DNA and You

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.

Music and Your Genes: One Step Closer to Understanding the Biological Basis of Musical Ability

We've all come across certain people who seem to have a particularly high ability to play and/or appreciate music.  As a geneticist, my assumption has always been that this is inherent and heritable to some degree.  Nevertheless, it could certainly be argued that it is environmental. 

The literature provides some support for the concept that musical ability is genetic.  For example, musical talent has been noted to cluster in some families.  Additionally, the ability to identify pitch in the absence of a reference pitch clusters in families, as well.  Conversely, tone deafness, also known as congenital amusia, also seems to be genetic on the basis of strong familial clustering.  Lastly, in a formal study of pitch recognition in twins, the heritability of scores on the so-called Distorted Tunes Test were estimated to be more than 70%.

Now, a Finnish research group has demonstrated that it is highly likely that a gene on chromosome 4 (located in the vicinity of chromosome band 4q22) influences musical aptitude.  They utilized three different measures of musical aptitude in coming to this conclusion and performed a "genome-wide linkage test."  This study has narrowed the region containing the gene to a segment of the chromosome containing ~50 genes, so further studies will be necessary to find the precise genetic change influencing musical aptitude in these families. The authors also noted other regions of the genome in which there was suggestive linkage, suggesting that musical aptitude is likely to be affected by multiple genes.  It will be interesting to watch as these are hopefully identified in future studies.

Reference

K Pulli et al.  Genome-wide linkage scan for loci of musical aptitude in Finnish families: evidence for a major locus at 4q22.  Journal of Medical Genetics 45: 451-6, 2008. 

Rett Syndrome on Fox Show: "So You Think You Can Dance"

Tara Parker-Pope of the NY Times writes about an episode of the Fox reality show, "So You Think You Can Dance," in which Rett syndrome was featured.

For more on Rett Syndrome:

Rett Syndrome (MECP2-Related Disorders) GeneReview

International Rett Syndrome Foundation

More on Digital Clubbing...

I just noticed that there is a pretty good wikipedia article related to my earlier post on digital clubbing.

Digital Clubbing and Your Genes: Prostaglandin E2 in the Pathogenesis of Finger Clubbing (aka Hypertrophic Osteoarthropathy)

A new paper (abstract available here) published online in the journal Nature Genetics demonstrates the power of traditional Mendelian genetics to reveal clues to the underlying mechanisms of more common diseases.  Finger or digital clubbing, which is also known as hypertrophic osteoarthropathy, is one of the classic physical signs taught to medical students.  Hippocrates is commonly thought to have been the first to recognize digital clubbing in the fifth century BC.  The clubbing depicted in the figure below (from www.nail-disorders.com) is the hallmark of so-called pulmonary hypertrophic osteoarthropathy, a clinical sign that can develop in the context of a number of clinical conditions including intrathoracic neoplasms (i.e., cancers within the chest):

Some Clinical Conditions Associated with Digital Clubbing

• Lung Cancer
• Congenital Heart Disease
• Inflammatory Bowel Disease

Figure: Digital clubbing (aka hypertrophic osteoarthropathy).  From www.nail-disorders.com.

Despite the fact that the form of hypertrophic osteoarthropathy secondary to lung cancer and other disorders has been recognized for many centuries, its actual cause has remained remarkably enigmatic.  However, the new study in Nature Genetics breaks important new ground. 

The authors, led by Dr. David Bonthron of the Leeds Institute of Molecular Medicine and Yorkshire Regional Genetics Service, studied several families with a rare inherited form of digital clubbing, known as "primary (idiopathic) hypertrophic osteoarthropathy (PHO)."  They localized the gene responsible for PHO to the long arm of chromosome 4 and demonstrated that the responsible gene is HPGD, which provides the coding information to produce a protein called "15-hydroxyprostaglandin dehydrogenase."  The affected individuals in these families had mutations in both of their copies of HPGD, suggesting that the inheritance pattern is autosomal recessive (i.e., similar to cystic fibrosis in that a mutation in both copies of the gene are necessary to get the clinical condition). 

Importantly, 15-hydroxyprostaglandin dehydrogenase is the main enzyme responsible for breaking down prostaglandin E2 (PGE2, a lipid compound which has a number of functions in the lung, the GI tract, and in the uterus during pregnancy) and other prostaglandins and related compounds. 

