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Lane W.J.,Harvard University | Westhoff C.M.,Brigham and Womens Hospital | Uy J.M.,Harvard University | Aguad M.,Harvard University | And 7 more authors.
Transfusion | Year: 2016

BACKGROUND There are 346 serologically defined red blood cell (RBC) antigens and 33 serologically defined platelet (PLT) antigens, most of which have known genetic changes in 45 RBC or six PLT genes that correlate with antigen expression. Polymorphic sites associated with antigen expression in the primary literature and reference databases are annotated according to nucleotide positions in cDNA. This makes antigen prediction from next-generation sequencing data challenging, since it uses genomic coordinates. STUDY DESIGN AND METHODS The conventional cDNA reference sequences for all known RBC and PLT genes that correlate with antigen expression were aligned to the human reference genome. The alignments allowed conversion of conventional cDNA nucleotide positions to the corresponding genomic coordinates. RBC and PLT antigen prediction was then performed using the human reference genome and whole genome sequencing (WGS) data with serologic confirmation. RESULTS Some major differences and alignment issues were found when attempting to convert the conventional cDNA to human reference genome sequences for the following genes: ABO, A4GALT, RHD, RHCE, FUT3, ACKR1 (previously DARC), ACHE, FUT2, CR1, GCNT2, and RHAG. However, it was possible to create usable alignments, which facilitated the prediction of all RBC and PLT antigens with a known molecular basis from WGS data. Traditional serologic typing for 18 RBC antigens were in agreement with the WGS-based antigen predictions, providing proof of principle for this approach. CONCLUSION Detailed mapping of conventional cDNA annotated RBC and PLT alleles can enable accurate prediction of RBC and PLT antigens from whole genomic sequencing data. © 2015 The Authors Transfusion published by Wiley Periodicals, Inc. on behalf of AABB. Source


McLaughlin H.M.,Laboratory for Molecular Medicine | McLaughlin H.M.,Lansdowne Partners | Kelly M.A.,Lansdowne Partners | Hawley P.P.,Boston Childrens Hospital Boston | And 7 more authors.
BMC Medical Genetics | Year: 2013

Background: Variants in the desmin gene (DES) are associated with desminopathy; a myofibrillar myopathy mainly characterized by muscle weakness, conduction block, and dilated cardiomyopathy. To date, only ~50 disease-associated variants have been described, and the majority of these lead to dominant-negative effects. However, the complete genotypic spectrum of desminopathy is not well established.Case presentation: Next-generation sequencing was performed on 51 cardiac disease genes in a proband with profound skeletal myopathy, dilated cardiomyopathy, and respiratory dysfunction. Our analyses revealed compound heterozygous DES variants, both of which are predicted to lead to a loss-of-function. Consistent with recessive inheritance, each variant was identified in an unaffected parent.Conclusions: This case report serves to broaden the variant spectrum of desminopathies and provides insight into the molecular mechanisms of desminopathy, supporting distinct dominant-negative and loss-of-function etiologies. © 2013 McLaughlin et al.; licensee BioMed Central Ltd. Source


Olive M.,U.S. National Institutes of Health | Harten I.,Benaroya Research Institute | Harten I.,University of Washington | Mitchell R.,Harvard University | And 18 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2010

OBJECTIVE-: Children with Hutchinson-Gilford progeria syndrome (HGPS) exhibit dramatically accelerated cardiovascular disease (CVD), causing death from myocardial infarction or stroke between the ages of 7 and 20 years. We undertook the first histological comparative evaluation between genetically confirmed HGPS and the CVD of aging. METHODS AND RESULTS-: We present structural and immunohistological analysis of cardiovascular tissues from 2 children with HGPS who died of myocardial infarction. Both had features classically associated with the atherosclerosis of aging, as well as arteriolosclerosis of small vessels. In addition, vessels exhibited prominent adventitial fibrosis, a previously undescribed feature of HGPS. Importantly, although progerin was detected at higher rates in the HGPS coronary arteries, it was also present in non-HGPS individuals. Between the ages of 1 month and 97 years, progerin staining increased an average of 3.34% per year (P<0.0001) in coronary arteries. CONCLUSION-: We find concordance among many aspects of cardiovascular pathology in both HGPS and geriatric patients. HGPS generates a more prominent adventitial fibrosis than typical CVD. Vascular progerin generation in young non-HGPS individuals, which significantly increases throughout life, strongly suggests that progerin has a role in cardiovascular aging of the general population. © 2010 American Heart Association, Inc. Source


Bettinelli A.L.,Ochsner Clinic Foundation | Mulder T.J.,Ochsner Clinic Foundation | Funke B.H.,Laboratory for Molecular Medicine | Lafferty K.A.,Laboratory for Molecular Medicine | And 2 more authors.
American Journal of Medical Genetics, Part A | Year: 2013

Ebstein anomaly is a rare congenital heart defect that most often occurs sporadically within a kindred. Familial cases, although reported, are uncommon. At this time, the genetic etiology of Ebstein anomaly is not fully elucidated. Here, we describe clinical and molecular investigations of a rare case of familial Ebstein anomaly in association with a likely pathogenic mutation of the MYH7 gene. The severity of presentation varies, and Ebstein anomaly can be observed in association with such other heart defects as ventricular septal defect and left ventricular (LV) hypertrabeculation, as seen in our family of study. In our family of study, the 31-year-old father and four of his children have been diagnosed with Ebstein anomaly. Genetic testing revealed that the father was heterozygous for the Glu1220del variant detected in exon 27 of the MYH7 gene. The MYH7 gene encodes the β-myosin heavy chain and is expressed in cardiac muscle. DNA sequencing of three of his affected children confirmed that they carried the same variant while the fourth affected child was not available for testing. This is the first report of familial Ebstein anomaly associated with the Glu1220del mutation of the MYH7 gene. The mutation segregates with disease in a family with autosomal dominant transmission of congenital heart defects including Ebstein anomaly and other associated cardiovascular defects including LV hypertrabeculation and ventricular septal defect. © 2013 Wiley Periodicals, Inc. Source


Thompson B.A.,QIMR Berghofer Medical Research Institute | Thompson B.A.,University of Queensland | Spurdle A.B.,QIMR Berghofer Medical Research Institute | Plazzer J.-P.,Royal Melbourne Hospital | And 142 more authors.
Nature Genetics | Year: 2014

The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases. © 2014 Nature America, Inc. Source

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