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Identification of Three Novel Mutations in the FANCA, FANCC, and ITGA2B Genes by Whole Exome Sequencing
Abstract
Background: Various blood diseases are caused by mutations in the FANCA, FANCC, and ITGA2B genes. Exome sequencing is a suitable method for identifying single‑gene disease and genetic heterogeneity complaints
Methods: Among families who were referred to Narges Genetic and PND
Laboratory in 2015‑2017, five families with a history of blood diseases were analyzed using the whole exome sequencing (WES) method
Results: We detected two novel mutations (c.190‑2A>G and c.2840C>G) in the FANCA gene, c. 1429dupA mutation in the FANCC gene, and c.1392A>G
mutation in the ITGA2B gene. The prediction of variant pathogenicity has been done using bioinformatics tools such as Mutation taster PhD‑SNP and polyphen2 and were confirmed by Sanger sequencing
Conclusions: WES could be as a precise tool for identifying the pathologic variants in affected patient and heterozygous carriers among families. This highly successful technique will remain at the forefront of platelet and blood genomic research.
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Moghrabi NN, Johnson MA, Yoshitomi MJ, Zhu X,
Al‑Dhalimy MJ, Olson SB, et al. Validation of Fanconi anemia
complementation Group A assignment using molecular analysis.
Genet Med 2009;11:183‑92.
Kee Y, D’Andrea AD. Expanded roles of the Fanconi
anemia pathway in preserving genomic stability. Genes Dev
;24:1680‑94.
Kottemann MC, Smogorzewska A. Fanconi anaemia and
the repair of Watson and Crick DNA crosslinks. Nature
;493:356‑63.
Ameziane N, Sie D, Dentro S, Ariyurek Y, Kerkhoven L,
Joenje H, et al. Diagnosis of fanconi anemia: Mutation analysis
by next‑generation sequencing. Anemia 2012;2012:132856.
Bogliolo M, Schuster B, Stoepker C, Derkunt B, Su Y, Raams A,
Trujillo JP, et al. Mutations in ERCC4, encoding the DNA‑repair
endonuclease XPF, cause Fanconi anemia. Am J Hum Genet
;92:800‑6.
Bagby G. Recent advances in understanding hematopoiesis in
Fanconi Anemia. F1000Res 2018;7:105.
Solomon PJ, Margaret P, Rajendran R, Ramalingam R,
Menezes GA, Shirley AS, et al. A case report and literature
review of Fanconi Anemia (FA) diagnosed by genetic testing.
Ital J Pediatr 2015;41:38.
Hess J, Unger K, Orth M, Schötz U, Schüttrumpf L, Zangen V,
Gimenez‑Aznar I, et al. Genomic amplification of Fanconi anemia
complementation group A (FancA) in head and neck squamous
cell carcinoma (HNSCC): Cellular mechanisms of radioresistance
and clinical relevance. Cancer Lett 2016;386:87‑99.
Bogliolo M, Surralles J. Fanconi anemia: A model disease for
studies on human genetics and advanced therapeutics. Curr Opin
Genet Dev 2015;33:32‑40.
Solanki A, Mohanty P, Shukla P, Rao A, Ghosh K, Vundinti BR.
FANCA gene mutations with 8 novel molecular changes in
Indian Fanconi anemia patients. PLoS One 2016;11:e0147016.
Cerabona D, Sun Z, Nalepa G. Leukemia and chromosomal
instability in aged Fancc‑/‑ mice. Exp Hematol 2016;44:352‑7.
Sertorio M, Amarachintha S, Wilson A, Pang Q. Loss of
fancc impairs antibody‑secreting cell differentiation in mice
through deregulating the wnt signaling pathway. J Immunol
;196:2986‑94.
Kulkarni B, Ghosh K, Shetty S. Second trimester prenatal
diagnosis in Glanzmann’s Thrombasthenia. Haemophilia
;22:e99‑100.
Ghosh A, Kumar S, Chacko R, Charlu AP. Total extraction
as a treatment for anaemia in a patient of Glanzmann’s
thrombasthenia with chronic gingival bleed: Case report. J Clin
Diagn Res 2016;10:ZD11‑2.
Nurden AT, Pillois X, Wilcox DA. Glanzmann thrombasthenia:
State of the art and future directions. Semin Thromb Hemost
;39:642‑55.
Maclachlan A, Watson SP, Morgan NV. Inherited platelet
disorders: Insight from platelet genomics using next‑generation
sequencing. Platelets 2017;28:14‑9.
Coller BS, Shattil SJ. The GPIIb/IIIa (integrin alphaIIbbeta3)
odyssey: a technology‑driven saga of a receptor with twists,
turns, and even a bend. Blood 2008;112:3011‑25.
