Family Genomics Links DNA to Disease

Discover Magazine (April 28, 2011)- A decade ago, sequencing the dna in a person’s entire genome cost up to $1 billion, a price so prohibitive that only a few genetics pioneers had the honor of having it done. In 2010 the cost per genome tumbled to less than $10,000, making it possible to study dna variations within a single family. Almost immediately such familial genome sequencing proved its value, uncovering mutations responsible for diseases caused by defects in a single gene. “There are literally hundreds, if not thousands, of diseases falling into this category. This approach will allow us to very quickly find the genetic culprit,” says Leroy Hood, a geneticist at the Institute for Systems Biology in Seattle.

Earlier efforts to hunt 
down disease-causing genes—so-called genomewide association studies—frequently came up empty-handed because medical researchers had to take cost-saving shortcuts. Instead of trolling an individual’s entire genome, they limited their search to dna regions where variations are most often seen across large populations. “It was assumed that common variants might be responsible for common diseases, but many diseases turn out to have many different rare variants at their root,” says James Lupski, a medical geneticist at Baylor College of Medicine in Houston. “That’s why the power of whole-genome sequencing blows us away. It’s the only way we can get at these rare variants.”

Lupski himself suffers from Charcot-Marie-Tooth neuropathy, a rare hereditary disorder that reduces sensation in the limbs. Although neither of his parents had the condition, three of his seven siblings are also affected by it. “For 20 years we’ve been looking for the gene and mutation behind my family’s neuropathy, but we never found the variant,” he says. Then, in 2010, collaborating with his colleague Richard Gibbs and other Baylor geneticists, Lupski sequenced his own genome —and “Boom! We found it,” he says. (Each of his parents, it turns out, carried a different recessive mutation of the same gene. Consequently, only their children who inherited one from each parent developed the disorder.)

Other groups are finding similar success with whole-genome sequencing. A 2010 study led by Hood in collaboration with the University of Washington and the University of Utah sequenced the entire genomes of four family members. The mother and father were healthy, but their son and daughter both suffered from a rare hereditary disorder called Miller syndrome, which causes craniofacial deformation. The gene responsible was unknown until Hood’s team identified a recessive gene inherited from both parents. If you could diagnose the disease in utero, you might be able to provide preventive drugs before symptoms appeared, Hood says.

Still unclear is whether whole-genome sequencing will work as well at identifying the culprits for cancer, heart disease, and other disorders believed to involve multiple genes rather than a single mutation. Progress may be slower on that front, Duke University geneticist David Goldstein says. But even when the genetic mechanism is more complex, he adds, the new approach might yield insights into underlying disease processes that could pave the way for more finely targeted treatments.

One More Step Towards the End of Recessive Diseases

Genetic Future (Jan. 20, 2011)- "In the last century infant mortality has declined precipitously in the Western world, thanks in large part to the development of antibiotics and vaccination. Yet as the suffering and death from infectious disease has reduced, the burden from genetic disease has become proportionately greater: currently around 20% of all infant deaths in developed countries are a result of inherited Mendelian (single-gene) disorders.

What can be done to reduce this burden? Increasingly sophisticated methods for detecting disease in embryos during pregnancy will help, and these have recently taken another step forward with the development of accurate, non-invasive methods based on analysing foetal DNA in the blood of pregnant mothers (an article in the BMJ this week demonstrates the feasibility of this approach for a non-Mendelian disease, Down syndrome; and the same group showed late last year that this approach can also be applied to effectively any known disease-causing mutation). Yet these approaches detect disease after pregnancy has already begun.

Disease mutations can also be detected in embryos prior to implantation, for prospective parents undergoing IVF. But IVF remains an expensive, arduous and invasive procedure, and thus a weapon of last resort for most parents-in-waiting; as Armand Leroi notes drily in an exceptional 2006 article in EMBO Reports: “nature has contrived a cheap, easy and enjoyable way to conceive a child; IVF is none of these things.” (While Leroi goes on to argue that the challenges of IVF are less severe for young couples with no fertility problems, it still seems fairly implausible that this will become the default mode of reproduction in the near future.)

