Carrier Screening for Genetic Disorders

Carrier screening for certain disorders is traditionally offered to individuals and couples based on ethnicity and family history of specific genetic conditions. Professional organizations, including the American Congress of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG), provide varying recommendations for carrier screening of disorders like cystic fibrosis, fragile X syndrome, and spinal muscular atrophy (SMA). ARUP Laboratories offers several carrier screening testing options, including targeted mutation panels that screen for specific disorders, and expanded carrier screening panels by next generation sequencing and genotyping.

Quick Answers for Clinicians

Which testing algorithms are related to this topic?

Diagnosis

Indications for Testing

General population carrier screening for individuals or couples during or prior to pregnancy

Laboratory Testing

  • Targeted mutation panels
  • Expanded carrier screening panels
    • Screen for a large number of disorders with one test, independent of ethnicity, by genotyping or next generation sequencing (NGS)
  • Biochemical or hematologic testing
    • Analytes are used to screen for specific disorders; examples include
      • Hemoglobin evaluation with reflex to electrophoresis and/or RBC solubility – screen for hemoglobinopathies/thalassemia
      • Hexosaminidase A percent and total hexosaminidase in leukocytes – screen for Tay-Sachs Disease
  • For information about additional prenatal screening and diagnostic options, refer to the Prenatal Screening and Diagnosis for Chromosomal Abnormalities and Neural Tube Defects topic

Interpretation of Results

  • Carriers – individuals with a pathogenic variant identified in a gene that causes an autosomal recessive or X-linked recessive disorder
  • Carrier screening results
    • Positive – one pathogenic gene variant detected
      • The individual tested is predicted to be a carrier of the specified disorder
        • For most disorders, carriers do not usually have clinical findings of the disorder, but this may vary
      • His/her reproductive partner should be offered carrier screening for the disorder; genetic consultation is also recommended  
      • Couples identified as carriers of the same disorder may elect to pursue
        • Gamete donation/in vitro fertilization
        • Preimplantation genetic diagnosis (PGD)
        • Prenatal diagnostic testing for the disorder via chorionic villus sampling (CVS) or amniocentesis
    • Negative – no variants detected
      • Carrier risk and the risk of having a child affected with the specified genetic condition(s) has been reduced but not eliminated
  • ARUP tests and carrier frequencies/detection rates of select disorders by ethnicity
    • Cystic fibrosis
      • Additional Technical Information – Cystic Fibrosis (CFTR) 165 Pathogenic Variants
        Ethnicity Carrier Frequency Detection Rate (Clinical Sensitivity) Residual Carrier Risk After Negative Test Resulta

        African Americans

        1 in 61

        78%

        1/275

        Ashkenazi Jewish

        1 in 24

        96%

        1/575

        Asian Americans

        1 in 94

        55%

        1/210

        European Caucasians

        1 in 25

        92%

        1/300

        Hispanic Americans

        1 in 58

        80%

        1/285

        aThe residual risk of being a carrier following a negative test result (posttest carrier risk), assuming no family history of the disorder, is provided based on Bayesian statistical analysis; alternative Bayesian calculations are necessary to determine posttest carrier risk for those with a positive family history of the disorder

    • Spinal muscular atrophy
      • Additional Technical Information – Spinal Muscular Atrophya
        Ethnicity Carrier Frequency Detection Rate (Clinical Sensitivity) Residual Carrier Risk After Negative Test Resultb
        African Americans 1 in 72 90% 1/375
        Ashkenazi Jewish

         

        1 in 67 93% 1/918
        Asian Americans

         

        1 in 59 93% 1/907
        Caucasians

         

        1 in 47 95% 1/921
        Hispanic Americans

         

        1 in 67 93% 1/906

        aResidual risk for this test is based on a result of 2 copies of SMN1 detected without the SNP associated with silent carriers

        bThe residual risk of being a carrier following a negative test result (posttest carrier risk), assuming no family history of the disorder, is provided based on Bayesian statistical analysis; alternative Bayesian calculations are necessary to determine posttest carrier risk for those with a positive family history of the disorder

        Source: Feng, 2017; Sugarman, 2012

    • Ashkenazi Jewish diseases
      • Additional Technical Information – Ashkenazi Jewish Genetic Diseases

        Disease

        Ethnicity

        Carrier Frequency

        Detection Rate (Clinical Sensitivity)

