cardiovascular instability; survival typically until 30 yrs of age |
| Fanconi anemia group C (FANCC) | 1/32,000 | 1/93 | Progressive bone marrow failure during first decade of life; increased risk of malignancy (hematologic in ~20%, nonhematologic in ~30%); physical malformations that may include short stature, abnormal skin pigmentation, or malformations of the eyes, ears, heart, forearms, thumbs, kidneys; survival usually until childhood or teenage yrs |
| Gaucher disease (GBA) | 1/900 | 1/18 | Type 1 (most prevalent type among individuals of Ashkenazi Jewish descent): bone disease; hepatosplenomegaly; anemia, thrombocytopenia; lung disease; no primary CNS disease Type 2: CNS degeneration by 2 yrs of age with a rapidly progressive course; survival until 4 yrs of age Type 3: slowly progressive CNS degeneration; survival until 20s |
| Mucolipidosis type IV (MCOLN1) | 1/63,000 | 1/100-1/127 | Severe psychomotor delay; progressive visual impairment due to retinal degeneration and corneal clouding; static neurologic state until 30 yrs of age in most affected individuals; neurologic degeneration in ~15%; variable life expectancy (most individuals live into adulthood) |
| Niemann-Pick disease type A (SMPD1) | 1/32,000 | 1/80-1/100 | Hepatosplenomegaly; developmental delay and severe neurodegeneration; progressive hypotonia and rigidity; cherry-red spot on the macula of the retina; survival until 3-5 yrs of age |
| Tay-Sachs disease (HEXA) | 1/3,000 | 1/27.4 | Progressive loss of motor skills beginning at 3-6 mos of age; progressive neurodegeneration resulting in blindness, seizures, and eventually total incapacitation; survival until 4-6 yrs of age |
| Diseases Recommended for Consideration for Carrier Screening by ACOG | |||
| ABCC8-related hyperinsulinism (ABCC8) | 1/10,800 | 1/52 | Neonatal onset; hypoglycemia that varies from mild to severe; normal lifespan with proper management |
| Glycogen storage disease type 1A (G6PC) | 1/20,000 | 1/71 | Hepatomegaly; growth delay/short stature; hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia; additional long-term complications include osteoporosis, delayed puberty, renal disease, systemic hypertension, hepatic adenomas with potential for malignant transformation; survival into adulthood with treatment |
| Joubert syndrome type 2 (TMEM216) | 1/34,000 | 1/92-1/100 | “Molar tooth sign” cerebellar and brain stem malformation; hypotonia; developmental delay/intellectual disability; normal lifespan (typically), but minority may have shortened lifespan depending on severity |
| Maple syrup urine disease type 1B (BCKDHB) | 1/50,000 | 1/113 | Maple syrup odor in urine; classically, presentation within first few days of life with irritability, poor feeding and lethargy, intermittent apnea; progression to coma and death within 7-10 days if untreated |
| Usher syndrome type 1F (PCDH15) | 1/20,500 | 1/40-1/127 | Profound congenital bilateral sensorineural hearing loss; adolescent-onset retinitis pigmentosa; loss of vestibular function |
| Usher syndrome type 3 (CLRN1) | 1/82,000 | 1/120 | Postlingual, progressive hearing loss; late-onset progressive loss of vision due to retinitis pigmentosa; variable loss of vestibular function |
| Additional Diseases Common in Individuals of Ashkenazi Jewish Descent | |||
| Lipoamide dehydrogenase deficiency (DLD) | 1/35,000 | 1/94-1/110 | Early-onset disease: presentation in infancy with hypotonia, lethargy, and vomiting with progressive encephalopathy; survival usually until 1-2 yrs of age Primarily hepatic disease: variable onset from infancy to 4th decade of life; liver injury/failure, usually preceded by nausea/vomiting; typically, normal intellect with no neurologic findings; variable lifespan depending on severity of condition |
| NEB-related nemaline myopathy (NEB) | 1/47,000 | 1/108 | Presentation in first year of life with static or slowly progressive muscle weakness of the face, neck, arms, and legs; hypotonia; feeding difficulties; typically, normal lifespan and active independent life |
CNS, central nervous system Sources: ACOG, 2017 ; ACMG, 2008 ; GeneReviews - ; Edelmann, 2001 ; GeneAware | |||
Disorder-Specific Screening
Tay-Sachs Disease
Tay-Sachs testing is recommended for individuals of Ashkenazi Jewish, French-Canadian, or Cajun descent, as well as reproductive partners of an individual with an identified Tay-Sachs pathogenic variant and individuals with a family history of Tay-Sachs disease. , Hexosaminidase A (HexA) enzyme testing is recommended for individuals from non-Ashkenazi Jewish backgrounds because it is the most sensitive test in individuals of all racial and ethnic backgrounds. , , HexA enzyme testing must be performed in leukocytes for women who are pregnant or taking oral contraceptives, given that false-positive results may occur when using a serum test for these patients. Molecular testing of the HEXA gene can be considered to identify pathogenic variants when HexA enzyme activity is abnormal.
