Fanconi Anemia . . .
Genetics of Fanconi Anemia
This web page goal is to provide you will detailed information about the genetics of Fanconi Anemia--information that you will not find all in one place anywhere else. You can obtain information down to the exact DNA sequence of the various FA genes if you so choose.
Click through the link above for a primer on how genes work and the terminology used. You will find this useful in understanding much of the information on this site.
The Fanconi Anemia/BRCA1 Pathway, by Alan D'Andrea and Markus Grompe, Nature Reviews Cancer 3, 23-34 (2003); doi:10.1038/nrc970
Fanconi Anemia, by M. D. Tischkowitz, S. V. Hodgson, Journal of Medical Genetics, 2003, 40:1-10
Fanconi Anemia and DNA repair, by Markus Grompe and Alan D'Andrea; Human Molecular Genetics, 2001, Vol. 10, No. 20, pages 2253-2259. This article was written prior to the discovery that FANCD1 is the same gene as BRCA2.
Genetic basis of Fanconi anemia, by GC Bagby Jr., Current Opinion in Hematology, 2003, January, Vol. 10, No. 1, pages 68-76.
The emerging genetic and molecular basis of Fanconi anaemia, by H. Joenje and K.J. Patel, Nature Reviews Genetics, 2001, June, 2(6), pages 445-457. This article was written prior to the discovery that FANCD1 is the same gene as BRCA2. Good overview with much detail on current knowledge of how the FA proteins interact. [Abstract]
The genetics of Fanconi's anaemia, by Inderjeet Dokal; Bailliere's Clinical Haematology, 2000, Vol. 13, No. 3, pages 407-425. A good overview of the genetics of Fanconi Anemia, although it is a little out of date at this point--which is due to the rapid discoveries being made regarding the FA genes. Available for purchase on-line at this site.
Current knowledge on the pathophysiology of Fanconi anemia: from genes to phenotypes, by T. Yamashita and T. Nakahata, International Journal of Hematology, 2001, July, 74(1), pages 33-41. This article was written prior to the discovery that FANCD1 is the same gene as BRCA2. Good overview.
Unraveling the Fanconi anemia--DNA repair connection, by Larry H Thompson; Nature Genetics 37, 921-922 (2005). Contains overview information on FANCJ and FANCM.
Faconi Anemia follows an autosomal recessive pattern on inheritance. "Autosomal" refers to any of the non-sex related chromosomes, of which there are 22. "Recessive" refers to the need of an individual to inherit two copies of the gene to show the trait. In the case of FA, the "trait" is the disease Faconi Anemia.
Autosomal recessive inheritance can be understood using the principles of inheritance first described by Gregor Mendal in 1865. Some genes, such as the FA genes, will have variations where one variation is dominant over other, recessive, variations. If a person inherits at least 1 dominant gene, they will not be affected by FA. A person needs to inherit two recessive genes in order to be affected by FA. This can be seen in a genetic cross table:
Parents Aa x Aa |
||
| A | a | |
| A | AA | Aa |
| a | Aa | aa |
In this case, both parents are heterozygous for the gene--each having one dominant gene (A), and on recessive gene (a). Their offspring will then be one of the four possibilities show in the cross table: AA (dominant homozygous), Aa (heterozygous, carriers of the recessive gene), and aa (recessive, affected). Note that 1/4 is AA, 2/4 are Aa, and only 1/4 are aa. So the probability of a heterozygous parents having an affected baby is only 25%.
Note that Fanconi complementation B is an exception here. The FANCB gene is X-linked. The X chromosome is a sex chromosome, not an autosomal chromosome. See the cross tables for information on this inheritence pattern.
You can derive the expected number of FA babies by knowing the frequency of pathogenic mutations in the FA genes. The frequency I've seen most often is 1 in 300 people carries a pathogenic mutation to an FA gene. Therefore, the probability of two carriers meeting is (1/300)*(1/300) = 1/90000. The probability of them having an FA baby is 1/4; so (1/90000)*(1/4) = 1/360000. So we would expected 1 in every 360,000 births to be affected by Fanconi Anemia--although reliable statistics are hard to come by with such a rare disease, so it's often stated as being "less than 1 in every 100,000 births".
See this page for other genetic crosses involving dominant and recessive genes.
