Comprehensive Analysis of Pathogenic Deletion Variants in Fanconi Anemia Genes
Comprehensive Analysis of Pathogenic Deletion Variants in Fanconi Anemia Genes
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DOI：
10.1002/humu.22680
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发表时间：
2014-11-01
期刊：
影响因子：
3.9
通讯作者：
Chandrasekharappa, Settara C.
中科院分区：
文献类型：
--
作者：
Flynn, Elizabeth K.;Kamat, Aparna;Chandrasekharappa, Settara C.
范可尼贫血（FA）是一种罕见的隐性疾病，至少有16个不同的基因之一的突变造成的。FA的突变类型和表型表现是高度异质性的，并影响疾病的临床管理。我们分析了202个FA家族的大缺失，使用高分辨率比较基因组杂交阵列，单核苷酸多态性阵列和DNA测序。我们在88个FANCA、7个FANCC、2个FANCD 2和1个FANCB家族中发现致病性缺失。我们发现35%的FA家族携带大的缺失，占所有FA致病变异的18%。跨越缺失断点的克隆和测序显示，52个FANCA缺失末端，和一个FANCC缺失末端延伸超出基因边界，潜在地影响具有表型后果的邻近基因。75%的FANCA缺失是α-Alu介导的，主要由α-Alu Y元件介导，并且似乎是由非等位基因同源重组引起的。确定了单个Alu热点。定义由多个家庭共享的四个FANCA缺失的单倍型显示，三个共享一个共同的祖先。了解导致疾病的确切分子变化对于更好地理解FA表型以及深入了解驱动这些致病性缺失变体的机制可能至关重要。(C)2014 Wiley Periodicals，Inc.
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. (C) 2014 Wiley Periodicals, Inc.