DNA and You

Brain Hemorrhage Lands Bret Michaels of Poison in the ICU - Can Risk for Subarachnoid Hemorrhage Be Genetic?

Rocker Bret Michaels, of Poison fame, has unfortunately reportedly suffered a subarachnoid hemorrhage (a type of brain hemorrhage) and is apparently in an intensive care unit in critical condition (according to People magazine).

It's sort of surreal as I was just thinking last weekend, when I saw Hot Tub Time Machine (which features a Poison cover band), that I probably hadn't thought about the band in over a decade (obviously I am not a Celebrity Apprentice fan). 

It's terribly sad to hear when someone has suffered a subarachnoid hemorrhage as it is often a pretty grim diagnosis (as KevinMD has carefully explained here).  Hopefully, Bret Michaels will have a better outcome than most.  As a physician, subarachnoid hemorrhage is one of those adversaries that you hope you don't see again for a long time.  When I was training in Internal Medicine in Seattle at the University of Washington, I remember seeing quite a few at Harborview Medical Center.  One of my very first admissions as an intern was a subarachnoid hemorrhage, and at times as a 2nd year resident in the ER at Harborview, it seemed like far too many were being helicoptered in from Alaska and rural areas all over the Pacific Northwest.

Later, in my Clinical Genetics training in Seattle, I learned that for some subarachnoid hemorrhages, there can be a genetic connection.  So, in light of the fact that tomorrow is DNA Day, I thought it might be worth touching on the genetics of subarachnoid hemorrhage, particularly those caused by rupture of an intracranial aneurysm.   

Subarachnoid Hemorrhage and Intracranial Aneurysms

Subarachnoid hemorrhage (SAH) affects about 30,000 people each year in the United States and accounts for somewhere between 1 in 20 to 1 in 50 of all new strokes.  Subarachnoid hemorrhages are very serious; about one-half of the time they result in death.  Almost 50% of survivors have some long-term cognitive impairment and a significant fraction require lifelong care.

There are several causes of subarachnoid hemorrhage, including trauma.  Often they are due to rupture of an intracranial aneurysm - an abnormal outpouching of the arterial system in the brain that can be prone to rupture.  About 3/4 of nontraumatic subarachnoid hemorrhages are due to rupture of so-called "berry aneurysms" that are often found in the arterial system around the base of the brain.

With respect to risk for SAH, there are likely factors that affect both the risk of developing an intracranial aneurysm in the first place, and also factors that impact risk of rupture of an existing aneurysm leading to the SAH.  Interestingly, there are several major known risk factors for SAH that are potentially modifiable.  Among them:

• cigarette smoking
• high blood pressure
• cocaine use
• heavy alcohol use

Thus, to some extent, lifestyle clearly can impact risk for SAH. 

However, it is also clear that risk is elevated in first-degree relatives (parents, brothers, sisters, and children) of individuals who have had a subarachnoid hemorrhage.  Overall, first-degree relatives may have somewhere between 2- and 6-fold elevated risk.  In some cases this is due to rare Mendelian conditions that are associated with a significantly elevated risk; however, there is also evidence supporting a heritable genetic influence on intracranial aneurysms and SAH that occurs outside of the context of rare syndromes.  In this case, risk is complex and associated with weaker genetic influences and environmental risk factors.

Rare Mendelian Conditions Associated With Intracranial Aneurysms

Among the rare conditions with Mendelian inheritance in which intracranial aneurysms and subarachnoid hemorrhage may be seen with increased frequency are the following:

• Autosomal Dominant Polycystic Kidney Disease
• Ehlers-Danlos Syndrome Type IV (aka the vascular type)
• Loeys-Deitz Syndrome

Complex Genetics of Sporadic Intracranial Aneurysm Development

Although risks for development of intracranial aneurysms (which can lead to subarachnoid hemorrhages) are substantially elevated in the above Mendelian conditions, with the exception of ADPKD they are all rare (ADPKD is the most common potentially lethal single gene disorder and affects approximately 600,000 people in the United States). 