There are 12 known complementation groups (genetic subtypes) that cause Fanconi Anemia when they have pathogenic mutations. The groups have the names A, B, C, D1, D2, E, F, G, I, J, L, and M. The genes that correspond to these groups are given names of FANCA (the most common cause of FA), FANCB (not yet discovered), FANCC (the first discovered), FANCD1 (recently discovered to be the BRCA2 gene!), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also BRIP1) , FANCL (also PHF9 and POG), and FANCM (also FAAP250). So 11 of at least 12 Fanconi Anemia genes have now been identified--the only one outstanding to be identified is FANCI. Why no "H" group? An H group was announced, but it was later discovered that it was really group A. So "H" has been retired as the name of a complementation group.
Information on the discovery of complementation groups "I" and "J" was released January 2003. These were discovered at the Department of Clinical Genetics and Human Genetics, VU University Medical Center, Amsterdam, The Netherlands. This article in Blood announces the discovery of the "I" and "J" groups. . If your complementation analysis came back as "unknown," please email Dr. Hans Joenje (h.joenje.humgen@med.vu.nl) to see if they can help you.
The discovery of FANCL was announced on September 15, 2003. Also known as the PHF9 or POG gene. See the technical section (link below) for more information on this discovery.
The discovery of the FANCB gene was announced in October of 2004. Also known as the FAAP95 gene. It is unusual for a fanconi anemia gene in that it is on the X chromosome. See the technical section (link below) for more information on this discovery.
The discovery of FANCM was announced August 22, 2005. Also known as FAAP250, it has sequence similiary to known DNA repair proteans, and it is involved with FANCD2. See the technical section (link below) for more information on this discovery.
So what is a "complementation group" anyhow? We must understand "complementation" first. "Complementation" means adding to the genome of a cell to correct (complement) the genetic defect. This has historically been done by cell fusion studies. You fuse two cells together, thereby joining there genetic material. You then test the cells for the genetic defect--in the case of FA, this would be with the DEB test or the MMC test. Hybrids where the hypersensitivity to DEB or MMC had been corrected (complemented) can be assumed to result from the fusion of cells from different genetic sub-groups (complementation groups), whereas hybrids that still show the sensitivity are the result of fusion of cells from the same group. The initial studies used this technique to show that there were two FA complementation groups, A and non-A. This was later extended to a total of 8, and now 12, groups.
So a complementation group is just a common genetic sub-group. You can know the complementation group without knowing the exact gene involved--so this is often the first step in understanding a genetic disease.
However, now that we know 11 of the genes, the complementation analysis doesn't need to use cell fusion studies anymore. Instead, retroviral vectors can be used to insert corrected genes into the cells.
Click on the link above to see information on the location, size, etc. of the known Fanconi Anemia genes. It also has links to other sites with much more detailed information.
A slightly out-of-date model for the Fanconi pathway is shown below.
It starts on the left, with the DNA damage. That activates the FA complex--a
conglomeration of the A, C, E, F, and G genes--and the ATM gene. Then follow the
arrows. FANCD2 is next in the sequence, where it interacts with BRCA1, BRCA2
(FANCD1), and RAD51--ultimately resulting in DNA repair.
Note that FANCB is missing from this diagram--it's exact role hasn't been
figured out yet (not to mention the roles of I, J, L, and M!). FANCL is unique among
Fanconi genes in that it produces a protein (a type called a ligase), whereas the others
do not.
As we saw above in the inheritance section, any future child has a 25% chance of being affected by FA. To look at it in a more positive light, you could say that any future child has a 75% chance of not being affected by FA. Whether you find these odds an acceptable risk is only a decision you can make.
So what are other options for having children that are not affected by FA? These will be explored below:
There are several options for having future children that would not be affected by FA. You could consider one of the following:
All 4 of the above are good options and you should consider them. There is another option, PGD, which is covered below.
Preimplantation Genetic Diagnosis (PGD) is a technique in which embryos obtained from in-vitro fertilization (IVF) are biopsied and tested for their genetic composition. Only those embryos that are free of genetic disease are transferred to the uterus to try and achieve a pregnancy.
Clearly this technique could be used to have additional children that would not be affected by Fanconi Anemia. In addition, this technique has been used to also select embryos that are an exact HLA match for a sibling affected by FA. So using this technique, you could have a new baby that is both not affected by FA and is also an exact HLA match for an existing child--and then use the cord blood of the new baby for a bone marrow transplant of the affected sibling.
Since this is a complicated technique, I have created a separate page for it specifically. Just follow the link above in the title of this section to access it.
Back to main Fanconi
Anemia Information page
Last updated: 01 Sep 2005