Carrier Screening for Genetic Disorders

Individuals who have a pathogenic gene variant that causes an autosomal recessive or X-linked disorder (but who often have no clinical findings or symptoms of the disorder) are known as carriers. Carrier screening refers to testing that is performed to determine if an individual is a carrier, assess the risk for the particular disorder in the individual’s offspring, and enable informed reproductive choices.^, There are many acceptable strategies for carrier screening, including targeted screening for specific conditions (based on ethnicity and family history) and expanded screening to detect multiple conditions simultaneously.^, Professional organizations, including the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG), provide varying carrier screening recommendations for commonly screened disorders, including cystic fibrosis (CF), fragile X syndrome (FXS), and spinal muscular atrophy (SMA).^,^, Carrier screening for these and other disorders may entail single-gene analysis, targeted variant panels, or expanded panels.

This topic discusses carrier screening for genetic disorders; for more information on the use of laboratory tests in screening for fetal aneuploidy and neural tube defects, refer to the ARUP Consult Prenatal Testing for Chromosomal Abnormalities and Neural Tube Defects topic.

Quick Answers for Clinicians

Who should be offered carrier screening, and when should it be offered?

The American College of Obstetricians and Gynecologists (ACOG) recommends that information about carrier screening be provided to every individual who is pregnant or is planning to become pregnant.^, The specific tests that should be offered depend on the patient’s family history and ethnic background. Testing is also appropriate in reproductive partners of known carriers, family members of known carriers, and gamete (ie, egg or sperm) donors. Ideally, carrier screening should be performed before pregnancy to enable individuals to make informed reproductive decisions^,^,; however, carrier screening can also be performed during pregnancy. Regardless of the timing of carrier screening, testing for a specific disorder is typically recommended only once in an individual’s lifetime. For more information, refer to the Indications for Testing section.

Which disorders should be considered for carrier screening?

The American College of Obstetricians and Gynecologists (ACOG) recommends including disorders in carrier screening panels if they (1) have a carrier frequency of 1:100 or greater; (2) exhibit a well-defined phenotype; (3) have a detrimental effect on quality of life; (4) result in cognitive or physical impairment; (5) require surgical or medical intervention; and (6) have an onset early in life. The American College of Medical Genetics and Genomics (ACMG) recommends including disorders on screening panels if at-risk individuals would consider a prenatal diagnosis of those disorders to be beneficial for decision-making purposes. The carrier risks and detection rates should be known so that residual risk can be calculated, and the clinical associations between pathogenic variants and disease severity should be well defined. Disorders with variable expressivity, incomplete penetrance, or a mild phenotype should be considered optional for inclusion in panels.

Which types of laboratory tests are used in carrier screening?

Although molecular genetic techniques are used to screen for most disorders, biochemical or hematologic testing is appropriate in some cases (eg, hemoglobin electrophoresis for hemoglobinopathies or biochemical [enzyme] testing for Tay-Sachs disease). Refer to the Carrier Screening Tests section for more information.

Are newborn screening and carrier screening interchangeable?

No. Carrier screening is not a substitute for newborn screening, and vice versa. Newborn screening tests are state mandated and are intended to detect, at an early age, disorders for which a treatment or intervention is available. Given that carriers may never develop any signs or symptoms of disease, newborn screening tests are not suitable for identifying carriers. Carrier screening is intended to determine if an individual has a variant associated with a genetic disease, and therefore has the potential to pass that disease to offspring. Furthermore, newborn screening and carrier screening panels may test for different conditions. For more information on newborn screening, refer to the CDC's Newborn Screening Portal.

Indications for Testing

Carrier testing may be offered or recommended based on a variety of factors such as ethnicity, family history, or abnormal ultrasound findings. If an individual is identified as a carrier of an autosomal recessive disorder, that person’s reproductive partner should be offered carrier screening for that disorder, or simultaneous testing can be offered to both partners.^, Testing for a particular disorder is usually recommended only once in a person’s lifetime, unless a genetics professional determines that advances in testing (eg, new methodologies or the discovery of additional variants associated with a specific disease) warrant rescreening.

Professional organizations offer the following recommendations for commonly screened conditions.

