DNA and You

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

Matt Mealiffe, M.D. — Fri, 18 Apr 2008 06:30:00 -0700

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:

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

Matt Mealiffe, M.D. — Tue, 12 Feb 2008 00:27:07 -0800

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.

More NEJM Genomics: High-Throughput Sequencing Utilized to Identify a New Arenavirus in Transplant-Associated Infections

Matt Mealiffe, M.D. — Sun, 10 Feb 2008 19:00:00 -0800

In a new paper by Gustavo Palacios and colleagues published in the New England Journal of Medicine, the 454 Life Sciences (Roche) high-throughput sequencing platform was utilized to investigate the cause of a fatal febrile illness in three patients who died about a month after receiving transplanted organs from the same donor (abstract here). This approach allowed the identification of a new arenavirus transmitted through solid-organ transplantation that is likely responsible for the fatal infections in these transplant recipients. An accompanying editorial (available to subscribers only) points out that the application of high-throughput sequencing technologies may transform the clinical microbiology lab. Dr. Richard Whitley suggests several clinical conditions caused by infectious diseases that may be particularly amenable to a high-throughput sequencing diagnostic approach: particularly central nervous system encephalitis and acute respiratory tract infections.

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

Matt Mealiffe, M.D. — Sun, 10 Feb 2008 12:41:09 -0800

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

Matt Mealiffe, M.D. — Wed, 09 Jan 2008 20:06:04 -0800

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

Matt Mealiffe, M.D. — Mon, 07 Jan 2008 20:42:58 -0800

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.

KNOME, George Church, and Personalized Whole Genome Sequencing

Matt Mealiffe, M.D. — Thu, 29 Nov 2007 17:44:40 -0800

I just received the following (copied and pasted) information in an email from Knome:

Human Whole-genome sequencing hits commercial market

20 individuals to be among first in history to be fully sequenced

CAMBRIDGE , Massachusetts — Nov. 29, 2007  — Knome, a personal genomics company, today announced the launch of the first commercial whole-genome sequencing and analysis service for individuals.

"In 2003, the Human Genome Project completed a 12-year effort to sequence the first human genome at a cost of $3 billion. Only very recently have costs come down to a level where it is now feasible for private individuals to be sequenced and analyzed. We expect this evolution to quickly usher in a new era in personalized medicine," said Dr. George Church, PhD, a co-founder of the firm and Professor of Genetics at Harvard Medical School.

First to know, first to benefit

Knome today opens enrollment for its first sequencing flight. Because the sequencing and analysis process is both labor and computationally intensive, initial capacity is expected to be limited to approximately 20 clients.

"To date, Craig Venter and James Watson are the only named individuals to have their genome sequenced. Our first 20 clients will have a historic opportunity to help pioneer the emerging field of personal genomics. They will be among the first to know and the first to benefit from the latest advances in our rapidly developing understanding of the human genome," said Jorge Conde, the firm's CEO.

Building the gold standard

Whole-genome sequencing decodes the 6 billion bits of information that make up an individual's genome. Unlike existing genome scanning or "SNP chip" technologies that provide useful but limited information on approximately 20 conditions, whole-genome sequencing allows for the analysis of up to 2,000 common and rare conditions, and over 20,000 genes – numbers that are rapidly growing.

"Whole-genome sequencing is the endgame," according to Mr. Conde. "It will enable us to look at nearly 100% of your genetic code compared to the less than 0.02% currently available on SNP chips. This is the approach that most fully reveals what our genomes can tell us about ourselves."

Pricing for Knome's service will start at $350,000, including whole-genome sequencing and a comprehensive analysis from a team of leading geneticists, clinicians and bioinformaticians. This team will also provide continued support and counseling.

"Knome's goal is to establish the gold standard in personal genomic services for individuals. We are bringing our clients the latest sequencing technology, Knome's proprietary analytic engine and security solutions, and access to top genomic scientists and medical professionals," said Conde. "Analytics, privacy and on-going client service are as important to us as the actual sequencing."

Core to the fundamental principles of the company, clients will retain full ownership of their personal genome and have the ability to anonymously share all or portions of their genome with researchers and other medical professionals.

About Knome

Based in Cambridge, Massachusetts, Knome has the distinction of being the first personal genomics company to commercially offer whole-genome sequencing and analysis services for individuals. Working alongside leading geneticists, clinicians and bioinformaticians from Harvard and MIT, Knome enables its clients to obtain, understand, and share their genomic information in a manner that is both anonymous and secure. Knome is a privately funded company. Please visit www.knome.com for more information.

Knome is a trademark of Knome, Inc. All other company and product names may be trademarks of the respective companies with which they are associated.

