FANCONI ANEMIA--HETEROGENEITY AND CARRIER DETECTION

Rockefeller University, New York NY

Investigators

Linked publications & trials

Abstract

The purpose of this study is to determine the genetic basis of Fanconi[unreadable] anemia (FA), an autosomal recessive disorder characterized by diverse[unreadable] congenital abnormalities, and a predisposition to bone marrow failure and[unreadable] malignancy, particularly acute myelogenous leukemia (AML The specific[unreadable] objectives of this project are: (1) To identify mutations in the genes[unreadable] for FA complementation group A (FA-A) and group C (FA-C) and other FA[unreadable] genes when they are isolated, and to make genotype-phenotype correlations;[unreadable] (2) To develop screening methods using DNA technology, for FA diagnosis[unreadable] and carrier detection. (3) To isolate and clone other FA genes by a[unreadable] combination of positional and functional complementation; (4) To study[unreadable] the structure and expression of these other genes. A major resource and[unreadable] unique feature of this proposal is our access to a large number of[unreadable] patients with FA exhibiting the full spectrum of its diverse features,[unreadable] through the International Fanconi Anemia Registry (IFAR) maintained by us[unreadable] at the Rockefeller University. This provides us with phenotypic[unreadable] information on FA patients as well as a source of cells for molecular[unreadable] studies; we currently have DNA samples from a total of 422 patients[unreadable] affected with FA. Understanding the genetic defect in FA should lead to[unreadable] a better understanding of birth defects and cancer predisposition in[unreadable] general, and the interaction of genetic and epigenetic factors in their[unreadable] pathogenesis.[unreadable] Mutation screening will initially be performed by sizing PCR amplified[unreadable] fragments from cDNA, by genomic DNA blot hybridization and by restriction[unreadable] endonuclease fingerprinting (REF). As mutations are characterized at the[unreadable] genomic level and sequenced, ARMS assays will be developed to permit rapid[unreadable] DNA based screening methods for (1) assignment of FA patients to[unreadable] complementation group, (2) prenatal diagnosis in FA families, and (3)[unreadable] identification of carriers in FA families and in populations at risk. It[unreadable] is an objective of this project to extend our ability to define the FA[unreadable] genotype of all patients and to make genotype-phenotype correlations.[unreadable] This would enable physicians to better predict clinical outcome and aid[unreadable] decision-making regarding major therapeutic modalities for this clinically[unreadable] heterogeneous disorder. A positional cloning approach will be used to[unreadable] clone the FAB and FAE genes, made feasible by the detailed physical[unreadable] mapping information that is rapidly becoming available through the Human[unreadable] Genome Project. Linkage analysis will be used to map these loci; cDNAs[unreadable] will be isolated by direct selection from cosmid contigs from the[unreadable] appropriate region. This will be combined with functional complementation[unreadable] in an effort to accelerate the identification of these genes.[unreadable] [unreadable]