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Supplements Expanded Carrier Screening in Prenatal Care: Recent Advances and Key Considerations

Genetic Carrier Screening: Historical Perspective and Overview

Genetic carrier screening and counseling is an important part of preconception and prenatal care.1 As genetic testing technology rapidly evolves, clinicians often face questions regarding the most appropriate testing methods to use for their patients. In addition, prospective mothers often have questions about whether to undergo particular screening tests or procedures. This article, the first of a 3-part series, reviews the purpose of genetic carrier screening and summarizes current preconception and prenatal screening guidelines.

Inheritance of Autosomal Recessive Disorders

Genetic conditions are inherited in one of several patterns.2 In autosomal recessive disorders, both copies of a gene must carry a variant for the patient to be affected with a condition.2 Heterozygous carriers have 1 copy of the variant gene, do not show symptoms of the condition, and may be unaware of their carrier status.1,2 If 2 reproductive partners are both heterozygous carriers, each offspring has a 1 in 4 risk of inheriting the variant in both gene copies, 1 from each parent.1,2 This child will be homozygous for the mutation and will be affected by the condition.

Purpose of Carrier Screening

Carrier screening allows individuals without a known personal or family history of recessive disorders to learn about potential risks that may affect their offspring.3 If screening reveals carrier status in both reproductive partners, they can receive information about the disease’s natural history and management, as well as available reproductive options.1 In this way, couples can make autonomous choices.3

If a patient is a carrier for a genetic condition, the reproductive partner should also be tested. Results acquired from the test can lead to more accurate information regarding potential reproductive outcomes.4 Genetic counseling should be available for couples in which both partners have been identified as carriers of a genetic disorder.4 Reproductive options to reduce the risk of an affected offspring should be discussed.4 In addition, if an individual is found to be a carrier for a genetic disease, the individual should be encouraged to inform his or her relatives because these relatives are also at risk of carrying the same genetic variant. 4 

Carrier screening and counseling performed before pregnancy allows couples the opportunity to consider the most reproductive options.4 The range of reproductive possibilities include the choice to not attempt conception, use of reproductive technologies such as donor gametes and preimplantation genetic diagnosis, and other family building options such as adoption.1,4 When genetic screening is performed during pregnancy, knowledge of carrier status allows patients to consider pregnancy management options, including early prenatal diagnosis, pregnancy termination, or planning for the birth of an affected offspring.1

Conventional Genetic Screening

Traditionally, carrier screening is performed in select patients based on:
  • Family and personal history of known or suspected genetic disorders1
  • Ethnicity, some of which are considered to be high risk for specific autosomal recessive disorders1
  • History of children born with congenital anomalies1
Genetic counseling should accompany carrier screening.1 In addition to the nature of the disorders being tested, individuals should be provided with information about the limitations of the screening tests.1 Because some genetic screening tests do not screen for all possible mutations associated with the disorder, residual risks exist despite a negative test result.1 In some ethnic groups, specific mutations responsible for the disease may be incompletely understood, and conventional genetic screening may not detect these mutations.4,5

Guideline-Recommended Carrier Screening

Cystic Fibrosis

Cystic fibrosis is an autosomal recessive disease affecting the airways, pancreas, intestines, and in males, the vas deferens.4 It is caused by genetic mutations in the cystic fibrosis transmembrane regulator (CFTR) gene.4

Carrier frequencies of cystic fibrosis vary by ethnic origin, with non-Hispanic whites having an especially high carrier frequency.4 Cystic fibrosis is also most common in this ethnic group (incidence of 1 in 2500).4

Guideline-Based Carrier Screening

According to guidelines from the American College of Obstetrics and Gynecology (ACOG) and the National Society of Genetic Counselors (NSGC), cystic fibrosis carrier screening should be offered to all women of reproductive age (women considering pregnancy and all pregnant women) regardless of ethnicity, ancestry, and personal or family history for cystic fibrosis.4,6 If a woman is found to be a carrier for cystic fibrosis, her reproductive partner should also be tested.4,6

