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!
Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University
How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung
Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.
Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....
Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.
The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....
An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.
We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...
Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.
Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...
An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...
24.05.2017 | Event News
23.05.2017 | Event News
22.05.2017 | Event News
26.05.2017 | Life Sciences
26.05.2017 | Life Sciences
26.05.2017 | Physics and Astronomy