Universal carrier screening

Screening for fetal chromosomal anomalies such as Down syndrome has become a routine part of prenatal care, but it is only possible during pregnancy. On the other hand, identifying pregnancies at risk for single-gene autosomal recessive disorders, or "Mendelian" disorders, is possible as part of preconception care.

Although Mendelian disorders are individually rare, some are more prevalent than we have thought. When considered collectively, Mendelian disorders are among the most common causes of admissions to pediatric hospitals, a significant cause of infant mortality, and a considerable public health concern.

Screening for carriers of Mendelian disorders has traditionally focused on a limited number of diseases, as determined by the parents’ ethnicity and race. For example, Tay Sachs disease has been seen primarily in the Ashkenazi Jewish community, and sickle cell disease occurs most frequently among African Americans. Until very recently, carrier screening was offered only to members of these groups.

The problem with this approach is that we have become a significantly intermixed population. There has been so much intermarriage among different racial and ethnic groups, and assimilation of different populations, that it has become increasingly difficult to discern a single ethnicity for individuals to determine who is "high risk." An increasing number of people report mixed ancestry, and many patients often prefer not to categorize themselves by race or ethnicity.

For example, an increasing number of carriers of a mutation for Tay Sachs disease do not report Ashkenazi Jewish ancestry. Similarly, the ethnic lines that have traditionally defined risk for cystic fibrosis have changed, and more widespread carrier screening has been increasingly encouraged over the past decade.

In 2011, the American College of Obstetricians and Gynecologists’ (ACOG) Committee on Genetics issued an update on carrier screening for cystic fibrosis, in which it stressed that, although cystic fibrosis is still more common among non-Hispanic white individuals and those of Ashkenazi Jewish ancestry, it "is reasonable to offer CF carrier screening to all patients" (Committee Opinion 486, Obstet. Gynecol. 2011;117:1028-31). Pan-ethnic screening for spinal muscular atrophy also has increasingly been incorporated into routine practice.

With newly available high-throughput genomic methods, we can now screen all patients, regardless of ethnicity, using a universal, pan-ethnic approach, which can identify 100-plus disease-causing mutations at a fraction of the cost of ethnic targeted screening.

Currently, the majority of carrier screening is performed as part of prenatal care; however, preconception carrier screening would allow patients and couples to consider all reproductive options. Knowledge that they carry the gene for a recessive disease, and thus have a 1-in-4 chance of having an affected child, gives parents the opportunity to consider their options before conception. These choices can include early prenatal diagnostic testing with or without pregnancy termination, use of donor gametes or election not to conceive their own child, or preimplantation genetic diagnosis (PGD), wherein a monogenetic disorder is diagnosed using only a few cells from the developing zygote.

In our practice at Columbia, we have been performing pan-ethnic screening for less than a year, and have already identified four couples at risk for having a child with severe genetic diseases. Two of these couples were both carriers for spinal muscular atrophy, and two were found to be carriers for rare genetic diseases that would not have been screened for were it not for our new pan-ethnic screening approach.

Carrier frequency

There are new options available for pan-ethnic carrier screening provided by a number of commercial companies. One of the more frequently used panels covers 417 disease-causing mutations associated with 108 recessive diseases, nearly all of which are considered to be severe, associated with progressive disease and reduced life span, or requiring significant intervention or treatment. This panel includes all of the currently recommended disorders recommended by ACOG for routine obstetrical care of individuals of Eastern European Jewish descent (i.e., Tay-Sachs disease, Canavan disease, familial dysautonomia, and cystic fibrosis) as well as the 10 disorders recommended for routine screening by the American College of Medical Genetics (ACMG).

A challenge of the expanded panels is that as many as 1 in 4 individuals who are screened will be identified as a carrier of at least one autosomal recessive disease. However, when both partners are screened, relatively few couples are found to be at risk of having an affected child. Overall, fewer than 1% of couples who take the test will turn out to be carriers of the same disease.

In a recent study of carrier frequencies, 24% of more than 23,400 individuals were found to be heterozygous for at least one non-mild condition. Approximately 5% were carriers for multiple disorders. Not surprisingly, carrier rates varied by ethnicity, ranging from 43.6% of Ashkenazi Jewish individuals to 8.5% of East Asians.