Dataset Information

Newborn Screening Quality Assurance Program for CFTR Mutation Detection and Gene Sequencing to Identify Cystic Fibrosis.

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.

SUBMITTER: Hendrix MM

PROVIDER: S-EPMC5332130 | biostudies-literature | 2016 Jan-Dec

REPOSITORIES: biostudies-literature

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Newborn Screening Quality Assurance Program for CFTR Mutation Detection and Gene Sequencing to Identify Cystic Fibrosis.

Hendrix Miyono M MM Foster Stephanie L SL Cordovado Suzanne K SK

Journal of inborn errors of metabolism and screening 20160101

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 (<i>CFTR</i>) gene. Centers for Disease Control and Prevention's Newborn Screening Quality Assurance Program houses a dried blood spot repository of samples containing <i>CFTR</i> mutations to assist newborn screening laboratories and ensure high-quality mutation detection in ...[more]

PMID: 28261631

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Project description:The objective of this study was to examine relationships between pulmonary health and health-related quality of life (HRQOL) in patients with cystic fibrosis (CF) evaluated longitudinally in the Wisconsin Newborn Screening Project.Patients aged 8 to 18 years (mean ± SD, 13.5 ± 2.8) in early diagnosis (n = 45) and control (n = 50) groups completed Cystic Fibrosis Questionnaires (CFQs) to measure HRQOL at three data points over a 2-year period. Pulmonary health was evaluated concurrently by the Wisconsin chest x-ray scoring system (WCXR) and pulmonary function tests (PFTs).WCXR showed significant group differences (P ? .023), with the early diagnosis group showing more-severe lung disease. When adjusted for group differences in mucoid Pseudomonas aeruginosa status and pancreatic status, however, WCXR differences and PFT data were not significant. Most patients (74%) had FEV(1) values ? 80% predicted (within normal range). For patients aged < 14 years, as WCXR scores worsened CFQ respiratory and physical domain scores decreased (both P ? .007). FEV(1)/FVC showed a positive relationship with the respiratory and physical domains (both P ? .006). WCXR scores for patients aged ? 14 years were associated with CFQ weight, respiratory, and health domains (all P ? .011). FEV(1) was associated with CFQ weight, respiratory, health, and physical domains (all P ? .003). Changes in pulmonary health were not associated with changes in CFQ over time. Significant group differences on the CFQ-Child social functioning domain favored the control group.To our knowledge, this study is the first to compare pulmonary outcomes with HRQOL indicators assessed by serial, standardized, patient-reported outcome measures for patients with CF identified either through newborn screening or diagnosed by use of traditional methods. This study found no benefits of newborn screening for pulmonary health or HRQOL after controlling for risk factors. Using WCXR and PFT data collectively helped to identify associations between pulmonary health and HRQOL.

Project description:The distribution and frequency of the CFTR gene mutations vary considerably between countries and ethnic groups. Russians are an East Slavic ethnic groups are native to Eastern Europe. Russians, the most numerous people of the Russian Federation (RF), make about 80% of the population. The aim is to reveal the molecular causes of CF in ethnic Russian patients as comprehensively as possible. The analysis of most common CFTR mutations utilized for CF diagnosis in multiethnic RF population accounts for about 83% of all CF-causing mutations in 1384 ethnic Russian patients. Variants c.1521_1523delCTT (F508del), c.54-5940_273+10250del21kb (CFTRdele2,3), c.2012delT (2143delT), c.2052_2053insA (2184insA), and c.3691delT (3821delT) are most typical for CF patients of Russian origin. DNA of 154 CF patients, Russian by origin, in whom at least one mutant allele was not previously identified (164 CF alleles), was analyzed by Sanger sequencing followed by the multiplex ligase-dependent probe amplification (MLPA) method. In addition to the 29 variants identified during the previous test for common mutations, 91 pathogenic CFTR variants were also revealed: 29 missense, 19 nonsense, 14 frame shift in/del, 17 splicing, 1 in frame ins, and 11 copy number variations (CNV). Each of the 61 variants was revealed once, and 17 twice. Each of the variants c.1209G>C (E403D), c.2128A>T (K710X), c.3883delA (4015delA), and c.3884_3885insT (4016insT) were detected for three, c.1766+1G>A (1898+1G>A) and c.2834C>T (S945L) for four, c.1766+1G>C (1898+1G>C) and c.(743+1_744-1)_(1584+1_1585-1)dup (CFTRdup6b-10) for five, c.2353C>T (R785X) and c.4004T>C (L1335P) for six, c.3929G>A (W1310X) for seven, c.580-1G>T (712-1G>T for eight, and c.1240_1244delCAAAA (1365del5) for 11 unrelated patients. A comprehensive analysis of CFTR mutant alleles with sequencing followed by MLPA, allowed not only the identification of 163 of 164 unknown alleles in our patient sample, but also expansion of the mutation spectrum with novel and additional frequent variants for ethnic Russians.

Dataset Information

Newborn Screening Quality Assurance Program for CFTR Mutation Detection and Gene Sequencing to Identify Cystic Fibrosis.

Publications

Newborn Screening Quality Assurance Program for CFTR Mutation Detection and Gene Sequencing to Identify Cystic Fibrosis.

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