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    The Genetic Landscape of Diamond-Blackfan Anemia

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    Authors
    Ulirsch, Jacob C.
    Newburger, Peter E.
    Korostelev, Andrei A.
    Sankaran, Vijay G.
    Gazda, Hanna T.
    UMass Chan Affiliations
    Department of Biochemistry and Molecular Pharmacology
    RNA Therapeutics Institute
    Department of Pediatrics
    Document Type
    Journal Article
    Publication Date
    2018-12-06
    Keywords
    Diamond-Blackfan anemia
    RNA sequencing
    congenital hypoplastic anemia
    hematopoiesis
    human genetics
    rare disease
    whole-exome sequencing
    Congenital, Hereditary, and Neonatal Diseases and Abnormalities
    Genetic Phenomena
    Genetics and Genomics
    Hematology
    Hemic and Immune Systems
    Hemic and Lymphatic Diseases
    Medical Genetics
    Nucleic Acids, Nucleotides, and Nucleosides
    Pediatrics
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    Link to Full Text
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288280/
    Abstract
    Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 7 out of 1,000,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole-exome sequencing (WES). We identified relevant rare and predicted damaging mutations for 78% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and located in 1 of 19 previously reported ribosomal protein (RP)-encoding genes. Using exon coverage estimates, we identified and validated 31 deletions in RP genes. We also observed an enrichment for extended splice site mutations and validated their diverse effects using RNA sequencing in cell lines obtained from individuals with DBA. Leveraging the size of our cohort, we observed robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. We further identified rare mutations in seven previously unreported RP genes that may cause DBA, as well as several distinct disorders that appear to phenocopy DBA, including nine individuals with biallelic CECR1 mutations that result in deficiency of ADA2. However, no new genes were identified at exome-wide significance, suggesting that there are no unidentified genes containing mutations readily identified by WES that explain > 5% of DBA-affected case subjects. Overall, this report should inform not only clinical practice for DBA-affected individuals, but also the design and analysis of rare variant studies for heterogeneous Mendelian disorders.
    Source

    Am J Hum Genet. 2018 Dec 6;103(6):930-947. doi: 10.1016/j.ajhg.2018.10.027. Epub 2018 Nov 29. Link to article on publisher's site

    DOI
    10.1016/j.ajhg.2018.10.027
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/43690
    PubMed ID
    30503522
    Notes

    Full author list omitted for brevity. For the full list of authors, see article.

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    ae974a485f413a2113503eed53cd6c53
    10.1016/j.ajhg.2018.10.027
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      Whole exome sequencing links dental tumor to an autosomal-dominant mutation in ANO5 gene associated with gnathodiaphyseal dysplasia and muscle dystrophies

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