Screening Recommendations by Disorder
Disorder	Recommendations
CF	Offer screening to all individuals who are pregnant or considering pregnancy A panel of the most common CFTR variants (present in at least 0.1% of the population) associated with classic CF is recommended Complete sequencing of the CFTR gene is not appropriate for carrier screening
FXS	Offer screening to individuals with a family history of FXS or intellectual disability suggestive of FXS, ovarian insufficiency, ovarian failure, or elevated follicle-stimulating hormone before 40 yrs of age
SMA	Offer screening to all individuals who are pregnant or considering pregnancy, regardless of ancestry or family history
Hemoglobinopathies	Perform a CBC in all individuals who are pregnant or, ideally, considering pregnancy Perform hemoglobin electrophoresis for individuals of African, Mediterranean, Middle Eastern, Southeast Asian, or West Indian descent or if a hemoglobinopathy is suspected based on CBC results
Ashkenazi Jewish genetic diseases	Offer screening to individuals of Ashkenazi Jewish descent who are pregnant or planning to become pregnant Tay-Sachs screening should be offered to all individuals of Ashkenazi Jewish, French-Canadian, or Cajun descent
Sources: ACOG, 2017; Edwards, 2015; ACOG, 2017

Laboratory Testing

Carrier Screening Tests

Screening tests may take the form of single-disorder biochemical tests (eg, hexosaminidase A testing for Tay-Sachs disease), single-gene sequencing or deletion/duplication tests (eg, copy number analysis of the SMN1 gene associated with SMA), targeted panels (eg, panel tests for common CFTR variants associated with CF), expanded panels, or massively parallel sequencing. Regardless of the strategy used, genetic counseling is recommended.^,^,

Single-Disorder Tests

Individual conditions commonly screened for include CF, FXS, and SMA. For more information on CF tests, refer to the ARUP Consult Cystic Fibrosis topic. For information on FXS, refer to the Fragile X Syndrome Test Fact Sheet. For more information on SMA, refer to the Spinal Muscular Atrophy Test Fact Sheet. Ethnicity-based carrier screening for hemoglobinopathies using biochemical tests is also recommended; refer to the ARUP Consult Hemoglobinopathies topic for more information.

Expanded Carrier Screening Panels

Expanded carrier screening for multiple disorders using a panel of genetic and/or biochemical tests can be considered for individuals from specific ethnic backgrounds (eg, multigene panels for individuals of Ashkenazi Jewish descent) or for couples with consanguinity, or can be considered for all individuals regardless of ethnicity (panethnic screening), given the difficulty of precisely determining an individual’s ethnic background and the associated difficulty of estimating carrier risk.^,^, Decisions about which disorders to include on a screening panel should be based on the background, family history, and needs of the patient. Genetic consultation is also advised.

For more information on expanded screening for individuals of Ashkenazi Jewish descent, refer to the ARUP Consult Ashkenazi Jewish Genetic Diseases topic and the Ashkenazi Jewish Genetic Diseases Panel Test Fact Sheet.

Interpretation of Results

A negative result on a carrier screening test indicates that no pathogenic variant has been detected; therefore, the carrier risk is reduced, but not eliminated. A positive result on a carrier screening test indicates that one or more pathogenic variants were detected, and that the individual is predicted to be a carrier of specific disorders.

If an individual is identified as a carrier of one or more autosomal recessive disorders, that person’s reproductive partner or gamete donor should be offered carrier screening for the disorder(s).^, Genetic consultation is also recommended. If a female is identified as a carrier of an X-linked recessive disorder, carrier screening is typically not indicated for the male reproductive partner. Couples identified as carriers of the same disorder may elect to pursue reproductive options such as prenatal diagnosis, gamete donation with in vitro fertilization, or preimplantation genetic diagnosis.

Relatives of individuals with an identified pathogenic variant are also at risk of being carriers of the variant(s) and should be offered screening. ACOG recommends that patients identified as carriers be encouraged to inform relatives of the risk.

ARUP Laboratory Tests

Screening Tests for CF, FXS, and SMA

3000258

Genetic Carrier Screen, (CF, FXS, and SMA) with Reflex to Methylation 3000258

Method

Matrix-Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) Mass Spectrometry/Polymerase Chain Reaction (PCR)/Capillary Electrophoresis/Multiplex Ligation-Dependent Probe Amplification (MLPA)

2013661

Cystic Fibrosis (CFTR) Expanded Variant Panel 2013661

Method

Matrix-Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) Mass Spectrometry

2009033

Fragile X (FMR1) with Reflex to Methylation Analysis 2009033

Method

Polymerase Chain Reaction (PCR)/Capillary Electrophoresis

2013436

Spinal Muscular Atrophy (SMA) Copy Number Analysis 2013436

Method

Multiplex Ligation-Dependent Probe Amplification (MLPA)