Today in an advance online publication at Nature Genetics, Christopher Mathew, Helmut Hananberg, Detlev Schindler, and colleagues from an international collaboration report the identification of a new cause for a Fanconi anemia-like disorder (that ultimately may be recognized as a new genetic cause for Fanconi anemia).
Fanconi Anemia
Fanconi anemia is a rare condition that includes various physical abnormalities, bone marrow failure (low counts of blood cells because the bone marrow is not churning them out like it should), and an increased risk for certain types of cancer. The physical abnormalities are present in about two-thirds to three-quarters of affected individuals and can include the following:
- Short stature
- Malformations of the thumb, forearm, and other parts of the skeleton
- Malformations of the kidneys and/or urinary tract
- Male genital malformations
- Gastrointestinal tract malformations
- Malformations of the heart
- Hearing loss
- Central nervous system abnormalities
- Abnormalities of skin pigmentation (color)
- Other abnormalities and malformations
Although there is a wide variety of both major and minor malformations in Fanconi anemia (FA), the fact that they are not present in everyone with FA means that their absence cannot be used to rule out the disorder.
Most individuals with FA develop bone marrow failure leading to decreased counts of blood cells (platelets, white blood cells and/or red blood cells before the age of 10). However, the blood count problems can also develop later in life.
Unfortunately, there is a very high risk of several types of cancer in Fanconi anemia. By the fifth decade of life, approximately one in ten to one in three people with FA will have developed a blood cancer (particularly acute myeloid leukemia), and about three in ten people will develop a solid tumor (non-blood cancer), especially those of the head and neck and GI tract.
Diagnosis of Fanconi Anemia
When doctors suspect FA, they order a test that looks for certain chromosome abnormalities after cells from the patient are treated in the lab with something called a "DNA interstrand cross-linking agent". The genetics of Fanconi Anemia are complicated by the fact that FA can be caused by mutations in a number of different genes. In fact, mutations in at least 13 different genes have been known to cause FA.
Fanconi Anemia Genes
- FANCA
- FANCB
- FANCC
- BRCA2 (FANCD1)
- FANCD2
- FANCE
- FANCF
- FANCG
- FANCI
- BRIP1 (FANCJ)
- FANCL
- FANCM
- PALB2 (FANCN)
For all but one of these examples, inheritance of FA occurs in an "autosomal recessive" manner. This means that an affected child must inherit a mutated copy of the gene from each parent. Thus, the parents are FA carriers, but don't have FA themselves (although being a FA carrier can have significant implications for cancer risk if the FA gene is BRCA2, PALB2, or BRIP1!!). The lone example of non-autosomal recessive inheritance in FA is X-linked inheritance in FA due to FANCB.
Study of a Family with a Distinct Fanconi Anemia-Like Disorder Not Explained by the Previously Known FA Genes
Christopher Mathew and colleagues studied a family in which three children had multiple severe congenital anomalies that were consistent with FA. The parents of the affected children were first cousins and were of Pakistani origin. Two of the affected children were shown to have elevated chromosome abnormalities when their cells were treated in the lab with a DNA interstrand cross-linking agent. Given the congenital anomalies in the children and the results of the lab tests, the children were diagnosed with a Fanconi anemia-like syndrome (the authors elected to call it this rather than Fanconi anemia because none of the children had yet developed any abnormal blood cell counts).
The researchers then did several different types of tests on cells from the patients to determine whether their FA-like disorder was due to a problem with one of the 13 known FA genes. The tests suggested that a different gene was behind the disorder in this family.
Because the parents were cousins, the researchers chose to use a strategy called "autozygosity mapping" to identify the region of the genome responsible for the FA-like disorder. This allowed them to focus on a region of chromosome 17 where they ultimately were able to determine that mutations in the RAD51C gene were responsible.
Their assertion that RAD51C was the culprit was supported both by evidence that the amino acid changed by the mutation in this family is evolutionarily conserved. In this family, the mutation leads to the substitution of the amino acid histidine for arginine at a key area of the protein. Across species, this amino acid is an arginine in RAD51C, RAD51, RAD51B, or the related protein XRCC3, whether the protein is in a human, a chicken, a zebrafish, a sea urchin or thale cress (which I just had to Google to determine it is Arabidopsis thaliana, a small flowering plant that is often studied in biology labs).
The researchers were also able to prove that RAD51C was the culprit here by reinserting a functioning normal RAD51C gene into cells with the mutations; this led to correction of cellular abnormalities observed in the cells from the patients in this family.
RAD51C
As RAD51C, like previously known FA genes, was already known (from studies of its function in the lab) to protect against hypersensitivity to DNA interstrand cross-linking agents (the key cellular abnormality seen in humans with FA), it is perhaps not so surprising that it turns out to cause the syndrome found in the family that Mathew and colleagues studied. However, this appears to be the first time that mutations in this gene have been shown to cause a human disorder (this study led to another published online in Nature Genetics today demonstrating that heterozygous mutations in RAD51C are associated with Hereditary Breast and Ovarian Cancer - we've covered that paper now at Cancer and Your Genes). Although it might have been expected that mutations in this gene would be a more common cause of FA-like disorders or FA, it has been shown that loss of the gene in mice is associated with embryonic lethality (i.e., is not compatible with life). This could explain why inherited mutations in this gene have not been seen more commonly in human disease.
Key References
Auerbach AD, Buchwald M, Joenje H. Fanconi anemia. In Scriver CR, Beaudet AL, Sly WS, et al., Eds., The Metabolic & Molecular Bases of Inherited Disease, 8th Ed. New York, McGraw-Hill, 2001, pp 753-68.
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