The authors measured PGE2 levels in the urine of the study subjects and showed that they were elevated in the individuals from the families with mutations in both copies of HPGD.  Interestingly, intermediate elevations of urinary PGE2 levels were seen in some of the family members with one normal copy and one mutated copy of HPGD.  Some of these individuals had mild, late-onset digital clubbing, which is consistent with the degree of elevation of prostaglandin levels within the body determining the severity and age of onset of the digital clubbing.

In hindsight, the identification of HPGD, the key enzyme in prostaglandin degradation, as a disease gene for PHO makes a great deal of sense.  PGE2 is known to have a number of effects upon bone.  The demonstration, in this rare disorder, that mutations in the key enzyme of prostaglandin degradation lead to PHO suggests that elevated prostaglandin levels are critical in causing the much more common clubbing seen in pulmonary hypertrophic osteoarthropathy (the clubbing seen in association with lung cancer and other disorders).  As the lung is known to be a site of PGE2 clearance by HPGD, perhaps the lung diseases associated with pulmonary hypertrophic osteoarthropathy lead to decreased clearance and degradation of PGE2.

PGE2 is also known to be important in the context of a type of congenital heart disease known as "patent ductus arteriosus" (PDA).  Normally, the ductus arteriosus is closed after birth when circulating PGE2 levels fall significantly (due to exposure of the blood to HPGD in the newborn's lung).  One might expect that PGE2 levels would not drop as rapidly in individuals with mutations in HPGD, and, indeed, 4 of the 13 HPGD-deficient individuals in this study had patent ductus arteriosus.  Although, this association was previously recognized, it now makes much more sense given the association with a disruption in the capacity to metabolize PGE2.  It will be interesting to see if significant numbers of individuals with PDA have mutations in one or both copies of HPGD.

The authors point out that there were some previous clues to the involvement of prostaglandins in clubbing.  For example, liver transplant patients who received prostaglandin E therapy developed clubbing.  Nevertheless, this novel result suggests that PHO and the more common secondary pulmonary hypertrophic osteoarthropathy have a common cause: elevated prostaglandin levels. 

There are two important clinical implications for the future:

1. Strategies aimed at decreasing prostaglandin levels might be helpful in individuals with PHO.
2. For middle-aged or elderly individuals presenting to a physician with clubbing in the future, it may be worthwhile considering whether there are HPGD mutations, as their presence could help the patient avoid an extensive work-up looking for other underlying causes including malignancy.

A HOXA2 mutation is responsible for one type of autosomal recessive microtia (congenital deformity of the outer ear)

Congenital deformities of the outer ear, referred to as microtia, occur in about 1 out of every 9000 births and can be either unilateral (one-sided) or bilateral (both sides).  Most cases are unilateral, and interestingly, the right ear is more frequently affected in these cases.  Additionally, microtia occurs more frequently in males.

The condition is divided into four grades depending on the severity of the deformity.  Syndromic forms of microtia are seen in individuals in whom microtia occurs together with other congenital abnormalities.  Among the associated malformations in these syndromic cases are cleft lip or palate, kidney abnormalities, cardiac defects, and others, in addition to hearing loss.

Syndromes associated with microtia include the following:

• Oculo-auriculo-vertebral spectrum (which includes hemifacial microsomia aka Goldenhar radial defect syndrome
• Treacher Collins syndrome
• CHARGE association
• Nager syndrome

A new paper published online in the American Journal of Human Genetics reports the identification of a gene involved in an autosomal recessive form of microtia.  Fatemeh Alasti, Guy Van Camp, and colleagues studied a consanguineous Iranian family in which four cases of bilateral microtia were seen in association with hearing impairment (prelingual onset), and partial cleft palate. 

The authors performed linkage analysis and localized the disease gene to chromosome 7p between 7p14.3-p15.3.  Further fine mapping revealed an identical homozygous region that was approximately 10MB in length and contained >100 genes.  The authors chose to sequence genes from the HOXA gene cluster (HOX genes are homeobox genes which play a very important role in development).  A DNA sequence change in HOXA2 causing an amino acid change (Q186K) in the HOXA2 protein was found in the homozygous haplotype in all affected individuals in the family and in heterozygous fashion in the unaffected parents.  The authors demonstrated that this variant DNA sequence was absent from 231 Iranian and 109 Belgian control individuals (without microtia).   

Although the collective evidence from this study regarding the involvement of HOXA2 in ear malformations is very solid, ultimately further proof will be necessary from the identification of additional microtia patients with HOXA2 mutations and/or solid functional analysis of the mutant Q186K HOXA2 protein. 

