Anemia / 2012 / Article
Special Issue

A Molecular, Genetic, and Diagnostic Spotlight on Fanconi Anemia

View this Special Issue

Editorial | Open Access

Volume 2012 |Article ID 650730 |

Laura E. Hays, Stefan Meyer, Henri J. van de Vrugt, "A Molecular, Genetic, and Diagnostic Spotlight on Fanconi Anemia", Anemia, vol. 2012, Article ID 650730, 3 pages, 2012.

A Molecular, Genetic, and Diagnostic Spotlight on Fanconi Anemia

Received26 Jun 2012
Accepted26 Jun 2012
Published02 Oct 2012

Eighty-five years ago Dr. Guido Fanconi described a family with three brothers with microcephaly, hyperpigmentation of the skin, hypoplasia of the testes, and who developed a lethal anemia between the ages of 5 and 7 [1, 2]. Since 1931, patients with this distinctive combination of clinical features have been classified as having Fanconi anemia (FA). To date, diagnosis of this disease, which as we know can manifest with variable clinical presentation, is based on increased chromosomal breakage in response to DNA crosslinking agents.

In addition to anemia, FA patients are highly predisposed to leukemia, head and neck squamous cell carcinoma, and gynecological cancers [3]. FA is caused by biallelic or X chromosome-linked mutations in one of 15 different genes, eight of whose gene products (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM) form a nuclear core complex that must be intact to ubiquitinate FANCD2 and FANCI. The ubiquinated FANCD2/FANCI heterodimer then functionally interacts with down-stream FA proteins (FANCD1/BRCA2, FANCJ/BRIP1, FANCN/PALB2, FANCO/RAD51C, and FANCP/SLX4) to mediate DNA damage responses [4].

This special issue provides a wide range of scientific papers and reviews that examine in detail techniques for diagnosis of FA, molecular and genetic mechanisms of FA protein function, comprehensive details of the varied clinical manifestations, new model systems for study of this disease, and potential new therapeutics. Three papers describe FA relevant aspects in FA diagnoses using chromosomal breakage analysis and mutation detection by multiplex ligation-dependent probe amplification (MLPA) and PCR-based Sanger sequencing, or next generation sequencing. The strategy to detect mutations and the genetic counseling of involved families should be adapted when there is evidence for a founder effect, which results in a high prevalence of a common mutation in a specific population. In this special issue, Y. de Vries et al. provide evidence that FA-C patients with the FANCC c.67delG mutation in the Dutch and Canadian Manitoba Mennonite populations originate from a common founder.

One impediment to FA research has been the relative lack of a murine model that truly recapitulates the severity of FA hematopoietic defects. In the data reported by J. H. E. Verhagen-Oldenampsen et al., Ercc1-deficient mice were used as model for FA-like bone marrow failure. Although no ERCC1 mutations have been detected in FA patients, ERCC1 interacts with FANCP/SLX4 and functions in interstrand crosslink repair [5], the critical type of DNA damage recognized and repaired by the FA/BRCA pathway [6] (Figure 1).

Another group of papers in this issue provides detailed and thorough scientific reviews of the varied clinical and molecular aspects of this disease, new model systems, and potential future treatments. First, the review by M. D. Milsom et al. details FA-associated defects in hematopoietic stem cell biology and resultant bone marrow failure. FA chromosomal aberrations associated with clonal evolution and leukemic transformation are the focus of the review by S. Meyer et al. T. Kaddar and M. Carreau review aspects of FA protein function that have been placed in the shadow by the recent focus on the role of the FA pathway in DNA repair. The paper by C. Hodson and H. Walden comprehensively reviews aspects of protein interactions and function in the FA core complex, while the review by M.R. Jones and A.M. Rose focuses on utilization of a relatively new model system for FA, the worm C. elegans. They examine the functions of DOG1, a functional ortholog of FANCJ, and FANCD2 in interstrand crosslink repair. To conclude the special issue, Jenkins et al. summarize the efforts that have been made to generate and utilize FA pathway inhibitors as novel anticancer therapies.

The great progress in understanding FA on a molecular, cellular and clinical level illustrated in this special issue has made a big difference to people affected by FA, but also an enormous contribution to hematology, cancer, and developmental biology research. This has been achieved to a large extent through close interactions between scientists, clinicians and patients, which provide a resourceful platform for not only exchange and stimulation, but also a constant reminder of the goals of this research—aiming to understand biology in order to make the journey of families with FA a more hopeful one.

FA Patient Support Groups by Bob Dalgleish, Fanconi Hope, UK
FA patients, although relatively few in number in each country, are fortunate in having a number of strong family support groups that coordinate their activities on an international basis to ensure a coherent approach to supporting research. The longest established group, the United States-based Fanconi Anemia Research Fund (FARF: has been responsible for sponsoring a significant amount of research for over 20 years. Also in existence over a similar period, the German group Deutsche Fanconi-Anämie-Hilfe e.V. (Fanconi Anemia Aid Association:, has been actively involved on an international scale in long-term research programs. The more recently formed UK-based organization, Fanconi Hope ( has been supporting research through the auspices of the FARF Scientific Advisory Board, for UK research projects selected by FARF.
Fanconi Hope and FARF also sponsor an International FA Gene Therapy Working Group, now in its third year, which aims to accelerate the transition from research to gene therapy trials for FA patients by coordinating activities on an international scale. FA patients, their families and friends are in large part responsible for raising the funds for this research. This is of great benefit to those affected as this allows them to believe they can make a difference, if not to the current generation of FA patients then at least as a legacy to the benefit of the next generation.

Laura E. Hays
Stefan Meyer
Henri J. van de Vrugt


  1. S. Lobitz and E. Velleuer, “Guido Fanconi (1892–1979): a jack of all trades,” Nature Reviews Cancer, vol. 6, no. 11, pp. 893–898, 2006. View at: Publisher Site | Google Scholar
  2. G. Fanconi, “Familiare, infantile, perniziosaartige Anamie (pernizioses Blutbild und Konstitution). [Familial Infantile Pernicious-like Anemia (Pernicious Blood Picture and Constitution)],” Jahrbuch fur Kinderheilkunde, vol. 117, pp. 257–280, 1927. View at: Google Scholar
  3. P. S. Rosenberg, M. H. Greene, and B. P. Alter, “Cancer incidence in persons with Fanconi anemia,” Blood, vol. 101, no. 3, pp. 822–826, 2003. View at: Publisher Site | Google Scholar
  4. J. Soulier, “Fanconi anemia,” Hematology/the Education Program of the American Society of Hematology. American Society of Hematology Education Program, vol. 2011, pp. 492–497, 2011. View at: Google Scholar
  5. S. Fekairi, S. Scaglione, C. Chahwan et al., “Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases,” Cell, vol. 138, no. 1, pp. 78–89, 2009. View at: Publisher Site | Google Scholar
  6. A. J. Deans and S. C. West, “DNA interstrand crosslink repair and cancer,” Nature Reviews Cancer, vol. 11, no. 7, pp. 467–480, 2011. View at: Publisher Site | Google Scholar

Copyright © 2012 Laura E. Hays et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.