Cystic Fibrosis
Individuals of Ashkenazi Jewish descent are at increased risk for cystic fibrosis. Cystic fibrosis carrier screening should be offered to women of all ethnicities who are pregnant or planning to become pregnant. , , See the Cystic Fibrosis topic for more information about appropriate laboratory testing.
Other Ashkenazi Jewish Genetic Diseases
Carrier screening is recommended for non-Ashkenazi Jewish individuals whose reproductive partner is a carrier of one or more disorders or in individuals with a family history of a particular disorder when the familial pathogenic variant is unknown. , Disorder-specific testing may be ordered in these circumstances; however, the detection rate of the Ashkenazi Jewish common variant panels varies by disorder and is largely unknown for other populations.
Diagnosis
The diagnostic testing strategy for Ashkenazi Jewish genetic diseases depends on the specific disease that is suspected (see table above).
Tay-Sachs Disease
HexA enzymatic testing is the initial test to confirm a diagnosis of Tay-Sachs disease in a symptomatic individual. Molecular testing of the HEXA gene can be used to identify pathogenic variants when HexA enzyme activity is abnormal. Molecular genetic testing is also necessary to distinguish pseudodeficiency alleles from pathogenic variants.
Cystic Fibrosis
Diagnostic testing for cystic fibrosis includes sweat chloride and genetic testing (see the ARUP Consult Cystic Fibrosis topic for additional information).
Other Ashkenazi Jewish Genetic Diseases
Genetic testing for diagnostic purposes for many Ashkenazi Jewish disorders typically includes full sequencing of the associated gene. Alternatively, an Ashkenazi Jewish common variant panel can be used in individuals of Ashkenazi Jewish descent or with a family history of a pathogenic variant that is present on the panel. Additionally, if both expectant parents are identified as carriers of a specific disorder, fetal targeted sequencing for the familial pathogenic variants can be used as follow-up testing. Targeted sequencing can also be used for postnatal diagnosis of a specific disorder.
ARUP Laboratory Tests
Polymerase Chain Reaction (PCR)/Fluorescence Monitoring
Massively Parallel Sequencing
Polymerase Chain Reaction (PCR), Fluorescence Monitoring
Matrix-Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) Mass Spectrometry
Polymerase Chain Reaction (PCR), Fluorescence Monitoring
Polymerase Chain Reaction (PCR), Fluorescence Monitoring
Polymerase Chain Reaction (PCR), Fluorescence Monitoring
Polymerase Chain Reaction (PCR), Fluorescence Monitoring
Polymerase Chain Reaction (PCR), Fluorescence Monitoring
Polymerase Chain Reaction (PCR), Fluorescence Monitoring
Polymerase Chain Reaction (PCR), Fluorescence Monitoring
Polymerase Chain Reaction (PCR), Fluorescence Monitoring
Polymerase Chain Reaction (PCR)/Fluorescence Monitoring
Polymerase Chain Reaction (PCR)/Fluorescence Monitoring
Polymerase Chain Reaction (PCR), Fluorescence Monitoring
Polymerase Chain Reaction (PCR), Fluorescence Monitoring
Polymerase Chain Reaction (PCR), Fluorescence Monitoring
Polymerase Chain Reaction (PCR), Fluorescence Monitoring
Massively Parallel Sequencing
Massively Parallel Sequencing
References
-
28225426
ACOG Committee on Genetics. ACOG Committee Opinion No. 691: carrier screening for genetic conditions. Obstet Gynecol. 2017;129(3):e41-e55.
