Feasibility and limitations of cultured skin fibroblasts for germline genetic testing in hematologic disorders
TLDR
In this article , the authors conducted a retrospective cohort study of 350 subjects with hematologic disorders who underwent skin fibroblast culture for germline genetic testing, and the median culture time was 28 days (IQR 22−29 days).Abstract:
To avoid acquired variants found in the blood, cultured skin fibroblasts are a recommended DNA source for germline genetic testing in patients with hematologic disorders, but data are lacking regarding practicality and limitations. We conducted a retrospective cohort study of 350 subjects with hematologic disorders who underwent skin fibroblast culture for germline genetic testing. We analyzed next-generation sequencing data from the targeted capture of 144 inherited cancer and bonemarrow failure genes to identify variants at heterozygous and subclonal variant allele frequencies. Sixteen (5%) biopsies failed to culture. Culture failure was more likely in samples with delays in culture initiation (OR = 4.3; p < 0.01) or a pathogenic variant in a telomere gene (OR = 42.6; p < 0.01). Median culture time was 28 days (IQR 22−29 days). Culture time was longer for subjects with prior allogeneic stem cell transplantation (+10.7%; p = 0.02) and shorter in subjects with a heterozygous pathogenic variant (−11.9%; p < 0.01), larger biopsy size (−10.6%; p < 0.01), or lymphoid malignancy (−8.4%; p < 0.01). Subclonal variants were identified in 10 (4%) and confirmed in five (56%) of eight with alternate samples available. Subclonal and discordant variants illustrate that germline testing from cultured skin fibroblasts requires phenotypic correlation and, in rare cases, follow-up studies for optimal interpretation. read more
Citations
More filters
Journal ArticleDOI
Feasibility and limitations of cultured skin fibroblasts for germline genetic testing in hematologic disorders
TL;DR: In this article , the authors conducted a retrospective cohort study of 350 subjects with hematologic disorders who underwent skin fibroblast culture for germline genetic testing, and the median culture time was 28 days (IQR 22−29 days).
Journal ArticleDOI
Germline CHEK2 and ATM Variants in Myeloid and Other Hematopoietic Malignancies
TL;DR: The role that deleterious germline CHEK2 and ATM variants play in the development of hematopoietic malignancies is reviewed, and how this influences clinical practice, including cancer screening, hematoplastic stem cell transplantation, and therapy choice is reviewed.
Journal ArticleDOI
Beyond Pathogenic RUNX1 Germline Variants: The Spectrum of Somatic Alterations in RUNX1-Familial Platelet Disorder with Predisposition to Hematologic Malignancies
TL;DR: In this article , the authors summarized previously published patients harboring (likely) pathogenic RUNX1 germline alterations in whom somatic alterations were additionally analyzed, and provided an overview of their phenotypes and the most frequent somatic genetic alterations.
Journal ArticleDOI
Approach Toward Germline Predisposition Syndromes in Patients with Hematologic Malignancies
TL;DR: The approach to recognizing patients suspected to carry a germline predisposition to hematologic malignancies and evaluation within a hereditary hematologists' clinic (HHMC) is described.
Journal ArticleDOI
Germline Predisposition to Myelodysplastic Syndromes
TL;DR: In this paper , the authors present the biological features and main clinical manifestations of hereditary hematologic malignancies, which are essential to recognizing and referring patients with myelodysplastic syndrome, who may underlie inherited predisposition, for appropriate genetic evaluation.
References
More filters
Journal ArticleDOI
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Sue Richards,Nazneen Aziz,Nazneen Aziz,Sherri J. Bale,David P. Bick,Soma Das,Julie M. Gastier-Foster,Wayne W. Grody,Madhuri Hegde,Elaine Lyon,Elaine B. Spector,Karl V. Voelkerding,Heidi L. Rehm +12 more
TL;DR: Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends thatclinical molecular genetic testing should be performed in a Clinical Laboratory Improvement Amendments–approved laboratory, with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or the equivalent.
Journal ArticleDOI
The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia
Daniel A. Arber,Attilio Orazi,Robert P. Hasserjian,Jürgen Thiele,Michael J. Borowitz,Michelle M. Le Beau,Clara D. Bloomfield,Mario Cazzola,James W. Vardiman +8 more
TL;DR: The 2016 edition of the World Health Organization classification of tumors of the hematopoietic and lymphoid tissues represents a revision of the prior classification rather than an entirely new classification and attempts to incorporate new clinical, prognostic, morphologic, immunophenotypic, and genetic data that have emerged since the last edition.
Journal ArticleDOI
Telomeres shorten during ageing of human fibroblasts.
TL;DR: The amount and length of telomeric DNA in human fibroblasts does in fact decrease as a function of serial passage during ageing in vitro and possibly in vivo.
Journal ArticleDOI
Telomere length predicts replicative capacity of human fibroblasts.
Richard C. Allsopp,Homayoun Vaziri,Christopher Patterson,S Goldstein,Edward V. Younglai,A B Futcher,Carol W. Greider,Calvin B. Harley +7 more
TL;DR: Telomere length is a biomarker of somatic cell aging in humans and is consistent with a causal role for telomere loss in this process, and fibroblasts from Hutchinson-Gilford progeria donors had short telomeres, consistent with their reduced division potential in vitro.
Journal ArticleDOI
High burden and pervasive positive selection of somatic mutations in normal human skin
Inigo Martincorena,Amit Roshan,Moritz Gerstung,Peter R. Ellis,Peter Van Loo,Peter Van Loo,Peter Van Loo,Stuart McLaren,David C. Wedge,Anthony Fullam,Ludmil B. Alexandrov,Jose M. C. Tubio,Lucy Stebbings,Andrew Menzies,Sara Widaa,Michael R. Stratton,Philip H. Jones,Peter J. Campbell,Peter J. Campbell +18 more
TL;DR: Across 234 biopsies of sun-exposed eyelid epidermis from four individuals, the burden of somatic mutations averaged two to six mutations per megabase per cell, similar to that seen in many cancers, and exhibited characteristic signatures of exposure to ultraviolet light.