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

Genetic Carrier Screening: Historical Perspective and Overview


α-thalassemia results when 2 or more copies of the 4 α-globin genes are deleted.4 Individuals with a deletion of 2 α-globin genes have α-thalassemia trait (α-thalassemia minor) and mild microcytic anemia.4 Individuals with a deletion of 3 or 4 copies of the α-globin gene have α-thalassemia major.4 Deletion of 3 α-globin genes can be associated with mild or moderate hemolytic anemia.4 Deletion of 4 copies of the α-globin gene (absence of α-globin) leads to intrauterine death, hydrops fetalis, and preeclampsia.4


Beta-thalassemia is caused by variants in the β-globin gene, leading to deficient or absent β-chain production and absence of hemoglobin A.4 Beta-thalassemia variants are found in high frequencies in persons of Asian, Mediterranean, Middle Eastern, West Indian, and Hispanic descent.4 Individuals with β-thalassemia minor are heterozygous for the variant. Individuals with β-thalassemia major (Colley’s anemia) or thalassemia intermedia are homozygous for the variant.4 Patients with β-thalassemia major have severe anemia, delayed sexual development, and poor growth.4 Patients usually succumb to the disease by age 10 unless periodic blood transfusions are initiated early.4 In thalassemia intermedia, a variable amount of hemoglobin A is produced.4 An individual can inherit a β-thalassemia mutation from one parent and a hemoglobin S mutation from the other parent, resulting in hemoglobin S/β-thalassemia.4 

Guideline-Based Carrier Screening

ACOG suggests obtaining a complete blood count with red blood cell indices in all pregnant women to assess for the risk of hemoglobinopathy.4 Hemoglobin electrophoresis should be performed in cases of low mean corpuscular volume or low mean corpuscular hemoglobin.4 Hemoglobin electrophoresis should be performed routinely in patients of high-risk ethnic groups (African, Mediterranean, Middle Eastern, Southeast Asian, or West Indian ancestry), ideally before pregnancy.4 In some cases, DNA analysis may be needed to assess for the presence of α-globin gene deletions. This can occur when mean corpuscular volume is low, or if results of hemoglobin electrophoresis are not consistent with the β-thalassemia trait; iron deficiency anemia must also be excluded.4

Fragile X Syndrome

The most commonly inherited cause of intellectual disability is fragile X syndrome.4 Impairment ranges from learning disabilities to severe cognitive and behavioral disabilities.4 Study results suggest that autism spectrum disorder occurs in 21% of individuals with fragile X syndrome, particularly males.11

The syndrome is transmitted through the X chromosome.4 It is characterized by expansion of a repeated trinucleotide, cytosine-guanine-guanine, that leads to abnormal transcription of the fragile X mental retardation 1 gene (FMR1).4 The number of triplet cytosine-guanine-guanine repeats varies among individuals and is used to classify individuals into 4 groups: unaffected, intermediate, premutation, and full mutation.

Individuals may have tremor or ataxia if they are premutation carriers (55-200 repeats), but not fragile X syndrome.4 Females with a premutation may have FMR1-related premature ovarian insufficiency.4 A male with a full mutation (more than 200 repeats) is considered to be affected with fragile X syndrome.4 A female with a full mutation may have variable expression.4 During spermatogenesis in the male, repeats very rarely expand.4 Hence, only an affected male can pass on the full mutation to his female offspring.4 Because the number of maternal triplet repeats increases the likelihood of expansion into a full mutation, repeats may expand during oogenesis in the female, resulting in an affected child.4

In the United States, carrier frequency (premutation and full mutation) of fragile X is 1 in 257 women with no family history of intellectual disability and 1 in 86 in individuals with a family history.12

Guideline-Based Carrier Screening

The ACOG and ACMG recommend fragile X premutation carrier screening in pregnant women and women considering pregnancy if they have a family history of intellectual disability or fragile X-related disorders, unexplained ovarian insufficiency, or an elevated follicle-stimulating hormone prior to 40 years of age.4,13 The NSGC supports ACMG and ACOG guidelines on patient selection for FMR1 mutation testing.14 Genetic counseling should be provided to individuals with intermediate, premutation, or full mutation.4

Tay-Sachs Disease

Tay-Sachs disease is a progressive neurodegenerative autosomal recessive disease.4 Deficiencies in  hexosaminidase A enzyme can cause an accumulation of GM2 gangliosides in individuals with Tay-Sachs disease.4 Accumulation of GM2 gangliosides in the central nervous system causes early childhood death in the affected individual.4 The carrier rate for Tay-Sachs disease is 1 in 30 in individuals of Ashkenazi Jewish (Eastern or Central European) descent, whereas the carrier rate is 1 in 300 in non-Jewish individuals.4 Individuals of Cajun and French-Canadian descent also have a carrier frequency (about 1 in 50).4  

Guideline-Based Carrier Screening

ACOG recommends that screening for carrier status should be offered to preconception or prenatal women if either partner is of Ashkenazi Jewish, French Canadian, or Cajun descent, or if there is a family history of Tay-Sachs disease.4 If the woman’s partner is from one of these high-risk groups, he should be offered screening.4 If one partner is a carrier, screening should be offered to the other partner.4