However, for some classes of Mendelian disease it’s possible to move the screening one step back. Recessive diseases are insidious things. The mutations that cause them lurk undetected – each of us carry perhaps 5 to 10 of them – as their carriers are protected by the presence of a healthy second copy of the affected gene. These mutations can thus wait silently for generation after generation, until a carrier is unlucky enough to fall for someone who carries the same mutation, or another mutation in the same gene. The children of such a couple will each have a 25% chance of inheriting one damaged copy of the gene from each parent and thus developing the disease."

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New Genetic Test Screens Would-Be Parents

National Public Radio (January 13, 2011)- A newly developed test could screen would-be parents for hundreds of different disease genes, to make sure they are not passed on to any future children.

The test's makers say it should cost less than $400 and that routinely offering it to prospective parents could someday eliminate many deadly childhood diseases.

"We definitely want it to be pre-pregnancy. We do want it to be couples," says Stephen Kingsmore, a physician-researcher at Children's Mercy Hospital in Kansas City, Mo., who led the team that developed this new test. "I think it's going to be a personal decision, whether a couple wants to be tested."

The inspiration for this new test came from Craig and Charlotte Benson, of Austin, Texas. In 2008, their daughter Christiane was diagnosed with Batten disease, a rare neurodegenerative disorder that currently has no cure. It progresses from vision loss to memory problems and seizures, and eventually death.

"Both her mom and I carry a gene mutation, a single gene mutation," explains Craig Benson. He and his wife didn't know they were carriers before they had children — indeed, they'd never heard of Batten disease."

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World's Largest DNA Scan Reveals Rare Variants That Disrupt Gene Activity in Autistic Children

ScienceDaily (June 10, 2010) — The world's largest DNA scan for familial autism has uncovered new genetic changes in autistic children that are often not present in their parents. Identified in less than 1 percent of the population, these rare variants occur nearly 20 percent more in autistic children.

Using blood samples from 996 elementary school-age children diagnosed on the autism spectrum from the United States, Canada, and Europe, the scientific teams combed the children's DNA for rare deletions and duplications. In particular, they hunted for changes in the genetic information that a child inherits from each parent. The families consisted of parents with one autistic child.

"We discovered two striking things. First, the rare variants interfered nearly 20 percent more in the genes of autistic children than in the healthy children," said Dr. Daniel Geschwind, Gordon and Virginia MacDonald Distinguished Chair in Human Genetics and UCLA professor of neurology and psychiatry. "Second, we found a number of disruptions that are new, or de novo. The autistic child is the first in their family to carry that variant. The parents do not have it.

"This suggests that tiny genetic errors may occur during formation of the parents' eggs and sperm, and these variations are copied during creation of their child's DNA," added Geschwind, who is also director of the UCLA Center for Autism Research and Treatment. "The finding parallels what takes place in chromosomal disorders like Down's syndrome."

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Newer Genetic Test for Autism More Effective

MONDAY, March 15 (HealthDay News) -- A newer type of genetic test is better at detecting abnormalities that predispose a child to autism than standard genetic tests, new research has determined.

Researchers offered about 933 people aged 13 months to 22 years who had been diagnosed with an autism spectrum disorder three genetic tests: G-banded karyotype testing, fragile X testing or chromosomal microarray analysis (CMA), which has been available only for the past few years.

Karyotype tests identified chromosomal aberrations associated with autism in about 2 percent of patients, while the fragile X genetic mutation was found in about 0.5 percent of patients.
CMA detected chromosomal abnormalities in slightly more than 7 percent of patients, making it the best available genetic test for autism spectrum disorders, the study authors said.

"The CMA test alone has triple the detection rate of karyotyping or fragile X," said co-senior author Bai-Lin Wu, director of the Genetics Diagnostic Laboratory at Children's Hospital Boston. "CMA should be added to first-tier genetic testing for autism spectrum disorders."

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