+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Comprehensive analysis of pathogenic deletion variants in Fanconi anemia genes



Comprehensive analysis of pathogenic deletion variants in Fanconi anemia genes



Human Mutation 35(11): 1342-1353



Fanconi anemia (FA) is a rare recessive disease resulting from mutations in one of at least 16 different genes. Mutation types and phenotypic manifestations of FA are highly heterogeneous and influence the clinical management of the disease. We analyzed 202 FA families for large deletions, using high-resolution comparative genome hybridization arrays, single-nucleotide polymorphism arrays, and DNA sequencing. We found pathogenic deletions in 88 FANCA, seven FANCC, two FANCD2, and one FANCB families. We find 35% of FA families carry large deletions, accounting for 18% of all FA pathogenic variants. Cloning and sequencing across the deletion breakpoints revealed that 52 FANCA deletion ends, and one FANCC deletion end extended beyond the gene boundaries, potentially affecting neighboring genes with phenotypic consequences. Seventy-five percent of the FANCA deletions are Alu-Alu mediated, predominantly by AluY elements, and appear to be caused by nonallelic homologous recombination. Individual Alu hotspots were identified. Defining the haplotypes of four FANCA deletions shared by multiple families revealed that three share a common ancestry. Knowing the exact molecular changes that lead to the disease may be critical for a better understanding of the FA phenotype, and to gain insight into the mechanisms driving these pathogenic deletion variants.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 052269847

Download citation: RISBibTeXText

PMID: 25168418

DOI: 10.1002/humu.22680


Related references

A comprehensive approach to identification of pathogenic FANCA variants in Fanconi anemia patients and their families. Human Mutation 39(2): 237-254, 2018

Rare, Pathogenic Germline Variants in Fanconi Anemia Genes Increase Risk for Squamous Lung Cancer. Clinical Cancer Research 25(5): 1517-1525, 2019

A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay. Blood 118(9): 2430-2442, 2011

The spectrum of genetic variants in hereditary pancreatic cancer includes Fanconi anemia genes. Familial Cancer 17(2): 235-245, 2018

Analysis of 65 Turkish patients with congenital aplastic anemia (Fanconi anemia and non-Fanconi anemia): Hacettepe experience. Clinical Genetics 51(5): 296-302, 1997

A comprehensive strategy for the subtyping of patients with Fanconi anaemia: conclusions from the Spanish Fanconi Anemia Research Network. Journal of Medical Genetics 44(4): 241-249, 2007

Mutation analysis in the Fanconi Anemia genes FANCA and FANCG. European Journal of Human Genetics 8(Suppl. 1): 150, 2000

Fanconi Anemia germline variants as susceptibility factors in aplastic anemia, MDS and AML. Oncotarget 9(2): 2050-2057, 2018

UMD-USHbases: a comprehensive set of databases to record and analyse pathogenic mutations and unclassified variants in seven Usher syndrome causing genes. Human Mutation 29(8): E76-E87, 2008

Mitomycin c and di epoxy butane induced chromosome damage in fanconi anemia fanconi anemia hetero zygotes and idiopathic aplastic anemia. American Journal of Human Genetics 34(6): 120A, 1982

Molecular analysis of Fanconi anemia and mismatch repair genes in patients with colorectal carcinoma. Oncology Reports 25(4): 899-904, 2011

Mutation analysis of the Fanconi Anemia group A, C, E, F and G genes in sporadic acute myeloid leukemia. Blood 96(11 Part 2): 168b, 2000

Repair analysis of mitomycin C-induced DNA crosslinking in ribosomal RNA genes in lymphoblastoid cells from Fanconi's anemia patients. Mutation Research 217(3): 185-192, 1989

Cytogenetic differentiation of Fanconi anemia, "idiopathic" aplastic anemia, and Fanconi anemia heterozygotes. American Journal of Medical Genetics 15(2): 211-223, 1983

Analysis of FANCB and FANCN/PALB2 fanconi anemia genes in BRCA1/2-negative Spanish breast cancer families. Breast Cancer Research and Treatment 113(3): 545-551, 2009