Carrier screening should be performed by measuring hexosaminidase enzymatic activity in leukocytes or serum, or by using mutation analysis.4 Regardless of ethnicity, 98% of carriers are detected during enzyme testing. False positives are suspected in women talking oral contraceptives and women who are pregnant. Tests should be taken using leukocytes to avoid false-positive results. Although limited due to rare mutations, high-risk ethnic groups can use molecular testing.4


This article provides an overview and current guidelines of genetic carrier screening. Carrier screening describes genetic testing of an individual who may have a variant allele associated with a genetic disorder but does not have any overt phenotype for the disorder.4 The primary purpose of carrier screening in individuals without a known family history of recessive disorders is to inform their risk of having offspring affected by a genetic condition.3 If an individual is confirmed to be a carrier of a genetic condition, the reproductive partner should be tested as well to more accurately inform potential reproductive outcomes. Genetic counseling should be offered to partners that are both carriers of a genetic disorder.4 In addition, if an individual is found to be a carrier for a genetic condition, he or she 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 should ideally be performed before pregnancy because this allows couples to be informed about their reproductive risk and the opportunity to consider the most complete range of reproductive options.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 and expectant management of an affected offspring.4

ACOG provides recommendations for carrier screening of the more common genetic diseases including cystic fibrosis, spinal muscular atrophy, hemoglobinopathies (including sickle cell disease, α- and β-thalassemias), fragile X syndrome, and Tay-Sachs disease.4 ACOG recommends that carrier screening for cystic fibrosis and spinal muscular atrophy should be offered to all women considering pregnancy and all pregnant women, regardless of ethnicity, personal, or family history.4 In addition, a complete blood count together with red blood cell indices should be performed in all pregnant women and ideally to all women before pregnancy, to assess the risk of anemia as well as hemoglobinopathies.4 For other genetic diseases, ACOG recommends an ethnic group- and personal/family history-based approach.4

  1. Ioannides AS. Preconception and prenatal genetic counselling. Best Pract Res Clin Obstet Gynaecol. 2017;42:2-10. doi: 10.1016/j.bpobgyn.2017.04.003.
  2. U.S. National Library of Medicine. What are the different ways in which a genetic condition can be inherited? Accessed June 26, 2018.
  3. Henneman L, Borry P, Chokoshvili D, et al. Responsible implementation of expanded carrier screening. Eur J Hum Genet. 2016;24(6):e1-e12. doi: 10.1038/ejhg.2015.271.
  4. ACOG Committee on Genetics. Committee opinion No. 691: carrier screening for genetic conditions. Obstet Gynecol. 2017;129(3):e41-e55. doi: 10.1097/AOG.0000000000001952.
  5. Watson MS, Cutting GR, Desnick RJ, et al. Cystic fibrosis population carrier screening: 2004 Revision of American College of Medical Genetics mutation panel. Genet Med. 2004;6(5):387-391. doi: 10.1097/01.GIM.0000139506.11694.7C.
  6. Langfelder-Schwind E, Karczeski B, Strecker MN, et al. Molecular testing for cystic fibrosis carrier status practice guidelines: recommendations of the national society of genetic counselors. J Genet Couns. 2014;23(1):5-15. doi: 10.1007/s10897-013-9636-9.
  7. Cystic Fibrosis Centre Hospital for Sick Children. Cystic fibrosis mutation database. Accessed July 8, 2018.
  8. American College of Medical Genetics. Technical standards and guidelines for CFTR mutation testing. Published 2011. Accessed July 19, 201
  9. Hendrickson BC, Donohoe C, Akmaev VR, et al. Differences in SMN1 allele frequencies among ethnic groups within North America. J Med Genet. 2009;46(9):641-644. doi: 10.1136/jmg.200066969.
  10. Prior TW, Nagan N, Sugarman EA, Batish SD, Braastad C. Technical standards and guidelines for spinal muscular atrophy testing. Genet Med. 2011;13(7):686-694. doi: 1097/GIM.0b013e318220d523.
  11. Hatton D, Sideris J, Skinner M, et al. Autistic behavior in children with fragile X syndrome. Am J Med Genet A. 2006;140A:1804-1813. doi: 10.1002/ajmg.a.
  12. Cronister A, Teicher J, Rohlfs EM, Donnenfeld A, Hallam S. Prevalence and instability of fragile X alleles: implications for offering fragile X prenatal diagnosis. Obstet Gynecol. 2008;111(3):596-601. doi: 10.1097/AOG.0b013e318163be0b.
  13. Sherman S, Pletcher BA, Driscoll DA. Fragile X syndrome: diagnostic and carrier testing. Genet Med. 2005;7(8):584-587. doi: 10.1097/01.GIM.0000182468.22666.dd.
  14. Finucane B, Abrams L, Cronister A, Archibald AD, Bennett RL, McConkie-Rosell A. Genetic counseling and testing for FMR1 gene mutations: practice guidelines of the national society of genetic counselors. J Genet Couns. 2012;21(6):752-760. doi: 10.1007/s10897-012-9524-8.

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