However, physicians and scientists have recently begun to make headway in discovering regions of the genome that are (modestly) associated with risk for intracranial aneurysm and subarachnoid hemorrhage by studying large numbers of individuals with these conditions and unaffected controls in studies called genome-wide association studies (GWAS).  Some of the chromosomal regions and single nucleotide polymorphisms (SNPs) that have been associated in well-done peer reviewed studies are the following:

• Chromosome 9p21.3, rs10757278 - G (near the CDKN2A and CDKN2B genes)
• Chromosome 8q11.23, rs10958409 - A (near the SOX17 gene)
• Chromosome 10q24.32, rs12413409 - G
• Chromosome 13q13.1, rs9315204 - T (near the STARD13 and KL genes)
• Chromosome 18q11.2, rs11661542 - C (near the RBBP8 gene)

All of these are subject to a number of caveats related to genome-wide association-implicated SNPs that we will be discussing here at DNA and You soon.

If one makes the assumption that genes nearby these single nucleotide polymorphisms are actually involved in the process of aneurysm development, an emerging hypothesis is that some of the risk loci may affect cell cycle progression in cells involved in the formation and repair of blood vessels.  However, the underlying science is not well understood.  There is far more that we don't know than that which we know about the underlying science and the impact on risk at this time. 

It's also important to note that while these SNP associations are important initial clues toward underlying biology that may ultimately result in improved treatments, they are not helpful clinically at this time.  Future studies will address whether they can impact risk assessment and/or treatment strategies in a clinically meaningful way; however, given that the baseline risk for intracranial aneurysms is at most 5 percent and that these SNPs only explain about 4 percent of the familial component of risk for intracranial aneurysms, it seems unlikely that they will play a significant role in the clinic in the near future.

What You Can Do

The sad news about Bret Michaels and his hospitalization is an opportunity to reflect on those things that you can do if you are at risk for subarachnoid hemorrhage (either because of your family history or for other reasons).  If you or a family member has had a subarachnoid hemorrhage or are known to have intracranial aneurysm, talk with your doctor about how you can best do the following things:

• Stop smoking
• Control your blood pressure if it is high
• Do not use cocaine
• Do not drink alcohol heavily

Further Information and Support

• The Brain Aneurysm Foundation

 

Key References

Suarez JI, Tarr RW, Selman WR.  Aneurysmal subarachnoid hemorrhage.  New England Journal of Medicine 2006; 354:387-96.

Brisman JL, Song JK, Newell DW.  Cerebral aneurysms.  New England Journal of Medicine 2006; 355:928-39.

Yasuno K, Bilguvar K, Bijlenga P, et al.  Genome-wide association study of intracranial aneurysm identifies three new risk loci.  Nature Genetics 2010; Published online 4 April 2010, doi:10.1038/ng.563.

Bilguvar K, Yasuno K, Niemela M, et al.  Susceptibility loci for intracranial aneurysm in European and Japanese populations.  Nature Genetics 2008; 40:1472-77.

Helgadottir A, Thorleifsson G, Magnusson KP, et al.  The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm.  Nature Genetics 2008; 40:217-24.

Mutations in RAD51C: A New Genetic Cause for a Fanconi Anemia-Like Disorder

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

Vaz F, Hanenberg H, Schuster B, et al.  Mutation of the RAD51C gene in a Fanconi anemia-like disorder.  Nature Genetics 2010; published online 18 April 2010; doi:10.1038/ng.570

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.

Taniguchi T.  Fanconi anemia.  In GeneReviews (online resource), Last Revision: March 27, 2008.  Accessed April 18, 2010.

Steven Pinker of the PGP in the NY Times Magazine

Very interesting article by Steven Pinker of the Personal Genome Project in the NY Times Magazine.  Check it out here.