What genetic tests are performed on newborns in the hospital?

Newborn Genetic Screening Tests in Hospitals

Newborn screening in the United States tests for approximately 30 core conditions and 26 secondary conditions using primarily dried blood spot samples collected shortly after birth, with testing performed by state public health laboratories using tandem mass spectrometry and other specialized techniques. 1

Core Conditions Screened

• Newborn screening programs test almost all (≥97%) of the 4 million babies born in the United States each year using dried blood spots collected before hospital discharge 2, 1
• The highest priority conditions recommended by the American College of Medical Genetics include:
  • Medium-chain acyl CoA dehydrogenase (MCAD) deficiency
  • Congenital hypothyroidism (CH)
  • Phenylketonuria (PKU)
  • Biotinidase deficiency (BIOT)
  • Sickle cell anemia (Hb SS)
  • Congenital adrenal hyperplasia (CAH) 1

Screening Technologies

• Tandem mass spectrometry (MS/MS) is the primary technology that has enabled expansion of newborn screening to detect multiple metabolic disorders from a single dried blood spot 2, 1
• MS/MS can detect numerous metabolic disorders including:
  • Amino acidemias (phenylketonuria, maple syrup urine disease, homocystinuria)
  • Organic acidemias (propionic acidemia, methylmalonic acidemia, isovaleric acidemia)
  • Fatty acid oxidation disorders (MCAD, VLCAD, LCHAD deficiencies) 2
• Traditional biochemical testing methods are still required for conditions that cannot be detected by MS/MS, including:
  • Biotinidase deficiency
  • Hypothyroidism
  • Hemoglobinopathies
  • Congenital adrenal hyperplasia
  • Galactosemia 2

Screening Process

• Newborn screening is performed using a few drops of blood collected from the infant's heel, spotted onto filter paper cards 2
• Most states collect a fee for newborn screening, which varies by state and may be paid by third-party payers 2
• The screening process involves:
  1. Initial screening of dried blood spot specimens by state public health laboratories
  2. Referral of positive screens to specialty centers for follow-up testing
  3. Confirmatory diagnostic testing 2, 1

Diagnostic Confirmation

• Infants with abnormal screening results are referred to specialty centers for follow-up testing and diagnostic confirmation 2
• Confirmatory testing may include:
  • Repeat measurement of screening metabolites
  • Enzyme activity assays
  • Molecular genetic testing (mutation analysis)
  • Additional biochemical tests 2, 1
• Proper diagnostic confirmation is critical to prevent incorrect or unclear diagnoses, which can lead to inappropriate clinical management and unnecessary parental anxiety 3

Challenges and Considerations

• The expansion of newborn screening has led to identification of "metabolite diagnoses" - cases with mildly abnormal metabolites that require additional investigation 2, 3
• Variability exists in laboratory practices across states, including criteria for specimen acceptance and cutoff values for analytes 2
• False-positive and false-negative results remain a challenge, with reported false-negative rates of 1.1-3.3% for some primary markers 2
• Quality assurance programs like the CDC Newborn Screening Quality Assurance Program (NSQAP) help laboratories monitor and improve test performance 2

Future Directions

• Next-generation sequencing (NGS) technologies are being explored to expand newborn screening capabilities and potentially reduce false positives 4, 5
• Combined approaches using both biochemical and genetic screening methods may optimize newborn screening systems 5
• Standardized terminology, coding, and electronic messaging are being developed to facilitate complete and accurate data collection and prompt results delivery 2

Common Pitfalls to Avoid

• Relying solely on abnormal metabolite levels without confirmatory testing can lead to incorrect diagnoses 3
• Failing to refer infants with borderline results to metabolic specialists can delay proper diagnosis and treatment 3
• Treating borderline results as definitively diagnostic without appropriate confirmatory testing should be avoided 3
• Lack of standardized follow-up protocols can result in missed cases or delayed intervention 2