        Residual Carrier Risk After Negative Test Resulta

        ABCC8-related hyperinsulinism

        Ashkenazi Jewish

        1/52

        97%

        1/1,700

        Bloom syndrome

        Ashkenazi Jewish

        1/100

        97%

        1/3,300

        Canavan disease

        Ashkenazi Jewish

        1/50

        99%

        1/4,900

        Familial dysautonomia

        Ashkenazi Jewish

        1/32

        99%

        1/3,100

        Fanconi anemia group C

        Ashkenazi Jewish

        1/89

        99%

        1/8,800

        Gaucher disease type 1

        Ashkenazi Jewish

        1/15

        90%

        1/141

        Glycogen storage disease type 1A

        Ashkenazi Jewish

        1/71

        99%

        1/7,000

        Joubert syndrome type 2

        Ashkenazi Jewish

        1/92

        99%

        1/9,100

        Lipoamide dehydrogenase deficiency

        Ashkenazi Jewish

        1/94

        99%

        1/9,300

        Maple syrup urine disease type 1B

        Ashkenazi Jewish

        1/113

        99%

        1/11,200

        Mucolipidosis IV

        Ashkenazi Jewish

        1/127

        95%

        1/2,500

        NEB-related nemaline myopathy

        Ashkenazi Jewish

        1/108

        99%

        1/10,700

        Niemann-Pick disease type A

        Ashkenazi Jewish

        1/90

        90%

        1/890

        Tay-Sachs disease

        Ashkenazi Jewish

        1/30

        94%

        1/480

        Usher syndrome type 1F

        Ashkenazi Jewish

        1/72

        62%

        1/190

        Usher syndrome type 3

        Ashkenazi Jewish

        1/143

        98%

        1/7,100

        aThe residual risk of being a carrier following a negative test result (posttest carrier risk), assuming no family history of the disorder, is provided based on Bayesian statistical analysis; alternative Bayesian calculations are necessary to determine posttest carrier risk for those with a positive family history of the disorder

Prognosis

  • Conditions included on carrier screening panels vary in clinical severity
    • Many disorders are associated with significant adverse outcomes (eg, congenital anomalies, intellectual disability, shortened life expectancy)
    • Some conditions are chronic and have lifelong requirements for medical or surgical intervention
    • Some conditions have standard recommended treatment and can improve with early intervention
    • Some disorders have limited or no treatment options available

Screening

  • Traditionally, carrier screening for certain disorders is offered to individuals and couples based on ethnicity and family history of specific genetic conditions
  • Professional organizations offer varying recommendations for carrier screening
Screening Recommendations and Guidelines by Disorder
Disorder American Congress of Obstetricians and Gynecologists (ACOG), 2017 American College of Medical Genetics and Genomics (ACMG), 2008 and 2013 National Society of Genetic Counselors (NSGC), 2012 and 2014
Cystic fibrosis (CF)

Offer CF carrier screening to all women of reproductive age; complete sequencing of the CF gene is not appropriate for carrier screening

Offer population screening using a panel of 23 pathogenic variants in the CFTR gene associated with classic CF and present in at least 0.1% of patients with CF (2013 recommendation)

Carrier testing for CF should be offered to all women of reproductive age, regardless of ancestry, preferably before pregnancy (2014 recommendation)

 

Fragile X syndrome

Screening should be limited to individuals with family history of intellectual disability suggestive of fragile X, unexplained intellectual disability, developmental delay, autism, or primary ovarian insufficiency

Screening should be limited to individuals with family history of intellectual disability suggestive of fragile X (2013 recommendation)

Screening should be limited to individuals with family history of intellectual disability suggestive of fragile X (2012 recommendation)

Spinal muscular atrophy (SMA)

SMA carrier screening should be offered to all women who are currently pregnant or considering pregnancy

Offer SMA screening regardless of ancestry or family history (2008 recommendation)

n/a

Hemoglobinopathies

Hemoglobinopathies carrier screening should be offered to individuals of African, Southeast Asian, and Mediterranean descent

Complete blood count and hemoglobin electrophoresis are appropriate initial laboratory tests for all women to be screened for hemoglobinopathies, with subsequent molecular genetic testing if indicated

n/a

n/a

Ashkenazi Jewish genetic diseases

Recommend routine preconception or prenatal carrier screening for diseases common to individuals of Eastern European (Ashkenazi) Jewish descent, including Canavan disease, CF, familial dysautonomia, and Tay-Sachs disease; can also consider screening for Bloom syndrome, familial hyperinsulinism, Fanconi anemia group C, Gaucher disease type 1, glycogen storage disease type 1A, Joubert syndrome type 2, maple syrup urine disease type 1B, mucolipidosis IV, Niemann-Pick disease type A, and Usher syndrome

