A. Cecile J.W. Janssens A. Picornell Aaron Goldenberg Adam Buchanan Adam Butterworth Alan Bittles Alan Wu Albert O. Edwards Alex MacKenzie Allen N. Lamb Amy Kao Amy L. McGuire Andrea Gropman Angela R. Bradbury Anne Child Anne Lyerly Anne Tsai Arno Motulsky Arthur Aylsworth Arthur Beaudet Arthur Wilde Athena Cherry B. Bembi Barbara A. Bernhardt Barbara Bowles Biesecker Barbara DuPont Barbara Koenig Barbara Zehnbauer Barry Byrne Bassem A. Bejjani Behrooz Alizadeh Benjamin R. Bates Benjamin Wilfond Beth Tarini Blake Ballif Bonnie LeRoy Bruce Korf C. Philippe Carlos Bacino Carma Bylund Carolyn T. Spencer Catherine Rehder Catherine Wang Cathy Fomous Cecelia Bellcross Cecile Skrzynia Celeste Condit Chris Gignoux Chris Haiman Christa Lese Martin Christina Gurnett Christina Palmer Colleen Brown Colleen M McBride Cornelis Harteveld Cynthia Morton Cynthia Powell Dan Jonas Daniel Cohn Daniel Freeman Daniel Judge Darren G. Monckton David Chitayat David Goldgar David Ledbetter David Viskochil David Weinstein Deborah Krakow Debra Doyle Diane Bild Dietrich Matern Don Bailey Ed Ramos Eduardo F. Tizzano Elaine Lyon Elisabeth Wood Elizabeth Gillanders Ellen Wright Clayton Ephrat Levy-Lahad Eric Schon Erin Ramos Eugene N. Pergament Evan Eichler Ferrin Wheeler Fiona Lalloo Fleur van Dijk Frederick Schaefer Gail Henderson Gareth Evans Gary Gottesman Georgianne Arnold Glen Brice Han Brunner Hans Andersson Harmut Neumann Harry Ostrer Harvey Murff Hawazin Faruki Heather Hampel Heather Skirton Hela Azaiez Howard P. Levy Howard Saal H.P. Scholl Hutton Moore Kearney James P. Evans James Russell James Verbsky Jan Lowery Jan M. Friedman Janet Williams Jeffrey Botkin Jeffrey Towbin Jennifer Lin Jeroen Eikenboom Jiri Zeman Joan Scott John Graham, Jr John J. Mulvihill John P. Johnson Jon Bernstein Jon Weil Jonathan Sanford Berg Jose Abdenur Joseph Shieh Josh John Carlson Judith Balmana Julie Gastier June Peters Karen Edwards Karen L. Edwards Karen Stephens Karen Tsuchiya Karen Weck Katharine Harris Katherine Kolor Katherine Rauen Kathryn Phillips Katie Plunkett Katie Rudd Kelly E. Ormond Kirsten Kangelaris Laura M. Beskow Lauren Weiss Lee Shulman Leslie Biesecker Lisa Schimmenti Lisa Shaffer Lora Bean Lou Garrison Louanne Hudgins Lucia Hindorff Luisa Mestroni Madhuri Hegde Marc Greenblatt Marc Williams Maren Scheuner Margaret Kenna Mark Bailey Mark Domenic Pertile Mark Rothstein Mark Sands Mark Tarnopolsky Marvin Natowicz Mary Norton Mary-Joan MacLeod Maurice Godfrey May M. Luke Melanie Faith Myers Melanie Price Michael Arribas-Ayllon Michael Beck Michael Bober Michael Mennuti REVIEWERS

Purpose: Diagnostic and predictive testing for Huntington disease requires an accurate measurement of CAG repeats in the HD (IT15) gene. However, precise repeat sizing can be technically challenging, and is complicated by the lack of quality control and reference materials (RM). The aim of this study was to characterize genomic DNA from 14 Huntington cell lines available from the National Institute of General Medical Sciences Human Genetic Cell Repository at the Coriell Cell Repositories for use as reference materials for CAG repeat sizing.Methods: Fourteen Huntington cell lines were selected for study. The alleles in these materials represent a large range of sizes that include important diagnostic cutoffs and allele combinations. The allele measurement study was conducted by ten volunteer laboratories using a variety of polymerase chain reaction-based in-house developed methods and by DNA sequence analysis.Results: The Huntington alleles in the 14 genomic DNA samples range in size from 15 to 100 CAG repeats. There was good agreement among the ten laboratories, and thus, the 95% confidence interval was small for each measurement. The allele size determined by DNA sequence analysis agreed with the laboratory developed tests.Conclusion: These DNA materials, which are available from Coriell Cell Repositories, will facilitate accurate and reliable Huntington genetic testing.

