title: Comprehensive analysis of pathogenic deletion variants in Fanconi anemia genes.
abstract: 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.
authors.affiliation: Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, 20892.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Flynn
authors.forename: Aparna
authors.initials: A
authors.lastname: Kamat
authors.forename: Francis P
authors.initials: FP
authors.lastname: Lach
authors.forename: Frank X
authors.initials: FX
authors.lastname: Donovan
authors.forename: Danielle C
authors.initials: DC
authors.lastname: Kimble
authors.forename: Narisu
authors.initials: N
authors.lastname: Narisu
authors.forename: Erica
authors.initials: E
authors.lastname: Sanborn
authors.forename: Farid
authors.initials: F
authors.lastname: Boulad
authors.forename: Stella M
authors.initials: SM
authors.lastname: Davies
authors.forename: Alfred P
authors.initials: AP
authors.lastname: Gillio
authors.forename: Richard E
authors.initials: RE
authors.lastname: Harris
authors.forename: Margaret L
authors.initials: ML
authors.lastname: MacMillan
authors.forename: John E
authors.initials: JE
authors.lastname: Wagner
authors.forename: Agata
authors.initials: A
authors.lastname: Smogorzewska
authors.forename: Arleen D
authors.initials: AD
authors.lastname: Auerbach
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Ostrander
authors.forename: Settara C
authors.initials: SC
authors.lastname: Chandrasekharappa
mesh_terms: D020087:Alu Elements; D001483:Base Sequence; D056905:Chromosome Breakpoints; D003001:Cloning, Molecular; D055028:Comparative Genomic Hybridization; D017124:Conserved Sequence; D005199:Fanconi Anemia / Q000235:genetics*; D051856:Fanconi Anemia Complementation Group Proteins / Q000145:classification / Q000235:genetics*; D055106:Genome-Wide Association Study; D023281:Genomics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: D051856:Fanconi Anemia Complementation Group Proteins
keywords: FANCA; FANCB; FANCC; FANCD2; Fanconi anemia; arrayCGH