Genetic Screening and Prenatal Genetic Diagnosis

Key Points

• About 3% of liveborn infants have a major congenital anomaly due to a chromosome abnormality, single-gene mutation or multifactorial/polygenic inheritance, or exogenous factors (i.e., teratogens).

• Noninvasive screening tests for the common autosomal trisomies should be offered at any age, providing patient-specific aneuploidy risks. First-trimester screening using serum analytes (free hCG and pregnancy-associated plasma protein A) and an NT measurement has a detection rate of 85% to 87% with a false-positive rate of 5%. For women at high risk for trisomy 21, cfDNA analysis is available as early as 10 weeks’ gestation, with a detection rate of greater than 99%; however, confirmatory invasive diagnostic testing is recommended.

• Second-trimester noninvasive screening with four analytes—hCG, AFP, uE ₃ , and inhibin A—has an 80% detection rate and can be performed in conjunction with first-trimester screening to yield a higher detection rate of 95%.

• Invasive prenatal diagnosis with chromosome microarrays allows comprehensive analysis of the entire genome at a finer resolution than a routine karyotype and is capable of detecting trisomies and unbalanced translocations as well as submicroscopic deletions and duplications of the genome (CNVs). It has several advantages over conventional cytogenetic testing, especially in the fetus with a structural malformation. Clinically significant CNVs were detected in 6% of the fetuses with a normal karyotype and suspected structural anomalies or growth abnormalities.

• Screening for carriers for β-thalassemia and α-thalassemia can be inexpensively performed on the basis of an MCV less than 80% followed by hemoglobin electrophoresis, once iron deficiency has been excluded.

• Cystic fibrosis (CF) is found in all ethnic groups, but the heterozygote frequency is higher in non-Hispanic whites of northern European (1 in 25) or Ashkenazi Jewish origin (1 in 24) than in other ethnic groups (black 1/61, Hispanic 1/58, Asian 1/94). More than 1500 mutations have been identified in the gene for CF, but carrier screening is obligatory only for a specified panel of 23 mutations. In northern European white and Ashkenazi Jewish individuals, the heterozygote detection rate using the specified panel is 88% and 94%, respectively. In other ethnic groups, detection rates are lower (64% in blacks, 72% in Hispanics, and 49% in Asian Americans).

• Most single-gene disorders can now be detected by molecular methods if fetal tissue is available, given that the location of the causative mutant gene is known for most disorders. Linkage analysis can be applied if the gene has been localized but not yet sequenced or if the mutation responsible for the disorder in a given family remains unknown despite sequencing.

• Amniocentesis (15 weeks or later) and CVS (10 to 13 weeks) are equivalent in safety (1 in 300 to 500 loss rate) and diagnostic accuracy. Amniocentesis before 13 weeks is not recommended because of an unacceptable risk for pregnancy loss and clubfoot (talipes equinovarus).

• Congenital malformations that involve a single organ system (e.g., spina bifida, facial clefts, cardiac defects) are considered multifactorial or polygenic. After the birth of one child with a birth defect that involves only one organ system, the recurrence risk in subsequent offspring is 1% to 5%. Many of these congenital anomalies can be diagnosed in utero using ultrasonography or fetal echocardiography.

• NTDs may be detected by either ultrasonography or MSAFP screening in the second trimester.

• PGD requires removal of one or more cells (polar body blastomere, trophectoderm) from the embryo. Diagnosis uses molecular techniques to detect single-gene disorders and either fluorescence in situ hybridization or chromosome array comparative genome hybridization to detect chromosome abnormalities (e.g., trisomy). PGD also allows for avoidance of clinical pregnancy termination, fetal (embryonic) diagnosis without disclosure of parental genotype (e.g., Huntington disease), and selection of human leukocyte antigen–compatible embryos.