Introduction: DNA-based genetic tests for heritable conditions contribute to patient care decisions regarding diagnosis, treatment, counseling, and referral.A genotype has meaning in the context of the clinical indications, an understanding of the relevant genetic associations, and the analytical characteristics of the test.We undertook a study to assess reporting practices to identify and address shortcomings in the processes by which laboratory and clinical settings communicate.Methods: Using DNA-based cystic fibrosis as a model, we reviewed existing laboratory requisitions and reports.We surveyed laboratory professionals and clinicians about their experience in ordering, reporting, and using tests and results.A workgroup reviewed findings and proposed approaches to improve the quality and usefulness of reports.Results: Report content and format varied and was somewhat dependent on the requisition.Variation was particularly evident when describing residual risk and inconclusive diagnostic results.Non-medical personnel were found to have roles in reviewing reports and communicating results to patients.Our data also indicated physicians' general dissatisfaction with wording used in the report's interpretive component.At a workshop held in November 2005, attendees concluded a model for communicating test results in a clear context is needed.Conclusion: A model for reporting results has been developed for surgical pathology that is potentially applicable to genetic testing.This "synoptic" report uses standard language, arrived at through clinician feedback, in reporting the result in terms of what is clinically relevant and actionable.We propose this useful for effectively communicating such concepts as residual risk, uncertainty associated with negative findings, implications for family members, and test limitations.For example, many OB-GYNs order cystic fibrosis carrier testing during routine care and a synoptic report may aid in understanding the residual risk and its clinical relevance.Another potential advantage in developing a synoptic style report is the recognition and integration of good reporting practices and a practical means to implement professional recommendations.We anticipate these efforts will influence educational and information resource initiatives that address the appropriate use of genetic tests and integration of test results into patient care decisions.

Cystic fibrosis (CF) is the most common life-limiting recessive genetic disorder in Caucasians, with a carrier frequency of ∼1 in 25 and incidence of ∼1 in 2500–3300 live births (1). CF is caused by mutations affecting the transmembrane conductance regulator (CFTR) gene localized on the long arm of chromosome 7 (7q31.2). CFTR contains 27 exons and encodes a protein of 1480 amino acids that functions as a cAMP-regulated chloride channel in the apical membrane of epithelial cells (2)(3). Mutations in the CFTR gene lead to dysfunction of the lungs, sweat glands, testes, ovaries, intestines, and pancreas. More than 1000 mutations in this gene have been identified to date (4). The clinical manifestations of the disease are variable, ranging from severe pulmonary disease with pancreatic insufficiency to mild pulmonary disease and pancreatic sufficiency (1). Moreover, mutations in the CFTR gene have also been found in patients who have normal lung function but show other clinical signs, such as congenital bilateral absence of the vas deferens (CBAVD), nasal polyposis, bronchiectasis, and bronchopulmonary allergic aspergillosis (5)(6). Some of the variability in the CF phenotype has been attributed to the influence of the 5T allele at a polymorphic poly(T) tract in intron 8 (IVS8-T) of the CFTR gene. Genotype–phenotype correlations have shown that there is a strong association of the 5T allele with male infertility caused by congenital CBAVD and with other monosymptomatic forms of CF, such as bronchiectasis and chronic idiopathic pancreatitis (5)(6 …

Instability and enlargement of a CAG repeat region at the beginning of the huntingtin gene (IT-15) has been linked with Huntington`s disease. The CAG repeat size shows a highly significant correlation with age-of-onset of clinicial features in individuals with 40 or more repeats who have Huntington disease. The clinical status of nonsymptomatic individuals with 30 to 39 CAG repeats is considered ambiguous. In order to define more carefully the nature of the HD expansion instability, we examined patients in our HD population using a discriminating fluorescence-based PCR approach. The degree of somatic mutation increases with both earlier age of onset and the size of the inherited allele. A single prominent band one repeat larger than the index peak was typical in individuals with 40-41 CAG repeats. Three to four larger bands are typically discerned in individuals with 50 or more repeats. In an extreme example, an individual with approximately 95 repeats had at least 8 prominent bands. Plotting the degree of somatic mutation relative to the size of the HD allele shows somatic mutation activity increases with size. By this approach 40-60% of the alleles in a 40-41 CAG repeat HD loci is represented in the primary allele. In contrast,more » the primary allele represents a relatively minor proportion of the total alleles for expansions greater than 50 CAG repeats (10-20%). The limited range of somatic mutation suggest that the instability is restricted to very early stages of embryogenesis before tissue development diverges or that persistent somatic instability occurs at a slow rate. Therefore, the properties of somatic instability in Huntington`s disease have aspects that are both in common but also different from that found in other trinucleotide repeat expanding diseases such as myotonic muscular dystrophy and fragile X syndrome.« less