There are currently more than 2000 mutations identified for cystic fibrosis.7 For genetic screening, the American College of Medical Genetics and Genomics (ACMG) recommended a panel that contained 23 of the most common mutations present in patients with cystic fibrosis.5 Because this panel does not identify all known mutations, the sensitivity of the screening test differs among ethnic groups.4,8 In individuals with Asian ancestry, the sensitivity is less than 50%, as compared to 94% in individuals of Ashkenazi Jewish ancestry (Table 1).4,8 As such, a negative cystic fibrosis screening result does not entirely eliminate the possibility of being a carrier, and there is a residual risk of being a carrier and having an affected offspring.4 Because extended mutation panels and full CFTR gene sequencing are commercially available, sensitivity for carrier detection may increase.4

A complete analysis of the CFTR gene is not recommended for routine practice but is reserved for specific situations when carrier screening using the standard 23-mutation panel yields negative results.4 These include patients with a family history of cystic fibrosis, but the family test results are not available; and neonates with a positive newborn screening test result, but a negative genetic screening result.4

Importantly, newborn screening does not replace preconception or prenatal carrier screening.4 Newborn screening programs identify affected newborns but do not provide any information about the parents’ carrier status.4 Therefore, although cystic fibrosis screening is part of newborn screening panels in all 50 states, it is important that cystic fibrosis carrier screening continue to be offered to women considering pregnancy and those who are pregnant.4

Spinal Muscular Atrophy

Spinal muscular atrophy is a disorder characterized by spinal cord motor neuron degeneration, leading to skeletal muscle atrophy and muscle weakness.4 It is an autosomal recessive disease caused by a mutation in the survival motor neuron gene (SMN1).4 SMN1 is responsible for the production of a protein critical to motor neuron function.4

Approximately every 1 in 6000 to 10,000 births is affected with spinal muscular atrophy.4 Carrier frequencies vary among different ethnicities,9 with the risk lowest in Hispanics (Table 2).4 Spinal muscular atrophy is the most common cause for genetic infant death.4 Nusinersen (Spinraza), approved in March 2018, is currently the only drug available for the treatment of spinal muscular atrophy.

Guideline-Based Carrier Screening

Current recommendations from both ACOG and ACMG state that carrier screening for spinal muscular atrophy be offered to all women who are contemplating pregnancy or are currently pregnant.4,10  

Carrier screening measures SMN1 copy number.4 About 3% to 4% of the population have 2 SMN1 gene copies on the same chromosome and no copies on the other chromosome, and will not be identified as carriers.4 These individuals are known as silent carriers and run the risk of passing on the chromosome with the missing SMN1 allele to future offspring.4 The missing SMN1 allele is more common in African Americans. In this group, the carrier detection rate is only 71%.4,9 Hence, patients should be counseled about screening detection rates and residual risks.4  


The hemoglobin molecule is made up of 4 polypeptide chains, each with a heme molecule attached.4 The 4 chains are4:
  • Two α-chains, and;
  • Either:
    • Two β-chains (hemoglobin A)4, or
    • Two γ-chains (hemoglobin F)4, or
    • Two δ-chains (hemoglobin A2).4    

Sickle Cell Disease

In sickle cell disease, a single nucleotide substitution in the β-globin gene results in an abnormal hemoglobin S instead of the normal hemoglobin A.4 Heterozygous hemoglobin S carriers are asymptomatic and are considered to have sickle cell trait.4 An individual who is homozygous for hemoglobin S (hemoglobin SS) has sickle cell disease.4

In addition to hemoglobin S, hemoglobin C is another abnormal form of hemoglobin.4 In hemoglobin C, a single nucleotide substitution in the β-globin gene occurs. A patient with the hemoglobin genotype SC may have significant vaso-occlusive episodes and hemolytic anemia like individuals with hemoglobin SS, and is also considered to have sickle cell disease.4

Sickle cell disease is most commonly found in African Americans, presenting in about 1 in 350 individuals. (One in 10 African Americans has the sickle cell trait.) Other populations, such as Greek and Italian, also present with high frequencies of hemoglobin S.4

Red blood cells in individuals with sickle cell disease change their shape to resemble sickles, leading to hemolysis, anemia, increased viscosity, and a decrease in oxygenation. When sickling occurs in small blood vessels, the blood supply is obstructed from vital organs (vaso-occlusive crisis).4

The Thalassemias

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