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Comprehensive Analysis of Pathogenic Deletion Variants in F anconi Anemia Genes
Author(s) -
Flynn Elizabeth K.,
Kamat Aparna,
Lach Francis P.,
Donovan Frank X.,
Kimble Danielle C.,
Narisu Narisu,
Sanborn Erica,
Boulad Farid,
Davies Stella M.,
Gillio Alfred P.,
Harris Richard E.,
MacMillan Margaret L.,
Wagner John E.,
Smogorzewska Agata,
Auerbach Arleen D.,
Ostrander Elaine A.,
Chandrasekharappa Settara C.
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22680
Subject(s) - fanca , biology , fanconi anemia , genetics , fancd2 , gene , phenotype , alu element , breakpoint , genome , human genome , dna repair , chromosome
ABSTRACT F anconi 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 FANCD 2 , 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 A lu – Alu mediated, predominantly by A lu Y elements, and appear to be caused by nonallelic homologous recombination. Individual A lu 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.