Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Sequencing studies help pinpoint gene in Prader-Willi syndrome

As so many genome studies do, this study published online in the journal Nature Genetics began with a single patient and his parents who were in search of a diagnosis.

The parents of this first patient sought genetic testing for Prader-Willi syndrome when he was only a year old, but the test, which was still in its infancy, came back negative.

For the next 12 years, his parents were left in limbo. He had many features of the disease – including lack of muscle tone, feeding difficulties and failure to thrive early on. Autism spectrum disorder and mild intellectual disability became evident as he grew older.

Dr. C. Thomas Caskey, then with UTHealth and now with Baylor College of Medicine, referred the patient to Dr. Christian Schaaf, an assistant professor of molecular and human genetics at Baylor College of Medicine and a faculty member at the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, for an evaluation. Schaaf agreed that the boy had many of the outward signs consistent with Prader-Willi, but others were lacking, such as the morbid obesity, which is typically caused by a very aggressive appetite.

Dr. Manuel L. Gonzalez-Garay (co-first and co-corresponding author), assistant professor and bioinformatics expert at the University of Texas Health Science Center at Houston's Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, identified a single change (called a point mutation) in the gene MAGEL2 using highly accurate whole genome sequencing information from Complete Genomics, Inc., of Mountain View California. This gene is located in the area of chromosome 15, which researchers knew was involved in Prader-Willi syndrome. The single base deletion found in this GC-rich and difficult to sequence gene is a frame-shift mutation that disrupts activity of the protein product of MAGEL2.

Prader-Willi syndrome is an imprinted disease, which means only one of the two copies of the gene inherited from your parents is working. The other is "silenced," usually during the formation of eggs or sperm. In this case, neither parent had a mutation, meaning that the mutation occurred first in this child. However, it still mattered whether the mutation came from the mother or the father.

The team from UTHealth and Complete Genomics then performed an involved analysis that determined that the mutated gene was on the paternal chromosome 15.

"Because the mom's copy of the gene is silenced and the dad's copy is deficient, there is no functional copy of the gene in his body," said Schaaf. "It was a nice collaboration among Baylor, UTHealth and Complete Genomics. But it was only one patient. When you identify a new gene and want to prove that it is the real cause of disease, you really need to identify several patients with mutations in the same gene, and show that they also have similar clinical manifestations. You also ought to consider the severity of the mutation and how rare the mutation is."

To start, they began to look for other patients. They asked the Baylor Whole Genome Sequencing Laboratory to find out if there had been similar mutations found in patients who had their exomes or protein-coding portions of the genome sequenced. They searched through the records of 1,200 and found three more patients with mutations in the same gene. One of the three had classic Prader-Willi syndrome, the other two were classified as Prader-Willi like. All three children had the standard molecular testing for Prader-Willi when they were infants, with negative results.

"This is the first report of point mutations causing Prader-Willi syndrome," said Schaaf. "Always before, researchers had identified deletions in the chromosome or uniparental disomy, which means that both chromosomes 15 were inherited from the mother, and none from the father. We have shown that also a single base pair alteration (of nucleotides in the genetic material) can cause Prader-Willi syndrome."

The Baylor lab began offering the testing on July 15. Not only does it offer testing for the mutation but also to identify whether the mutation occurs on the gene from the mother or the father.

"This study speaks to the value of collaboration and the power of the whole genome testing," said Schaaf. "It showed me again how important it is to these families to find 'an answer'. Many have been through years of uncertainty, with dozens of diagnostic tests coming back with negative results. Finding the cause puts things at rest, and empowers the families, as they can get better anticipatory guidance and better estimate of recurrence risk within their family."

Perhaps some day, he said, it might be possible to "un-silence" the silenced copy of the gene. "It's been done in mice with other diseases involving imprinted genes, and there's some evidence it might work in humans as well."

Others who took part in this work include: Fan Xia, Lorraine Potocki, Baili Zhang, Arthur L. Beaudet, and Yaping Yang, all of BCM; Brock A. Peters, Mark A. McElwain, and Radoje Drmanac, all from Complete Genomics; and Karen W. Gripp of Alfred I. DuPont Hospital for Children in Wilmington, Delaware.

Funding for this work comes from the Joan and Stanford Alexander family, the Cullen Foundation for Higher Education and the Houston Foundation. Schaaf is also a recipient of a Clinical Scientist Development Award by the Doris Duke Charitable Foundation.

Glenna Picton | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht Gene therapy shows promise for treating Niemann-Pick disease type C1
27.10.2016 | NIH/National Human Genome Research Institute

nachricht 'Neighbor maps' reveal the genome's 3-D shape
27.10.2016 | International School of Advanced Studies (SISSA)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Etching Microstructures with Lasers

Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.

This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...

Im Focus: Light-driven atomic rotations excite magnetic waves

Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion

Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

'Neighbor maps' reveal the genome's 3-D shape

27.10.2016 | Life Sciences

Gene therapy shows promise for treating Niemann-Pick disease type C1

27.10.2016 | Life Sciences

Solid progress in carbon capture

27.10.2016 | Power and Electrical Engineering

More VideoLinks >>>