Cystic fibrosis population carrier screening: 2004 Revision of American College of Medical Genetics mutation panel

ACMG Cystic Fibrosis Carrier Screening Work Group, American College of Medical Genetics, Bethesda, Maryland 20814, USA.
Genetics in Medicine (Impact Factor: 7.33). 10/2004; 6(5):387-91. DOI: 10.1097/01.GIM.0000139506.11694.7C
Source: PubMed


experiencing challenges in delivering this service. 4 The current CF Foundation patient mutation database includes nearly double the number of CF patient chromosomes available for analysis in 2000. This report summarizes the major recom- mendations of our Working Group with the supporting justi- fication for these decisions. A number of articles in this issue of Genetics in Medicine provide some of the data on which our decisions were made, whereas others provide new information related to this topic.

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    • "In November 2013, Illumina received 510K clearance from the US Food and Drug Administration (FDA) for its MiSeqDx nextgeneration sequencing (NGS) system, which includes a panel targeting 139 CFTR variants. The MiSeqDx Cystic Fibrosis 139-Variant Assay (henceforth 139-VA) is the most comprehensive panel of validated CFTR variants commercially available, and includes the 23 mutations currently recommended by the ACMG/ACOG [Watson et al., 2004], and all variants classified as CF causing in the CFTR2 database ( as of August 2013. "
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    ABSTRACT: Infants are screened for Cystic Fibrosis (CF) in New York State (NYS) using an IRT-DNA algorithm. The purpose of this study was to validate and assess clinical validity of the FDA-cleared Illumina MiSeqDx CF 139-Variant Assay (139-VA) in the diverse NYS CF population. The study included 439 infants with CF identified via newborn screening (NBS) from 2002-2012. All had been screened using the Abbott Molecular CF Genotyping Assay or the Hologic InPlex CF Molecular Test. All with CF and 0-1 mutations were tested using the 139-VA. DNA extracted from dried blood spots was reliably and accurately genotyped using the 139-VA. Sixty-three additional mutations were identified. Clinical sensitivity of three panels ranged from 76.2% (23 mutations recommended for screening by ACMG/ACOG), to 79.7% (current NYS 39-mutation InPlex panel), up to 86.0% for the 139-VA. For all, sensitivity was highest in Whites and lowest in the Black population. Although the sample size was small, there was a nearly 20% increase in sensitivity for the Black CF population using the 139-VA (68.2%) over the ACMG/ACOG and InPlex panels (both 50.0%). Overall, the 139-VA is more sensitive than other commercially-available panels, and could be considered for NBS, clinical or research laboratories conducting CF screening. This article is protected by copyright. All rights reserved.
    No preview · Article · Nov 2015 · Human Mutation
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    • "Although one mutation (del- taF508) accounts for about 70% of CF alleles worldwide (Bobadilla et al. 2002), diverse heritages are reflected for the CFTR gene and distributed with varying frequencies among populations often complicating genetic analysis (Estivill et al. 1997). The current guidelines of the American College of Medical Genetics and Genomics (ACMG) recommend a panel of only 23 variants for populationbased CF carrier screening (Watson et al. 2004), leaving the vast majority of possible genotype changes untested. "
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    ABSTRACT: Genetic testing for cystic fibrosis and CFTR-related disorders mostly relies on laborious molecular tools that use Sanger sequencing to scan for mutations in the CFTR gene. We have explored a more efficient genetic screening strategy based on next-generation sequencing (NGS) of the CFTR gene. We validated this approach in a cohort of 177 patients with previously known CFTR mutations and polymorphisms. Genomic DNA was amplified using the Ion AmpliSeq™CFTR panel. The DNA libraries were pooled, barcoded, and sequenced using an Ion Torrent PGM sequencer. The combination of different robust bioinformatics tools allowed us to detect previously known pathogenic mutations and polymorphisms in the 177 samples, without detecting spurious pathogenic calls. In summary, the assay achieves a sensitivity of 94.45% (95% CI: 92% to 96.9%), with a specificity of detecting nonvariant sites from the CFTR reference sequence of 100% (95% CI: 100% to 100%), a positive predictive value of 100% (95% CI: 100% to 100%), and a negative predictive value of 99.99% (95% CI: 99.99% to 100%). In addition, we describe the observed allelic frequencies of 94 unique definitely and likely pathogenic, uncertain, and neutral CFTR variants, some of them not previously annotated in the public databases. Strikingly, a seven exon spanning deletion as well as several more technically challenging variants such as pathogenic poly-thymidine-guanine and poly-thymidine (poly-TG-T) tracts were also detected. Targeted NGS is ready to substitute classical molecular methods to perform genetic testing on the CFTR gene.
    Full-text · Article · Apr 2015
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    • "Moreover, specific mutations in this gene can contribute to a form of male infertility known as Congenital Bilateral Absence of the Vas Deference (CBAVD) (Daudin et al., 2000), idiopathic and chronic pancreatitis (Cohn, 2005; Sharer et al., 1998; Witt, 2003) and bronchiectasis (Feldman, 2011). Following the cloning of the CFTR gene, detailed studies of CF causing mutations and the elucidation of mutational panels for CF in the White-European populations emerged (Bobadilla et al., 2002; Grody et al., 2001; Watson et al., 2004). CF has an overall prevalence of approximately 1:2500 and a carrier frequency of 1:25 in White-European populations (Bobadilla et al., 2002). "
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    ABSTRACT: Cystic Fibrosis (CF) is an autosomal recessive disorder affecting the chloride transport in mucus-producing epithelial cells. The disease is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR), which is responsible for trans-epithelial chloride transport. Approximately 1900 mutations and gene variants of the CFTR have been described. The spectrum of major White-European mutations includes F508del, G542X, G551D and N1303K. F508del is the most common CF-causing mutation, found in approximately 70% of all CF patients worldwide. The spectrum of CF mutations of Arab populations is under-investigated. However, initial molecular-epidemiological studies indicate the existence of specific CF mutation clusters within geographical regions in the Middle East, suggesting specific distributions of CF mutation carrying chromosomes in this part of the world. We showed that the worldwide rare CF mutation S549R is the predominant disease causing mutation in the Omani population. We reported that S549R, together with two other identified mutations, F508del and the rare private mutation V392G, are genetically linked to the exonic methionine polymorphism c.1408A>G; p.Met470Val at exon 10 and the intronic dimorphic 4-bp GATT 6-repeat at intron 6, c.744_33GATT[6_8]. We detected three haplotypes in 28 alleles of the Omani CF cohort and 408 alleles of our control cohort of unrelated and unaffected Omani volunteers. The CF disease associated haplotype consisting of an M allele and a 6-repeat expansion, occurred with an allele frequency of only 0.174 in the normal Omani population. The discriminative power of the haplotype was attributed to the intronic dimorphic 4-bp GATT 6-repeat. Furthermore, we found only one mutation, c.1733_1734delTA in the Omani CF cohort which deviated from the rule and shared the most common haplotype, a V allele and a 7-repeat extension, with the normal population.
    Full-text · Article · Apr 2015
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