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Software pinpoints cause of mystery genetic disorder

June 23, 2011 By Brendan BM Maher This article courtesy of Nature News.

Genome analysis tools speedily track down previously unknown mutation.

Halena Black's first son, Kenny Rae, was born in November 1979. He struggled to put on weight, and had thin, wrinkled skin, big eyes and a broad mouth. In October the following year, he died from heart problems.

After Kenny Rae died, Black — a Mormon living in Ogden, Utah — had three healthy daughters before giving birth to another son in 1987. He had the same problem, and a similarly short lifespan. Her third son is healthy.

Black says she didn't dwell much on why her sons died until one of her daughters gave birth to a boy who looked just like Kenny Rae. "We didn't think that it passed on to the next generation. We didn't think that this would be a problem for them," says Black. All three daughters have since given birth to what the family calls 'little old men', one of whom died just last Sunday.

Today, Gholson Lyon, a medical geneticist and psychiatrist at the Children's Hospital of Philadelphia in Pennsylvania, and his colleagues reveal the genetic mutation responsible for the boys' disorder, tentatively named Ogden Syndrome.

The methods they used allowed them to pinpoint the guilty mutation remarkably quickly. "They make it look easy," says Richard Gibbs, a geneticist at Baylor College of Medicine in Houston, Texas, who was not involved with this work, "And that's the sign of real sophistication in the field."

Similar techniques, some say, could be used to reveal the causes of more widespread diseases.

Genetic logic

Mormons tend to have lots of children and keep extensive genealogies, so researchers hoping to unpick genetic disorders are able to track traits through the generations and take samples from many living family members. "I moved to Utah for the pedigrees," says Lyon, who began studying the Blacks while working at the University of Utah in Salt Lake City.

Because only male members of Black's family had the disease, Lyon assumed that the disorder's cause lay on the sex-determining X chromosome. If a woman inherits an X chromosome with a disease-causing mutation, the normal copy of her other X chromosome is often enough to keep her healthy. Males have only one X chromosome, so they are not protected.

Gholson collected blood samples from 12 members of the Black family. By late 2010, his team had sequenced exons — those parts of the genes that are most likely to encode proteins — from the roughly 2,000 genes on the X chromosomes of several members. From start to finish, determining the cause of the syndrome took about a year, says Lyon. The results are published in the American Journal of Human Genetics1.

To home in on the disease-causing mutation, the researchers used a new software programme, the Variant Annotation, Analysis & Search Tool (VAAST), that compared the family members' genomes with sequences from nearly 200 other people.

"We got the data. We ran them at the keyboard in my lab and we had the result in ten minutes," says Mark Yandell, a geneticist at the University of Utah, who developed VAAST2.

Armed only with samples from one affected boy and one female carrier, VAAST was able to identify a gene called NAA10 as being responsible for Ogden Syndrome. Another, unrelated, family has since emerged with the same mutation and symptoms.

Normally, NAA10 encodes a protein that helps to attach acetyl groups to the ends of other proteins. In individuals with a mutated NAA10 gene, the protein has a slightly altered structure, and does not acetylate other proteins as well.

This could damage any cell, perhaps explaining why the mutation's effects are so devastating. Lyon says that this is the first time this gene has been implicated in a disease.

Black says that her family has found some comfort in knowing that they are not alone, and some pride in having a disease possibly named after their home town. There is currently no treatment for the condition, although the family is recieving genetic counselling. The Church of Latter day Saints is against abortion except in some cases of rape incest and endangerment of the mother's life, but their stance on pre-implantation genetic diagnosis, which could screen out embryos with this condition, is less clear.

Targeted approach

Several geneticists say that the ability to find the causes of rare genetic disorders so quickly could have broad implications. "This exemplifies an exceptionally rare disease, but the same type of strategy is now going to be applied to more common diseases to get the root cause," says Eric Topol, a medical geneticist at the Scripps Research Institute in La Jolla, California.

This approach may be more effective than genome-wide association studies (GWAS), low-resolution genetic scans of many people with the same traits that have been commonly used to find genetic variations, says James Lupski, a geneticist at Baylor College. "By applying genome-sequencing technology to selected patients, we could learn a tremendous amount," he adds.

Many geneticists defend GWAS, but the approach has failed to find genes with strong links to diseases such as autism and obesity. Funding agencies are taking a renewed interest in rare and undiagnosed diseases, however, such as through the Undiagnosed Disease Program at the National Institutes of Health and the International Rare Disease Research Consortium, in hopes that understanding the genome through these rare cases will provide more general knowledge.

"This is one of the most exciting things in medicine," says Topol. "We're going to take the term 'idiopathic' which, basically means 'we don't' know,' and eliminate it."


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