Although the parents of a child with chromosomal aneuploidy may have normal chromosomes themselves, in some situations there may still be an increased risk for a chromosomal abnormality in a subsequent child. For example, if a woman at 30 years of age has a child with Down syndrome, her recurrence risk for any chromosomal abnormality is approximately 1 per 100, compared with the age-related population risk of approximately 1 per 390. Parental mosaicism is one possible explanation of the increased risk, but in the majority of cases, the mechanism of the increase in risk is unknown.
• Presence of structural chromosomal or genome abnormality in one of the parents
Here, the risk for a chromosome abnormality in a child varies according to the type of abnormality and sometimes the parent of origin. The greatest risk, 100% for Down syndrome, occurs only if either parent has a 21q21q Robertsonian translocation (see Chapter 6).
• Family history of a genetic disorder that may be diagnosed or ruled out by biochemical or DNA analysis
Most of the disorders in this group are caused by single-gene defects with 25% or 50% recurrence risks. Cases in which the parents have been diagnosed as carriers after a population screening test, rather than after the birth of an affected child, are also in this category. Mitochondrial disorders pose special challenges for prenatal diagnosis.
• Family history of an X-linked disorder for which there is no specific prenatal diagnostic test
When there is no alternative method, the parents of a boy affected with an X-linked disorder may use fetal sex determination to help them decide whether to continue or to terminate a subsequent pregnancy because the recurrence risk may be as high as 25%. For X-linked disorders, such as Duchenne muscular dystrophy and hemophilia A and B, however, for which prenatal diagnosis by DNA analysis is available, the fetal sex is first determined and DNA analysis is then performed if the fetus is male. In either of the situations mentioned, preimplantation genetic diagnosis (see text) may be an option for allowing the transfer to the uterus of only those embryos determined to be unaffected for the disorder in question.
• Risk for a neural tube defect (NTD)
First-degree relatives (and second-degree relatives at some centers) of patients with NTDs are eligible for amniocentesis because of an increased risk for having a child with an NTD; many open NTDs, however, can now be detected by other noninvasive tests, as described in this chapter.
• Increased risk as determined by maternal serum screening, ultrasound examination, and noninvasive prenatal screening test of cell-free DNA
Genetic assessment and further testing are recommended when fetal abnormalities are suspected on the basis of routine screening by maternal serum screening and fetal ultrasound examination.
• The pregnant woman or couple wishes invasive testing
Although limited at one time to a pregnant woman with no increased risk other than advanced maternal age, some current professional guidelines call for invasive testing to be offered to all couples.