-
28225420
ACOG Committee on Genetics. Committee Opinion No. 690 Summary: Carrier screening in the age of genomic medicine. Obstet Gynecol. 2017;129(3):595-596.
-
18197057
Gross SJ, Pletcher BA, Monaghan KG. Carrier screening in individuals of Ashkenazi Jewish descent. Genet Med. 2008;10(1):54‐56.
-
25730230
Edwards JG, Feldman G, Goldberg J, et al. Expanded carrier screening in reproductive medicine—points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. Obstet Gynecol. 2015;125(3):653-662.
-
GeneReviews - Bloom Syndrome
Flanagan M, Cunniff CM. Bloom syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Last update Feb 2019; accessed May 2020.
-
GeneReviews Canavan Disease - Jewish Genetic Dz
Matalon R, Delgado L, Michals-Matalon K. Canavan disease. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Last update Sep 2018; accessed May 2020.
-
GeneReviews Familial Dysautonomia - Jewish Genetic Dz
Shohat M, Weisz Hubshman M. Familial dysautonomia. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Last update Dec 2014; accessed May 2020.
-
GeneReviews - Fanconi anemia
Mehta PA, Tolar J. Fanconi anemia. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Last revision Mar 2018; accessed May 2020.
-
GeneReviews - Gaucher Disease
Pastores GM, Hughes DA. Gaucher disease. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews, University of Washington; 1993-2020. [Last Update: Jun 2018; Accessed: May 2020]
-
GeneReviews Mucolipidosis IV - Jewish Genetic Dz
Schiffmann R, Grishchuk Y, Goldin E. Mucolipidosis IV. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Last update Jul 2015; accessed May 2020.
-
GeneReviews Acid Sphingomyelinase Deficiency - Jewish Genetic Dz
Wasserstein MP, Schuchman EH. Acid sphingomyelinase deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Last update Jun 2015; accessed May 2020.
-
Hexosaminidase A deficiency
Kaback MM, Desnick RJ. Hexosaminidase A deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Last Update Aug 2011; accessed May 2020.
-
GeneReviews - Familial Hyperinsulinism
Gillis D. Familial hyperinsulinism. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews, University of Washington; 1993-2020. Last update Mar 2019; accessed May 2020.
-
GeneReviews - Glycogen storage disease type I
Bali DS, Chen YT, Austin S, et al. Glycogen storage disease type I. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Last update Aug 2016; accessed May 2020.
-
GeneReviews - Joubert syndrome
Parisi M, Glass I. Joubert syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Last update Jun 2017; accessed May 2020.
-
GeneReviews - Maple Syrup Urine Disease
Strauss KA, Puffenberger EG, Morton DH. Maple syrup urine disease. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Last update May 2013; accessed May 2020.
-
GeneReviews - Usher Syndrome Type I
Lentz J, Keats BJB. Usher syndrome type I. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Last update May 2016; accessed May 2020.
-
GeneReviews - Dihydrolipoamide Dehydrogenase Deficiency
Quinonez SC, Thoene JG. Dihydrolipoamide dehydrogenase deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Initial posting Jul 2014; accessed May 2020.
-
11509994
Edelmann L, Wasserstein MP, Kornreich R, et al. Maple syrup urine disease: identification and carrier-frequency determination of a novel founder mutation in the Ashkenazi Jewish population. Am J Hum Genet. 2001;69(4):863-868.
-
GeneAware - Reproductive Carrier Screening
GeneAware. Reproductive carrier screening. Baylor Genetics. Accessed Jun 2020.