It is difficult to speculate at this point about the percentage of autosomal recessive microtia that might be secondary to HOXA2 mutations.  Most likely, this will prove to be a fairly genetically heterogeneous condition with involvement of other genes (including other homeobox genes) in some cases.

Further Resources:

• OMIM microtia entry
• OMIM HOXA2 entry
• Children's Craniofacial Association microtia info
• Hereditary Hearing Loss Homepage
• UCSC Genome Browser HOXA2 page
• AJHG Abstract for F Alasti et al. paper

Gene Found for Ghosal Hematodiaphyseal Dysplasia Syndrome: A Rare Syndrome with Increased Bone Density

A paper published online on Sunday in the journal Nature Genetics (abstract available here) describes the identification of mutations in a gene causing the rare, autosomal recessive, genetic syndrome Ghosal hematodiaphyseal dysplasia syndrome (GHDS).  GHDS is a disorder of increased bone density. 

The authors had previously mapped the disease gene to a segment of chromosome 7 by studying two families from Algeria and Tunisia.  In this study, they identified mutations in TBXAS1 - which encodes the enzyme thromboxane synthase - in the two original families, in addition to two other families from Tunisia and Pakistan with GHDS. 

Thromboxane synthase is one of the terminal enzymes in the arachidonic acid cascade and is involved in the production of thromboxane A2, which is known to be a powerful inducer of blood platelet aggregation in addition to having other physiologically important effects. 

The demonstration that TBXAS1 mutations cause GHDS, a disorder of increased bone density, suggests that thromboxane synthase and thromboxane A2 may play an important role in bone remodeling. 

Additionally, as is often the case with the identification of disease genes causing rare Mendelian (see "Mendelian trait" section of this article) syndromes, this paper suggests a candidate gene for a related, but much more common, condition; the involvement of TBXAS1 in a disorder of increased bone density suggests that it may be a candidate gene worth investigating in osteoporosis in the future.

Genetics Takes Over The New England Journal of Medicine...Again

There has been a sustained trend towards the publication of more and more genetics and genomics-related papers in The New England Journal of Medicine.  Last month I commented on it here.  This week's issue of the NEJM is no exception:

• There is a very interesting pharmacogenetics paper (abstract here) focused on the genetic basis of hypersensitivity reactions to abacavir, an important anti-retroviral drug utilized in the treatment of HIV.  About 5-8% of individuals of northern European descent develop a serious hypersensitivity reaction, mediated by their immune system, in the first 1-1/2 months of abacavir treatment.  Severe adverse drug reactions, whether occurring in the context of treatment with abacavir or with any of a number of other drugs, have a significant impact on morbidity, mortality, and total costs to our healthcare system and society.  In 2002, medical researchers determined that the HLA-B*5701 variant of the Human Leukocyte Antigen (HLA)-B gene was highly associated with abacavir hypersensitivity reactions, which are unpleasant and characterized by fever, rash, gastrointestinal symptoms, respiratory symptoms, and other constitutional symptoms.  Although several previous studies had suggested that genotyping for HLA-B*5701 (which can be done with DNA sequencing-based methods), could help to significantly reduce abacavir treatment-related hypersensitivity reactions, the present study was an impressively sized, randomized, double-blind, prospective study evaluating the clinical utility of HLA-B*5701 genotyping prior to abacavir treatment in HIV infection.  The HLA-B*5701 allele was found in 5.6% of patients (predominantly white).  This screening was able to eliminate abacavir-related hypersensitivity reactions in the prospective HLA-B*5701 screening group.  Thus, the study showed that in predominantly white populations, ~94% of patients do not have HLA-B*5701 and, therefore, have a low risk of hypersensitivity reaction to abacavir.  Likewise, the test can be utilized to prevent the toxic effect of the drug in the 6% of individuals with HLA-B*5701.   
• Another paper by Dr. William Gahl (from the NHGRI) and colleagues focuses on the natural history of the remarkable Hutchinson-Gilford Progeria (premature aging) Syndrome (H-GPS).  Although H-GPS (meet some kids with H-GPS here) is an extraordinarily rare genetic syndrome, the detailed description in this paper may significantly impact our description of normal aging.  I'll try to return to this subject in another post.
• A paper (abstract available here) by Dr. Stephen Kaler (of the NICHD) and colleagues describes attempts at early diagnosis and treatment of neonatal Menkes disease, a genetic disorder of copper transport.  This disease is caused by mutations in the copper-transporting gene, ATP7A.  The clinical symptoms in Menkes disease are secondary to decreased activity of enzymes that require copper as a cofactor.  Because early detection with newborn screening is not available and because infants with Menkes disease appear normal for a period of about 2 months prior to clinical deterioration, researchers have sought better methods of early diagnosis.  The need is underscored by the fact that outcomes may be improved in this disease if daily copper injections are started very soon after birth.  Dr. Kaler and colleagues utilized measurements of neurochemicals in blood plasma during the neonatal period to improve early diagnosis of Menkes disease.  Specifically, they showed that measurements of plasma catecholamines in infants at risk has both high sensitivity and high specificity, even in the period before infants become symptomatic.  Lastly, they also present evidence suggesting that response to copper treatment in these infants may depend on genotype: infants with mutations that do not completely destroy the function of the ATP7A copper transporter appear may be particularly responsive to early copper treatment.