Recommend routine preconception or prenatal carrier screening for diseases common to individuals of Eastern European (Ashkenazi) Jewish descent

Recommend screening for 9 disorders – Bloom syndrome, Canavan disease, CF, familial dysautonomia, Fanconi anemia group C, Gaucher disease type 1, mucolipidosis IV, Niemann-Pick disease type A, and Tay-Sachs disease (2008 recommendation)

 

n/a

Source: Compiled from Edwards, 2015

  • Limitations of single-condition screening
    • Inaccurate knowledge of ancestry/ethnicity
    • Uncertain carrier risk estimates for multiethnic individuals and couples
    • Lack of information about other disorders for which the individual or couple may be at risk
  • Expanded carrier screening or panethnic carrier screening
    • A newer approach to carrier screening based on the premise of testing individuals for many genetic disorders via a large panel of genes
    • More cost-effective way to screen for multiple conditions
    • Expanded carrier screening can be offered panethnically
  • For most genetic disorders, carrier screening significantly reduces the likelihood of being a carrier but does not exclude carrier status entirely; thus, a residual risk to be a carrier always exists
  • Individuals may be identified as a carrier for more than one disorder
  • Genetic counseling is recommended for any individual undergoing carrier screening

ARUP Lab Tests

Primary Tests

Screen for genetic variants that indicate carrier status for cystic fibrosis (CF), fragile X syndrome (FXS), and spinal muscular atrophy (SMA) in pregnant couples or those planning a pregnancy

Do not use for diagnostic testing in patients with symptoms of CF, FXS, or SMA

Carrier screening for expectant individuals and those planning a pregnancy AND diagnostic testing for individuals with symptoms of classic CF

Only the 165 CFTR variants and 5T variant will be interrogated

Diagnostic errors can occur due to rare sequence variations

Preferred test to diagnose fragile X syndrome and carrier screening in individuals with a positive family history

Estimated size is not provided for full mutations with >200 repeats

Methylation patterns are not fully established at the time of chorionic villus sampling for fetal testing

Amniocyte analysis is recommended to distinguish a small, full mutation from a large premutation

Rare mutations in FMR1 unrelated to trinucleotide expansion will not be detected

Diagnostic errors can occur due to rare sequence variations

Preferred initial test to diagnose suspected Tay-Sachs disease or identify carriers of Tay-Sachs disease

Use for individuals who are pregnant, use oral contraceptives, have severe liver or autoimmune disease, or had previously inconclusive HEX A enzyme serum/plasma level

Can detect Sandhoff disease

Results may be affected by alternate hexosaminidase isoforms, pseudodeficiency alleles, or the B1 variant

Diagnostic or carrier testing for SMA

Test also includes 2 SMN1 variants that are part of a haplotype associated with SMN1 duplication in silent carriers, especially in Ashkenazi Jewish and Asian populations

  • c.*3+80T>G (rs143838139), g.27134T>G
  • c.*211_*212del (rs200800214), g.27706-27707delAT

Test is unable to determine

  • Whether SMN1 copies are on the same or opposite chromosomes (≥1 copy of SMN1 on each chromosome [not a carrier] indistinguishable from ≥2 copies of SMN1 on 1 chromosome and zero copies on the opposite chromosome [silent carrier])
  • Whether SMN1 and SMN2 copies are on the same or opposite chromosomes

Only copy number will be detected for SMN1 and SMN2

Sequence variants in SMN1 or SMN2 ;will not be detected

Diagnostic errors can occur due to rare sequence variations

Screening and follow up of individuals with hemoglobinopathies

May not detect all hemoglobin variants

Acceptable first-tier genetic test for confirmation of suspected α thalassemia or α thalassemia trait

Rare α-globin deletions, nondeletional variants, gene duplications, and variants of the regulatory region will not be detected

α-globin gene duplications will not be detected

Diagnostic errors can occur due to rare sequence variations

Rare syndromic or acquired forms of α  thalassemia will not be detected

Preferred gene panel for carrier screening for individuals of Ashkenazi Jewish descent

Detects 51 variants associated with 16 disorders common in Ashkenazi Jews

Variants other than those tested on this panel will not be detected

Diagnostic errors can occur due to rare sequence variations

Prenatal or preconception carrier screening of individuals or couples in the general population via NGS for over 100 disorders

Refer to https://www.counsyl.com/
services/foresight/diseases/ for more information

Prenatal or preconception carrier screening of individuals or couples in the general population via NGS for over 100 disorders, including Fragile X syndrome

Refer to https://www.counsyl.com/
services/foresight/diseases/ for more information

Reports only clinically significant variants

Single Gene Tests

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