Collaborative evaluation study on 18 candidate diseases for newborn screening in 1.77 million samples

Area of Science:

• Biochemistry
• Genetics
• Public Health

Background:

• Newborn screening (NBS) programs are continuously expanding globally due to analytical and therapeutic advancements.
• Each expansion necessitates rigorous evaluation of feasibility, diagnostic quality, and health benefits versus limitations.

Purpose of the Study:

• To evaluate the suitability of 18 candidate inherited metabolic diseases for inclusion in newborn screening programs.
• To assess the diagnostic performance and limitations of expanding NBS to these specific conditions.

Main Methods:

• Conducted an evaluation study across three German NBS centers, analyzing 1,777,264 NBS samples.
• Utilized tandem mass spectrometry and established specific second-tier diagnostic analyses for 18 candidate diseases.
• Calculated prevalence, positive predictive values, and identified false-positive and false-negative cases.

Main Results:

• Reported 441 positive NBS results, leading to 68 confirmed diagnoses and 373 false positives, with a cumulative prevalence of ~1 in 26,000 newborns.
• Positive predictive values varied significantly, from 0.07 for carnitine transporter defect to 0.67 for HMG-CoA lyase deficiency.
• Three individuals were missed by screening, and 14 (21%) developed symptoms before NBS results were reported.

Conclusions:

• The majority of the 18 evaluated inherited metabolic diseases are suitable for inclusion in NBS programs.
• Multiple acyl-CoA dehydrogenase deficiency, isolated methylmalonic acidurias, propionic acidemia, and malonyl-CoA decarboxylase deficiency showed some limitations; carnitine transporter defect had significant limitations.
• Evaluation studies are essential for assessing the benefits and limitations of expanding NBS programs to new diseases.