Ashkenazi Jewish Genetic Diseases

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

For which genetic diseases is a patient of Ashkenazi Jewish descent commonly screened during pregnancy or if planning a pregnancy?

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.

Are there other individuals who should be tested for diseases commonly associated with Ashkenazi Jewish ancestry?

Individuals of French-Canadian and Louisiana Cajun ancestry are at increased risk for Tay-Sachs disease. Testing for hexosaminidase A (HexA) is recommended in these individuals.

Which laboratory tests are recommended for Tay-Sachs disease?

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.

Ashkenazi Jewish Genetic Diseases for Which Screening Is Recommended
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.