Abstract
All newborn screening laboratories in the United States and many worldwide screen for cystic fibrosis. Most laboratories use a second-tier genotyping assay to identify a panel of mutations in the CF transmembrane regulator (CFTR) gene. Centers for Disease Control and Prevention’s Newborn Screening Quality Assurance Program houses a dried blood spot repository of samples containing CFTR mutations to assist newborn screening laboratories and ensure high-quality mutation detection in a high-throughput environment. Recently, CFTR mutation detection has increased in complexity with expanded genotyping panels and gene sequencing. To accommodate the growing quality assurance needs, the repository samples were characterized with several multiplex genotyping methods, Sanger sequencing, and 3 next-generation sequencing assays using a high-throughput, low-concentration DNA extraction method. The samples performed well in all of the assays, providing newborn screening laboratories with a resource for complex CFTR mutation detection and next-generation sequencing as they transition to new methods.
Highlights
Cystic fibrosis (CF) is one of the most common autosomal recessive disorders that affects approximately 1:4000 people of Western European, North American, and Australasian descent
All US states and many international laboratories screen their newborn population for CF with the majority using second-tier CF transmembrane regulator (CFTR) mutation detection assay as part of their screening algorithm
The reason for the low-positive predictive value is that most programs use a panel of only 23 to 40 CF-causing mutations, and a screen-positive sample only has to contain 1 CFTR mutation.[12,18,31]
Summary
Cystic fibrosis (CF) is one of the most common autosomal recessive disorders that affects approximately 1:4000 people of Western European, North American, and Australasian descent. When CF is identified and treated early, patients avoid many of the devastating clinical consequences, allowing for improved growth, reduced hospitalizations, and longer life span, which resulted in the US Centers for Disease Control and Prevention (CDC) recommending that CF be included in newborn screening panels in the United States.[1,2] Newborn screening for CF begins with an immunoassay that measures the pancreatic enzyme immunoreactive trypsinogen (IRT), which is elevated in newborns affected with CF.[3,4] Since IRT can be elevated for reasons other than CF, this test alone does not have the specificity required for newborn screening. Most US programs use an algorithm that involves at least 1 initial measurement of IRT from a dried blood specimen (DBS) taken from all newborns and testing for a panel of CFTR mutations on a subset of babies with elevated IRT.[7,8] The panel of CFTR mutations can be variable between programs but typically includes the American College of Medical Genetics (ACMG) recommended 23 mutations and often additional mutations.[7,8,9,10] Newborns with either 1 or 2 CFTR mutations are considered screen positive by most programs and are sent to CF care centers for diagnostic
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