Abstract
Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome with 22 FA-related genes identified to date. Fragment deletions are frequently occurring aberrances accounting for ~30% of pathogenic variants in them, especially in FANCA, most of which are the results of genomic rearrangement events mediated by the highly concentrated Alu elements interspersing in it. Owing to the capability to detect genome-wide copy number variations (CNVs) with the resolution of 400 kb or larger, cytogenomic microarray is the most widely used method in the clinic currently. However, thereis still a technical gap in the detection of CNVs ranging from hundreds of bp to hundreds of kb between microarray, Sanger sequencing, and direct targeted high-throughput sequencing (THS). Here, we report the analysis of overlapping heterozygous novel submicroscopic deletions of FANCA gene in a FA patient, and discuss the mechanism of the deletions and the formation of FANCA–VPS9D1 fusion transcripts. Our results support that both low-coverage whole-genome sequencing and bioinformatics analysis of THS data for submicroscopic CNVs surpass SNP array in efficacy and accuracy.
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References
Kimble DC, Lach FP, Gregg SQ, Donovan FX, Flynn EK, Kamat A, et al. A comprehensive approach to identification of pathogenic FANCA variants in Fanconi anemia patients and their families. Hum Mutat. 2018;39:237–54.
Mori M, Hira A, Yoshida K, Muramatsu H, Okuno Y, Shiraishi Y, et al. Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients. Haematologica. 2019. https://doi.org/10.3324/haematol.2018.207241.
Castella M, Pujol R, Callen E, Trujillo JP, Casado JA, Gille H, et al. Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations. Blood. 2011;117:3759–69.
Morgan NV, Tipping AJ, Joenje H, Mathew CG. High frequency of large intragenic deletions in the Fanconi anemia group A gene. Am J Hum Genet. 1999;65:1330–41.
Yagasaki H, Hamanoue S, Oda T, Nakahata T, Asano S, Yamashita T. Identification and characterization of novel mutations of the major Fanconi anemia gene FANCA in the Japanese population. Hum Mutat. 2004;24:481–90.
Levran O, Diotti R, Pujara K, Batish SD, Hanenberg H, Auerbach AD. Spectrum of sequence variations in the FANCA gene: an International Fanconi Anemia Registry (IFAR) study. Hum Mutat. 2005;25:142–9.
Tipping AJ, Pearson T, Morgan NV, Gibson RA, Kuyt LP, Havenga C, et al. Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa. Proc Natl Acad Sci USA. 2001;98:5734–9.
Kuffel DG, Lindor NM, Litzow MR, Zinsmeister AR, Dewald GW, et al. Mitomycin C chromosome stress test to identify hypersensitivity to bifunctional alkylating agents in patients with Fanconi anemia or aplastic anemia. Mayo Clin Proc. 1997;72:579–80.
Tennekes M. tmap: thematic maps in R. J Stat Softw. 2018;84:1–39.
Boeva V, Popova T, Lienard M, Toffoli S, Kamal M, Le Tourneau C, et al. Multi-factor data normalization enables the detection of copy number aberrations in amplicon sequencing data. Bioinformatics. 2014;30:3443–50.
Abyzov UA, Snyder M, Gerstein M. CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. Genome Res. 2011;21:974–84.
Rausch T, Zichner T, Schlattl A, Stutz AM, Benes V, Korbel JO. DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics. 2012;28:i333–9.
Layer RM, Chiang C, Quinlan AR, Hall IM. LUMPY: a probabilistic framework for structural variant discovery. Genome Biol. 2014;15:R84.
Smith SD, Kawash JK, Grigoriev A. GROM-RD: resolving genomic biases to improve read depth detection of copy number variants. PeerJ. 2015. https://doi.org/10.7717/peerj.836. eCollection.
Flynn EK, Kamat A, Lach FP, Donovan FX, Kimble DC, Narisu N, et al. Comprehensive analysis of pathogenic deletion variants in Fanconi anemia genes. Hum Mutat. 2014;35:1342–53.
Song X, Beck CR, Du R, Campbell IM, Coban-Akdemir Z, Gu S, et al. Predicting human genes susceptible to genomic instability associated with Alu/Alu-mediated rearrangements. Genome Res. 2018;28:1228–42.
Möller-Krull M, Zemann A, Roos C, Brosius J, Schmitz J. Beyond DNA: RNA editing and steps toward Alu exonization in primates. J Mol Biol. 2008;382:601–9.
Schmitz BJ. Exonization of transposed elements: a challenge and opportunity for evolution. Biochimie. 2011;93:1928–34.
Payer LM, Steranka JP, Ardeljan D, Walker J, Fitzgerald KC, Calabresi PA, et al. Alu insertion variants alter mRNA splicing. Nucleic Acids Res. 2019;47:421–31.
Zhou B, Ho SS, Zhang XL, Pattni RR, Haraksing R, Urban AE. Whole-genome sequencing analysis of CNV using low-coverage and paired-end strategies is efficient and outperforms array-based CNV analysis. J Med Genet. 2018;55:735–43.
Dong Z, Zhang J, Hu P, Chen H, Xu J, Tian Q, et al. Low-pass whole-genome sequencing in clinical cytogenetics: a validated approach. Genet Med. 2016;18:940–8.
Shen W, Szankasi P, Sederberg M, Schumacher J, Frizzell KA, Gee EP, et al. Concurrent detection of targeted copy number variants and mutations using a myeloid malignancy next generation sequencing panel allows comprehensive genetic analysis using a single testing strategy. Br J Haematol. 2016;173:49–58.
McKerrell T, Moreno T, Ponstingl H, Bolli N, Dias JM, Tischler G, et al. Development and validation of a comprehensive genomic diagnostic tool for myeloid malignancies. Blood. 2016;128:e1–9.
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This work was supported in part by grants from the Shandong Nature Science Fund (ZR2016HP02).
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Nie, D., Cao, P., Wang, F. et al. Analysis of overlapping heterozygous novel submicroscopic CNVs and FANCA–VPS9D1 fusion transcripts in a Fanconi anemia patient. J Hum Genet 64, 899–909 (2019). https://doi.org/10.1038/s10038-019-0629-x
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DOI: https://doi.org/10.1038/s10038-019-0629-x
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