For more information CONTACT

info@knome.com

Clearly, it will be interesting to see how this plays out. I would be particularly interested to know what the specific plans are for the implied analysis and counseling from clinicians and other team members.

Anybody got a spare $350K they would like to part with?

NY Times Personalized Genomics Feedback

Matt Mealiffe, M.D. — Fri, 23 Nov 2007 08:32:40 -0800

For those who haven't seen it yet, a series of letters responding to the NY Times coverage of 23andMe, Navigenics, and deCODE Genetics are available here.

Interestingly, the author of the last letter in the NY Times series, Dr. Hugh Rienhoff, has made some news himself of late.

Who's your daddy?

Matt Mealiffe, M.D. — Mon, 19 Nov 2007 18:46:25 -0800

Once a year, I teach a case-based discussion section in the medical genetics course for the 2nd year med students at the University of Washington. Each year, there is an anomalous result in one of the cases that has several potential explanations. We encourage the students to think through the possible explanations...and one of them is non-paternity. That case sticks out in my mind, because one year, a student suggested that I was being sexist by suggesting that non-paternity was a possibility (i.e., if I bring up non-paternity...I must propose non-maternity as an option as well). The class laughed and another student pointed out that generally maternity is a little more difficult to fake than paternity. Now I look back on this with some amusement.

Over the past decade, (non)paternity has really been in the public eye - via Jerry Springer and other daytime TV, via court room drama, and via the increasing availability of cheap paternity testing. In my clinical genetics training, an oft quoted number was that ~5% of individuals in a clinic were not fathered by the person who is ostensibly their father. I've never been able to track down the primary reference for this; however, estimates in the literature range from a minimum of ~1% to ~20%. Regardless of the specific number, it is a substantial fraction of people. The beginning of an era of personalized direct-to-consumer genomics that may be utilized by a substantial fraction of the population may transform the way we think about this issue. At the very least, if companies like 23andMe and deCODE Genetics are successful in getting large numbers of families to utilize their genotyping services, there will be more...umm...transparency brought to this issue.

I'm confident that these companies have spent a lot of time thinking about this issue, and I'm not suggesting that it is a reason to regulate or ban the personalized genomic testing by any means. Nevertheless, inadvertent demonstration of nonpaternity is another way in which the personalized genomics revolution will affect the social fabric of our world.

What a week...

Matt Mealiffe, M.D. — Sun, 18 Nov 2007 11:32:53 -0800

What a wild couple of days...

First, deCODE Genetics unstealths its deCODEme foray into the personalized genomics market.

Then, just when you think they've been completely beaten to the punch, 23andMe throws a counterpunch.

I'd been wondering for a while what deCODE was up to in this arena, as they clearly have the infrastructure and the track record to make a serious play in personalized genomics.

Interestingly, even though many would argue that the Navigenics approach is the most responsible one, getting results on 20 or so SNPs is looking so "last week" right now.

Just in case you've been in a sound-proof bubble the last few days, here are some links to a few articles and posts about the events of the last few days:

While much has been said about the product launches, I find it interesting that there has been relatively little talk about something that is being left out of the products offered to the public (at least at the moment as far as I can tell). Specifically, that something is copy number variation.

For those not familiar with the concept, in addition to variation at single DNA base pairs, it is also crystal clear that individuals differ enormously from each other in terms of the presence or absence or elevated copy number of entire large "chunks" of DNA. These studies, pioneered by Evan Eichler and others, have shown that our genomes are more dynamic than was previously recognized. Thus, when copy number variation involves important genes or other important stretches of DNA not in genes, it can have an important impact on disease susceptibility. For example, copy number for a stretch of DNA containing the CCL3L1 gene has been beautifully shown to very significantly influence HIV/AIDS susceptibility. Likewise, low copy number of a gene called FCGR3B is associated with the development of the kidney disease, glomerulonephritis, in individuals with systemic lupus erythematosus.

Although first generation SNP genotyping approaches didn't always do so well with detecting copy number variation, more recent iterations have the ability to detect copy number variation (although a different technique called array comparative genomic hybridization is more commonly utilized to detect this clinically). For example, Affymetrix states on their website that their 500K arrays provide copy number variation information (Navigenics is partnering with Affymetrix for genotyping). Likewise, Illumina (23andMe's genotyping partner) points out that their product can also identify copy number variants.

Although the launch of genotyping services by 23andMe and deCODE Genetics appears likely to provide dramatically more information to the consumer than the small number of SNP results that will be reported by Navigenics, it would appear that both 23andMe and deCODE may have access to information related to copy number variation that can have important implications with respect to disease risk and which may not be reported back to the consumer. It will be interesting to see how this is dealt with in the future.