Dong H, Nebert DW, Bruford EA, Thompson DC, Joenje H,
et al. Update of the human and mouse Fanconi anemia genes.
Hum Genomics 2015;9:32.
Moghadam AA, Mahjoubi F, Reisi N, Vosough P. Investigation
of FANCA gene in Fanconi anaemia patients in Iran. Indian J
Med Res 2016;143:184‑96.
Knies K, Schuster B, Ameziane N, Rooimans M, Bettecken T,
de Winter J, et al. Genotyping of fanconi anemia patients by
whole exome sequencing: advantages and challenges. PLoS One
;7:e52648.
Auerbach AD. Fanconi anemia and its diagnosis. Mutat Res
;668:4‑10.
Centra M, Memeo E, d’Apolito M, Savino M, Ianzano L,
Notarangelo A, et al. Fine exon‑intron structure of the Fanconi
anemia group A (FAA) gene and characterization of two genomic
deletions. Genomics 1998;51:463‑7.
Aftab I, Iram S, Khaliq S, Israr M, Ali N, Jahan S, et al.
Analysis of FANCC gene mutations (IVS4+4A>T, del322G, and
R548X) in patients with Fanconi anemia in Pakistan. Turk J Med
Sci 2017;47:391‑8.
Niedzwiedz W, Mosedale G, Johnson M, Ong CY, Pace P,
Patel KJ, et al. The Fanconi anaemia gene FANCC promotes
homologous recombination and error‑prone DNA repair. Mol
Cell 2004;15:607‑20.
Esmail Nia G, Fadaee M, Royer R, Najmabadi H, Akbari MR.
Profiling Fanconi anemia gene mutations among Iranian patients.
Arch Iran Med 2016;19:236‑40.
Gillio AP, Verlander PC, Batish SD, Giampietro PF,
Auerbach AD, et al. Phenotypic consequences of mutations in
the Fanconi anemia FAC gene: An International Fanconi Anemia
Registry study. Blood 1997;90:105‑10.
de Vries Y, Lwiwski N, Levitus M, Kuyt B, Israels SJ,
Arwert F, Zwaan M, et al. A Dutch Fanconi anemia FANCC
founder mutation in Canadian manitoba mennonites. Anemia
;2012:865170.
Pace P, Johnson M, Tan WM, Mosedale G, Sng C, Hoatlin M,
et al. FANCE: The link between Fanconi anaemia complex
assembly and activity. EMBO J 2002;21:3414‑23.
Pang Q, Keeble W, Diaz J, Christianson TA, Fagerlie S,
Rathbun K, et al. Role of double‑stranded RNA‑dependent
protein kinase in mediating hypersensitivity of Fanconi
anemia complementation group C cells to interferon gamma,
tumor necrosis factor‑alpha, and double‑stranded RNA. Blood
;97:1644‑52.
Joenje H, Patel KJ. The emerging genetic and molecular basis of
Fanconi anaemia. Nat Rev Genet 2001;2:446‑57.
Sandrock‑Lang K, Oldenburg J, Wiegering V, Halimeh S,
Santoso S, Kurnik K, et al. Characterisation of patients with
Glanzmann thrombasthenia and identification of 17 novel
mutations. Thromb Haemost 2015;113:782‑91.
Poon MC, d’Oiron R, Zotz RB, Bindslev N, Di Minno MN,
Di Minno G, et al. The international, prospective Glanzmann
Thrombasthenia Registry: Treatment and outcomes in surgical
intervention. Haematologica 2015;100:1038‑44.
Jones ML, Murden SL, Bem D, Mundell SJ, Gissen P, Daly ME,
et al. Rapid genetic diagnosis of heritable platelet function
disorders with next‑generation sequencing: Proof‑of‑principle
with Hermansky‑Pudlak syndrome. J Thromb Haemost
;10:306‑9.
Westbury SK, Turro E, Greene D, Lentaigne C, Kelly AM,
Bariana TK, et al. Human phenotype ontology annotation and
cluster analysis to unravel genetic defects in 707 cases with
unexplained bleeding and platelet disorders. Genome Med
;7:36.
Simeoni I, Stephens JC, Hu F, Deevi SV, Megy K, Bariana TK,
et al. A high‑throughput sequencing test for diagnosing
inherited bleeding, thrombotic, and platelet disorders. Blood
;127:2791‑803.
Buitrago L, Rendon A, Liang Y, Simeoni I, Negri A,
ThromboGenomics Consortium, et al. AlphaIIbbeta3 variants
defined by next‑generation sequencing: predicting variants likely
to cause Glanzmann thrombasthenia. Proc Natl Acad Sci U S A
;112:E1898‑907.