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Träfflista för sökning "WFRF:(Lupski James R.) "

Sökning: WFRF:(Lupski James R.)

  • Resultat 1-7 av 7
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1.
  • Nilsson, D., et al. (författare)
  • Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights the Importance of Microhomology in the Mechanism of Formation
  • 2017
  • Ingår i: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 38:2, s. 180-192
  • Tidskriftsartikel (refereegranskat)abstract
    • Most balanced translocations are thought to result mechanistically from nonhomologous end joining or, in rare cases of recurrent events, by nonallelic homologous recombination. Here, we use low-coverage mate pair whole-genome sequencing to fine map rearrangement breakpoint junctions in both phenotypically normal and affected translocation carriers. In total, 46 junctions from 22 carriers of balanced translocations were characterized. Genes were disrupted in 48% of the breakpoints; recessive genes in four normal carriers and known dominant intellectual disability genes in three affected carriers. Finally, seven candidate disease genes were disrupted in five carriers with neurocognitive disabilities (SVOPL, SUSD1, TOX, NCALD, SLC4A10) and one XX-male carrier with Tourette syndrome (LYPD6, GPC5). Breakpoint junction analyses revealed microhomology and small templated insertions in a substantive fraction of the analyzed translocations (17.4%; n = 4); an observation that was substantiated by reanalysis of 37 previously published translocation junctions. Microhomology associated with templated insertions is a characteristic seen in the breakpoint junctions of rearrangements mediated by error-prone replication-based repair mechanisms. Our data implicate that a mechanism involving template switching might contribute to the formation of at least 15% of the interchromosomal translocation events.
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2.
  • Stray-Pedersen, Asbjorg, et al. (författare)
  • Primary immunodeficiency diseases : Genomic approaches delineate heterogeneous Mendelian disorders
  • 2017
  • Ingår i: Journal of Allergy and Clinical Immunology. - : MOSBY-ELSEVIER. - 0091-6749 .- 1097-6825. ; 139:1, s. 232-245
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/ 110) and management was directly altered in nearly a quarter (26/ 110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.
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3.
  • Pettersson, Maria, et al. (författare)
  • Cytogenetically visible inversions are formed by multiple molecular mechanisms
  • 2020
  • Ingår i: Human Mutation. - : WILEY. - 1059-7794 .- 1098-1004. ; 41:11, s. 1979-1998
  • Tidskriftsartikel (refereegranskat)abstract
    • Cytogenetically detected inversions are generally assumed to be copy number and phenotypically neutral events. While nonallelic homologous recombination is thought to play a major role, recent data suggest the involvement of other molecular mechanisms in inversion formation. Using a combination of short-read whole-genome sequencing (WGS), 10X Genomics Chromium WGS, droplet digital polymerase chain reaction and array comparative genomic hybridization we investigated the genomic structure of 18 large unique cytogenetically detected chromosomal inversions and achieved nucleotide resolution of at least one chromosomal inversion junction for 13/18 (72%). Surprisingly, we observed that seemingly copy number neutral inversions can be accompanied by a copy-number gain of up to 350 kb and local genomic complexities (3/18, 17%). In the resolved inversions, the mutational signatures are consistent with nonhomologous end-joining (8/13, 62%) or microhomology-mediated break-induced replication (5/13, 38%). Our study indicates that short-read 30x coverage WGS can detect a substantial fraction of chromosomal inversions. Moreover, replication-based mechanisms are responsible for approximately 38% of those events leading to a significant proportion of inversions that are actually accompanied by additional copy-number variation potentially contributing to the overall phenotypic presentation of those patients.
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6.
  • Fioretos, Thoas, et al. (författare)
  • Mechanisms underlying neoplasia-associated genomic rearrangements
  • 2006
  • Ingår i: Genomic disorders: The Genomic basis of disease. - : Humana Press. - 9781588295590 ; , s. 327-337
  • Bokkapitel (övrigt vetenskapligt)abstract
    • Neoplastic disorders are characterized by recurrent somatically acquired chromosomal aberrations that alter the structure and/or expression of a large number of genes. Most “cancer genes” discovered to date in human neoplasms have been identified through isolation of genes at the breakpoints of balanced chromosomal translocations. Although functional studies of such cancer-causing genes have demonstrated their causal role in tumorigenesis, the mechanisms underlying the formation of recurrent chromosomal changes in cancer remain enigmatic. Low-copy repeats (LCRs) are important mediators of erroneous meiotic recombination, resulting in constitutional chromosomal rearrangements. Recently, LCRs have been implicated in the formation of the frequent and characteristic neoplasia-associated chromosomal aberrations t(9;22)(q34;q1 1) and i(17q), suggesting that similar genome architecture features may play an important role in generating also other somatic chromosomal rearrangements.
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7.
  • Swierkowska, Joanna, et al. (författare)
  • Variants in FLRT3 and SLC35E2B identified using exome sequencing in seven high myopia families from Central Europe
  • 2021
  • Ingår i: Advances in Medical Sciences. - : ELSEVIER URBAN & PARTNER SP Z O O. - 1896-1126 .- 1898-4002. ; 66:1, s. 192-198
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: High myopia (HM) is an eye disorder with both environmental and genetic factors involved. Many genetic factors responsible for HM were recognized worldwide, but little is known about genetic variants underlying HM in Central Europe. Thus, the aim of this study was to identify rare sequence variants involved in HM in families from Central Europe to better understand the genetic basis of HM. Materials and methods: We assessed 17 individuals from 7 unrelated Central European families with hereditary HM using exome sequencing (ES). Segregation of selected variants in other available family members was performed using Sanger sequencing. Results: Detected 73 rare variants were selected for verification. We observed 2 missense variants, c.938C>T in SLC35E2B - encoding solute carrier family 35 member E2B, and c.1642G>C in FLRT3 - encoding fibronectin leucine rich transmembrane protein, segregating with HM in one family. Conclusions: FLRT3 and/or SLC35E2B could represent disease candidate genes and identified sequence variants might be responsible for HM in the studied family.
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  • Resultat 1-7 av 7

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