newborn screening – Lablogatory

The most recent disorder that has been recommended for addition to all US newborn screening (NBS) programs is severe combined immunodeficiency (SCID). SCID is actually a group of at least 14 primary immunodeficiencies which affect the individual’s immune system, making it impossible for them to adequately fight off infections. A baby with SCID who does not receive treatment rarely survives the first year of life, being unable to clear repeated and massive infections. Everyone probably remembers the story of the “Bubble Boy” who survived 12 years in a completely sterile environment. The “Bubble Boy” had SCID.

Screening newborns for this disorder would seem like a no-brainer; however, because SCID is actually many different primary immunodeficiencies, finding a screening test that would pick up all or the majority of them has been problematic. In recent years, people began looking at one of the hallmarks of all SCID, a lack or very low number of functional T-cells.

During maturation in the thymus, T-cells undergo gene rearrangement, and during this process small extra-chromosomal circles of DNA are created as the segments of DNA are clipped out of the gene. These small DNA circles are call T-cell receptor excision circles, or TREC. In 1998, Douek et al (1) developed a PCR assay to quantify TREC as a measure of thymic function. When that assay was published, researchers began wondering whether there would be any TREC produced in a disorder like SCID with no functional T-cells. Very quickly the TREC PCR assay was adapted to measure the presence of TREC in dried blood spots, and several papers showed that in SCID individuals, essentially no TREC are produced. Thus the PCR assay for TREC became a viable screening test for SCID in newborns.

Currently 18 States are either already screening for SCID or are in the process of adding SCID screening to their NBS. There is a ways to go before this screening becomes part of all programs in the US, however, given the morbidity and mortality associated with the disease and the availability of a test, it’s hopefully only a matter of time.

1. Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, et al. Changes in thymic function with age and during the treatment of HIV infection. 1998. Nature. 396:690-695.

-Patti Jones PhD, DABCC, FACB, is the Clinical Director of the Chemistry and Metabolic Disease Laboratories at Children’s Medical Center in Dallas, TX and a Professor of Pathology at University of Texas Southwestern Medical Center in Dallas.

Inborn Errors of Metabolism (IEM) are genetic disorders that often occur as enzyme deficiencies which interfere with the normal biochemical processes of the human body. Very often these disorders are not apparent at birth because the mother’s biochemical processes work for the baby in the womb. Shortly after birth, the infant begins to get into significant trouble when his own enzymes are deficient or insufficient to carry the biochemical load. Many of these disorders are eminently treatable, allowing the treated individual to lead a normal life or a life whose quality is vastly improved over untreated individuals. Thus detecting IEM and treating them before the baby becomes ill is the primary purpose of newborn screening (NBS) programs worldwide. The seeds of newborn screening (NBS) in the US began back in the early 1960s when Dr. Robert Guthrie developed a bacterial inhibition assay for phenylalanine and demonstrated that it could be used to screen entire populations for the presence of a devastating yet treatable disease called phenylketonuria (PKU). In 1960 Maine became the first State to offer newborn screening for PKU to all infants born in Maine.

In the years that followed this advent, the prevalence of NBS grew slowly and sporadically. Along the way there was debate over which disorders to include; at one time a disorder had to meet a long list of criteria to be included. In addition, the NBS performed in any given state is dependent on that state’s ability and willingness to fund the program. Even today, NBS is not nationally mandated but is in the purview of the individual states. Each state decides which disorders to screen for.

As late as 1997, only 2 disorders (PKU and congenital hypothyroidism) were screened for by all 50 states. However in the mid- to late 1990’s a technological development revolutionized NBS. The ability to screen for up to 50 different IEM from a single dried blood spot punch using tandem mass spectrometry changed the face of NBS. The American College of Medical Genetics (ACMG) fielded a task force called the Newborn Screening Expert Group which published a recommendation in 2006 entitled “Newborn Screening: Toward a Uniform Screening Panel and System”(1). This Group recommended a set of 29 “core conditions” that every state should screen for, as well as a set of “secondary conditions” that will be picked up during the differential diagnosis of the core conditions. They also revised the inclusion criteria into a set of three basic criteria for disease inclusion in NBS programs: the disorder must be detectable within 24-48 hours of birth, before it’s clinically detectable, a screening test with appropriate sensitivity and specificity must be available, and the disorder must be treatable with benefits to treatment. Currently all 50 states screen their newborns for the 29 Core Conditions recommended by the ACMG and the US Department of Health and Human Services. Thanks to a laboratory technology, NBS is now much closer to being standardized than ever before and covers the majority of the most common IEM.

1) https://www.acmg.net/ACMG/Publications/Practice_Guidelines_docs/NBS_report.aspx