Universal carrier screening

Across all ethnic groups, the most common carrier frequencies for clinically significant disorders were for cystic fibrosis, DFNB1 nonsyndromic hearing loss and deafness, spinal muscular atrophy, familial Mediterranean fever, Smith-Lemli-Opitz syndrome, sickle cell disease/beta-thalassemia, and Gaucher disease. Among the carrier states detected in the study, almost 77% and 70% were for diseases not included in ACOG carrier screening guidelines or in ACMG guidelines, respectively.

Investigators calculated that 433 of the individuals found to be carriers would not have learned their carrier status under conventional ethnicity-based screening paradigms. For example, approximately 26% of familial dysautonomia carriers in the study did not report Jewish ancestry. There also were multiple instances in the study of carrier frequencies being higher than expected for particular populations. For instance, the carrier frequency for cystic fibrosis was 1 in 40 among South Asians – a rate that is significantly higher than other reported rates (Genet. Med. 2013;15:178-186).

The study confirms a number of findings, the two most important being that there are numerous severe Mendelian conditions that are more prevalent than commonly understood, and that a significant proportion of Mendelian diseases are present in individuals outside the populations that have traditionally been characterized as high risk.

Clinical considerations

Usage of pan-ethnic expanded carrier screening is rapidly increasing, with many reproductive endocrinologists now recommending it prior to in vitro fertilization, and a growing number of obstetricians, other physicians, and patients using the tests both prenatally and in the preconception stage.

For ob.gyns., pan-ethnic screening is a significant paradigm shift which will impact our interactions with patients. For example, we will need to develop new ways of providing genetic counseling to our patients. Traditionally, we have spent significant time, prior to screening, describing each major genetic disease for which screening is performed. With the new screening paradigm, a broader, more generic consent process will be more practical – one in which we talk with patients and provide written or Web-based information about the benefits and limitations of the multidisease carrier screening panel, and then reserve in-depth discussions of specific risks and disorders for a later time, as needed.

Genetic counseling should be provided mainly on a post-test basis, and probably most often after both parents have been tested and found to be carriers. Ideally, both spouses/partners would be screened at the same time, but because most women visit their physicians by themselves, it is more practical overall to perform initial carrier screening for the woman first and then test her spouse/partner if she is found to be a carrier. Separate spouse/partner screening would require providers to contact carrier women quickly and reliably, and to obtain samples from their partners as soon as possible. The lab also should be made aware of the pre-identified carrier status of the patients before testing the spouses/partners.

A crucial message we should share with our patients during any counseling is that broader screening does not eliminate the risk of having an affected child, but reduces the risk. At present, many of the panels test only for established disease-causing mutations. There will always be patients who have a rare mutation that has not previously been described. This is particularly true as we begin screening populations not previously evaluated for Mendelian disorders. It is likely that the assortment of mutations causing specific diseases will be different in these groups, and that the residual risk of being a carrier will be higher than in well-studied populations.

With the cost for screening becoming more affordable, sequencing will become a major tool for determining carrier status of our patients. However, ob.gyns. must keep in mind that expanded screening should not substitute for obtaining a family history and referring a patient for genetic counseling when inheritable risk seems possible. Pan-ethnic screening may be able to identify patients’ risks for genetic disorders, minimizing the risk of having a child with a serious birth defect, but it has limitations. For example, not all pan-ethnic panels include analysis for premutation carriers, making it important to inquire about a history of unexplained mental retardation and autism in males, since this may stem from Fragile X syndrome.

Additionally, screening opens up the possibility of finding mutations with unknown or uncertain clinical significance. At present, when one parent is identified as a carrier of a disease-causing gene, the other can choose to have the disease-causing gene sequenced. This option should be offered to all carriers, but for many genes the additional information may be minimal and not worth the extra cost.

As we increase the frequency of carrier screening, we will identify individuals with mild forms of some diseases. For example, some mutations causing Gaucher disease are associated with a mild phenotype, and adults with these mutations may go undiagnosed for a lifetime. Patients should be made aware of this possibility and informed about the fact that some Mendelian disorders may only become evident in adulthood.