Couple screening for autosomal recessive inherited diseases: Current and historical perspectives

An innovative methodology, couple screening, was initially described by Wald in 1991. ¹ Couple screening is a method of screening for autosomal recessive disorders in which the screening unit is the couple, not the individual parent. In couple screening, samples are obtained initially from both partners with the woman's sample (e.g. saliva or blood) tested first. When a deleterious mutation is identified, the partner's sample is immediately tested. Only when both samples identify mutations in the same gene is the test designated as screen positive. The couple can then be informed and offered counseling and options such as diagnostic testing or pregnancy planning. Couple screening avoids the anxiety of a woman identified as screen positive in the usual sequential method, in which the individual receives a screening result, as well as the potential delay or inability of obtaining the partner's sample. An example illustrates the efficacy of couple screening during pregnancy: 1 in 4 couples with screen-positive results will have an affected pregnancy regardless of the carrier rate of the disorder. In contrast, for a disease with a carrier rate of 1 in 25, only 1 in 100 women with screen-positive results will have an affected pregnancy—33 times more false positives than with couple screening (99/3). Using either method, the overall detection rate is identical.

A 1993 pilot project in Oxford ² found that couple screening was feasible with an uptake of 67% (325/482). A 1994 study from Edinburgh ³ employed couple-based screening for cystic fibrosis (CF) in 5922 couples (pairs of samples) and identified four screen-positive couples. Two of these had affected pregnancies and chose termination. All couples were given the option of receiving their individual results and 89 (1.5%) chose to do so. Another study, from 1996, ⁴ screened 1656 pregnant couples in the United States for 7 CF pathogenic mutations. Overall, 69 of 74 providers contacted agreed to participate and 1682 couples were screened. Of these, 1645 (97.8%) had successful test results with one screen-positive couple. Diagnostic testing identified the fetus as homozygous for deltaF508; the fetus was terminated. Subsequent surveys of a subset of these couples found them to be informed and confident with little evidence of being nervous or worried. Participating physicians / staff reported that they were satisfied with providing CF testing and that CF screening and alpha-fetoprotein screening for open neural tube defects were associated with similar levels of patient anxiety. A study in 1999 ⁵ compared reported risks in pregnancies screened using couple versus sequential screening. Those undergoing couple screening for CF were 4.5 times more likely to correctly recall their reported risk.

A 2024 article from Australia reported on the Nationwide Study, ⁶ in which the couple-based model was used in a prenatal screening program that included over 750 inherited disorders in nearly 1300 genes causing serious childhood disease. These were mainly autosomal recessive disorders such as CF and x-linked diseases such as Duchenne muscular dystrophy. Screening for fragile X syndrome was also performed. The assay included testing for AGG triplets that interrupt the CGG repeats, making expansion less likely, which reduced the false positive rate for this disorder by over 70% while maintaining detection. Sampling kits were mailed to 9255 couples and screening results were provided to 9107 (98.4%). Among these couples, 8753 (96.1%) were screen negative. A newly discovered disorder was identified in 175 couples (1.9%) who were considered to be at background risk. Of these, 130 (74%) were screen positive for an autosomal recessive disorder and 45 (26%) for an X-linked disorder. An additional 180 couples (2.0%) with a history of consanguinity or family history were also screen positive.

The population studied included a wide range of geographic locations, racial/ethnic backgrounds, socioeconomic statuses, education levels, and ancestral origins. Among the 45 screen-positive couples with an ongoing pregnancy when screened, 17 (38%) chose to continue their pregnancy while the remaining 28 couples (62%) had a termination. Among the 130 screen-positive couples without an ongoing pregnancy, 106 chose to avoid the condition through in vitro fertilization with preimplantation testing for the monogenic condition (83%), prenatal diagnosis with termination of pregnancy if affected (14%), or avoiding pregnancy (3%).

Although the report of the Nationwide Study is extensive, it does not include reference to the origins of the couple-screening model as well as early screening program reports. The CF gene was identified in 1989 ⁷ when the major pathogenic variant (originally named deltaF508) was identified. Soon, more pathogenic variants were identified. Prenatal screening for CF was initially implemented using the sequential model where the mother was tested first, the result reported, and genetic counseling provided. In the women who were screen positive, the father's sample was then sought for testing. Only when both partners tested positive was additional counseling and diagnostic testing of the fetus offered. A 1992 study, performed in Edinburgh, ⁸ used this model to screen 3165 women; 111 carriers were identified (3.5%). Among the 111 partners four tested positive and one affected fetus was terminated. However, a survey of the 111 screen-positive women found a significant increase in stress prior to the partner's result. Sequential screening can also be problematic when the woman is screen positive and the father is not known or unavailable. A study from Germany ⁹ also used the sequential model to screen for CF with comprehensive pretest counseling. However, they also observed considerable anxiety in women after testing positive. Had this sequential methodology been used in the Nationwide Study, ⁵ over 90% of women would have been screen positive, posing an unprecedented need for genetic counseling resources.

In the United States, some prenatal screening programs for inherited diseases using large panels such as described above offer couple-based screening as an option, along with sequential screening. Sequential screening is often the most common choice and, therefore, the vast majority of couples will be screen positive for at least one disorder, leading to a huge burden on geneticists and genetic counselors for the initial counseling session, even though the average couple's risk of having an affected fetus is of the order of 2%. Alternatively, if such genetic testing and reporting were based on the couple screening model, the burden on genetic counselors would be reduced by 90% or more and the number of disorders for which the couple is screen positive would be considerably smaller. The same 2% of couples with an at-risk fetus would still be identified, but the burden of counseling would be greatly reduced, leaving them to fill other genetic counseling needs that often are lacking.

One facet of the Nationwide Study that was not examined was the costs associated with their screening program. Would it have been significantly less costly to remove screening for the rarest disorders compared to missing a small number of affected fetuses? It would be interesting to see whether this screening can be integrated into routine health care in Australia and elsewhere. In the United States, a high proportion of couples have different health insurance carriers. The insurer for the male partner may not cover the costs of testing the male, unless the woman is screen positive. In Rhode Island, for example, most prenatal care providers offer carrier testing during, rather than prior to pregnancy. When the woman is screen positive, these providers are not responsible for delivering screening services to the father of the pregnancy. Instead, such couples are often referred to genetic counseling for further testing of the putative father and the final interpretation for the couple.

Although couple screening is the preferred method of screening for autosomal recessive disorders, it is not applicable to screening for X-linked disorders because for this only women need to be screened. However, as Kirk and his colleagues have shown, the two methods can be combined in what could be called “enhanced couple screening” if, within a couple, the woman is always tested first. In couple screening for autosomal recessive disorders the positive rate is 1.4% (130/9107) and 1.9% for enhanced couple screening.

In summary, the Australian study shows that, for the same number of detectable cases, couple DNA screening for autosomal recessive disorders, either before or during pregnancy, has an estimated screen-positive rate of 1.4% (1.9% for enhanced couple screening) instead of an observed 93% screen-positive rate with individual sequential DNA screening. The advantage of couple screening over individual carrier screening is compelling.