Expanded carrier screening and the law of unintended consequences: From cystic fibrosis to fragile X

  • Grody W
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" In the nature of Arctic travel there was a reason why fourteen dogs should not drag one sled, and that was that one sled could not carry the food for fourteen dogs. " —Jack London, The Call of the Wild I n medical genetics as in all other fields of human endeavor, sometimes good intentions have unintended consequences. The initial attempts at sickle cell carrier screening in the African American community resulted in miscommunication, undue anxiety, stigmatization, and resentment, 1 and there have been similar problems related to carriers identified through expanded newborn screening programs. Some individuals who have un-dergone apoE genotyping for assessment of cardiovascular dis-ease risk were then shocked to learn that they were also at increased risk of Alzheimer disease. Even the universal and generally successful cystic fibrosis (CF) carrier screening pro-gram has provoked confusion and uncertainty among providers and patients with regard to unpredictable genotype-phenotype correlations, diversity of mutation screening panels, and wide clinical variability of the disease. It is notable that these adverse outcomes have occurred even in large public health programs that were planned, pilot-tested, vetted, and debated by experts and professional organizations before being put into practice. The problem usually arises either from failure to exercise in practice what was outlined in the planning, or, conversely, an impetus to go beyond the planned scope in search of increased catchment, test sensitivity, or simple market share. As illustrated by Jack London's hapless Yukon gold-seekers, it is human nature to be competitive and to try to distinguish oneself by going grander, taller, faster, stronger than one's contemporaries; this is especially so in a capitalist system. In the case of CF carrier screening, this impetus has played itself out in a quest for ever-larger and ostensibly more " comprehensive " muta-tion testing panels, beyond the original 25 (now 23) muta-tions recommended by the American College of Medical Genetics. 2,3 A previous commentary in this journal by the author and colleagues 4 bemoaned the many reasons why this trend is both unseemly and unscientific and has resulted in the inclusion of CFTR variants of extremely rare frequency, low pathogenicity or uncertain significance, potentially im-parting to screened couples either a false sense of security or unwarranted alarm. Now in the current issue, Strom et al 5 provide direct clinical evidence that such fears have indeed come to pass in practice. These authors work in a major commercial reference laboratory which has sufficient volume of CF tests that rare alleles are seen often enough and in different contexts (carrier screening, refer-rals from newborn screening, and diagnostic and prenatal test-ing) and that genotype-phenotype inferences can be made based on real-world experience rather than back-of-the-envelope esti-mates based solely on allele frequencies. Such is the case for the variant L997F which is the focus of their article. Searching their database of Ͼ2500 full-gene CFTR sequencing cases, they identified four patients who were compound heterozygous for L997F and a classical mutation such as ⌬F508. Clinical fol-low-up revealed that three of the patients are asymptomatic children of ages up to 5 years, whereas one has atypical CF consisting of recurrent pancreatitis and sinusitis. These results confirm not only the rarity of the L997F allele but also its very low penetrance, essentially negligible if classic CF is taken as the at-risk phenotype, which is the one that population carrier screening was instituted to identify. The three asymptomatic cases were referred for DNA sequencing because of elevated serum trypsinogen on newborn CF screening and the L997F allele thus discovered incidentally; but when included as a deliberate target in carrier screening, referrals will ensue for a less innocuous test—prenatal diagnosis—and, disturbingly, the authors report that they have already received two of those. The CF mutation screening panel that engendered these procedures is likely not the only one to include L997F, nor is L997F the only allele of questionable clinical significance in-cluded in other screening panels, including some that are Food and Drug Administration-approved (D1270N, D1152H, and L206W come readily to mind). But is this situation unique to CF carrier screening? Unfortunately not, as there are a number of other recessive disorders currently being screened in which reach similarly exceeds grasp. Indeed, the advent of highly parallel sequencing and microarray technologies has essentially forced the issue by making it technically easy to multiplex gene tests of unrelated biology and ethnicity together in virtually limitless number and for less total cost than that previously required for testing of one or two individual genes. One com-pany now offers couple-and in vitro fertilization-based screen-ing for a motley collection of more than 100 Mendelian disor-ders and a highly variable proportion of associated mutations, some providing carrier pick-up rates in the range of 1%. Soon we will be moving into the realm of whole-exome sequencing, initially for diagnosis but the temptation will be there for carrier screening as well, to theoretically identify couples at risk for any of the 13,000 known single-gene disorders and thereby reaching the asymptote of the " more is better " philosophy. One particular disorder has recently become a popular target for population " carrier screening, " seemingly in the absence of any pilot studies or professional recommendations, and, to this author at least, illustrates the law of unintended consequences only too well. Fragile X syndrome is considered the most common inherited cause of mental retardation, with an aggre-gate carrier frequency for the FMR1 premutation allele in the

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  • Wayne W. Grody

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