Diagnosis of Fanconi Anemia : Mutation Analysis by Next-Generation Sequencing

Abstract EN

Fanconi anemia (FA) is a rare genetic instability syndrome characterized by developmental defects, bone marrow failure, and a high cancer risk.

Fifteen genetic subtypes have been distinguished.

The majority of patients (≈85%) belong to the subtypes A (≈60%), C (≈15%) or G (≈10%), while a minority (≈15%) is distributed over the remaining 12 subtypes.

All subtypes seem to fit within the “classical” FA phenotype, except for D1 and N patients, who have more severe clinical symptoms.

Since FA patients need special clinical management, the diagnosis should be firmly established, to exclude conditions with overlapping phenotypes.

A valid FA diagnosis requires the detection of pathogenic mutations in a FA gene and/or a positive result from a chromosomal breakage test.

Identification of the pathogenic mutations is also important for adequate genetic counselling and to facilitate prenatal or preimplantation genetic diagnosis.

Here we describe and validate a comprehensive protocol for the molecular diagnosis of FA, based on massively parallel sequencing.

We used this approach to identify BRCA2, FANCD2, FANCI and FANCL mutations in novel unclassified FA patients.