Human Genetic Complexity

With the work of Guthrie and others allowing the inexpensive, reliable assessment of small dried blood spots for biochemicals linked to genetic disorders, mass screening of newborns became technically feasible. Since specific treatments or preventives for some of these conditions were also available, outcomes like catastrophic illness or chronic mental retardation could be avoided.

In the 1960s, the US Congress, under pressure from patient support groups, provided funds to the states to enable newborn screening programs using the Guthrie method. While all states took up this money and its associated mandate, the range of disorders included in these programs (generally part of the state’s public health department) and the quality of the service delivered varied.

There were also other problems. Phenylketonuria (PKU) was included in all states’ screening panels. But standards for defining what was “benign hyperphenlyalanemia,” an innocuous form of the disorder, and what levels of the amino acid phenylalanine indicated PKU were not yet developed.

Some children identified early in the evolution of these state screening efforts (before the implementation science was complete), who were at no risk for PKU, suffered significant developmental toxicity as a result of being put on a treatment in the absence of disease.

Also, in those states that included screening for hemoglobin S (a gene product associated with carriers and those affected with sickle cell anemia), proper education, consent and follow-up were not always offered.

As a result, identified HbS carriers who have no risk of developing sickle cell anemia were often ignorant of their unaffected state, and suffered stigmatization and discrimination. For this reason, some states passed laws prohibiting discrimination against carriers of genes linked to recessively inherited conditions. Other states suspended the screening.

Nonetheless, it is clear that despite implementation flaws which continue to require surveillance and improvement, the federal mandate and resulting state programs have averted suffering and illness that was indeed preventable.

Yet some of those gains are again being made more complex.

Since PKU screening became widespread, we have learned that women with PKU must be on a phenylalanine reduced diet prior to conception and during pregnancy. If they aren’t, their children are at risk for delayed development and mental retardation irrespective of their genotype for PKU genes.

But compliance with these arduous diets is not universal. Thus some cases of preventable PKU associated mental retardation are occurring in newborns who by the dint of their own genes would not be detected on state screening programs. The occurrence of their PKU is complicating assessment of the outcomes of the state screening programs.

I review this history as we consider recent reports of enhancements to prenatal testing including that reviewed by Maimon Cohen in this issue of GeneLetter. Clearly, technology that is accurate, more patient-friendly and less costly will allow detection of prenatal chromosome and specific gene anomalies in a larger and larger cohort. Offering universal prenatal screening with newer methods is within sight.

But before mandates for such programs exist and bureaucracies are erected for delivery and regulation, we may need to pause and consider what data we want beforehand, what issues in implementation and care will likely result and what is the best way to really make benefits universal.

Of primary importance, of course, is our continued commitment to research and care of those born with disorders that were missed by screening or to those who decline its offer.

Given our experiences with the newborn screening programs, I suspect that universal application of prenatal screening will restate the complexity of human genetics and life experience.

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