Genetics Takes Over The New England Journal of Medicine

One only has to briefly scan the table of contents of tomorrow's issue (Jan. 10) of The New England Journal of Medicine to figure out that 2008 is going to be a big year at the crux of genetics and medicine!  The issue includes the following (note that only a subset of the following full articles are available without subscription):

• A perspective by Drs. David Hunter, Muin Khoury, and Jeffrey Drazen on the medical implications - or lack thereof - of personalized genotyping services (i.e., 23andMe, Navigenics, and deCodeMe).  More on this in a follow-up post later this evening.  However, I can tell you that these three are not fans of personalized genotyping companies.  There is also an audio interview with Dr. Khoury available here.
• Dr. John Bissler and colleagues from Cincinnati Children's Hospital Medical Center present the results of a study of sirolimus treatment of angiomyolipomas in tuberous sclerosis complex (TSC) and sporadic lymphangioleiomyomatosis.  TSC is a Mendelian genetic disease in which the genetic defects lead to constitutive activation of the "mammalian target of rapamycin" (mTOR, a key cellular signaling pathway intermediate).  As sirolimus suppresses signaling through mTOR, this study represents a rational use of sirolimus to treat angiomyolipomas in TSC.  More on this soon at my other blog, Cancer and Your Genes.
• Dr. Antonio Pelliccia and colleagues present the results of a study looking at implications of EKG abnormalities referred to as "repolarization abnormalities."  They show that out of 81 athletes with a particular type of EKG abnormality (see free full text here for details), 5 (6%) ultimately developed cardiomyopathies (including one individual who died from arrhythmogenic right ventricular cardiomyopathy - which has a genetic basis). 
• Dr. Melanie Percy and colleagues demonstrate that an oxygen sensing gene called HIF2A is mutated in a family with Familial Erythrocytosis (i.e., a heritable condition in which affected individuals have too many red blood cells).
• There is also a review of the book, "Reprogenetics: Law, Policy, and Ethical Issues," edited by Lori P. Knowles and Gregory E. Kaebnick.
• As if all that were not enough, an article in the NEJM "Clinical Problem" series focuses on the approach to Long QT syndrome, an inherited, genetically heterogeneous condition that predisposes individuals to life-threatening arrhthymias (abnormal heart rhythms). 
• Last, but certainly not least, in an online article published today, Mark Daly and colleagues report the identification of a small, sub-microscopic region of chromosome 16 that when deleted or duplicated leads to autism susceptibility!  Although this is probably only responsible for about 1% or so of cases, this is a huge accomplishment.

In looking at just this single issue of NEJM, I think it is safe to say that we have a very interesting year ahead of us.  Stay tuned to DNA and You for more detailed posts on the above!

Donor Sperm and Genetic Disease...Again

Bertalan Mesko at ScienceRoll linked today to a Wall Street Journal Health blog post about a child with Tay-Sachs conceived with a donated egg.  This interesting story, originally reported in the LA Times, certainly isn't the first example of a rare genetic condition being passed on to a child via a donor egg or sperm.

For example, in 2006, Dr. Laurence Boxer of the University of Michigan and colleagues demonstrated that donor sperm from the same individual transmitted a mutation in the ELA2 gene to 5 separate children, giving them a condition called severe congenital neutropenia.  Children with SCN do not make enough neutrophils (a type of white blood cell that fights off bacterial and other infections).

The original report and news coverage (for example here) question whether mechanisms to identify clusters of genetic disease transmitted by single donors should be implemented.