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A genetic discovery provides answers for families with a multisystem disease

September 16, 2014
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Researchers have discovered mutations in a gene called NOTCH1 that causes Adams-Oliver syndrome (AOS), a rare and potentially fatal genetic disorder.

“These findings will allow clinicians to confirm the diagnosis of AOS more easily, as well as diagnose it in children who do not have all the usual symptoms,” says Dr. Millan Patel. “Our results will also open the door to developing therapies for some of the complications of the condition, which can be lethal in infancy or early childhood.”

Dr. Patel is the senior author of the study that was recently published in the American Journal of Human Genetics. Dr. Patel is a CFRI Associate Clinician Scientist, Medical Geneticist at BC Children’s Hospital and BC Women’s Hospital & Health Centre, and a Clinical Assistant Professor with the UBC Department of Medical Genetics. Dr. Anna Lehman, a study co-author, is a CFRI Investigator, Clinical Geneticist with the Provincial Medical Genetics Programme, and Assistant Professor with the UBC Department of Medical Genetics.

AOS is rare developmental disorder that affects an estimated one in every 225,000 people. Babies born with AOS often have a wide-range of serious birth defects. Many have open patches of missing hair or skin on the scalp. Almost all are born with deformed hands, feet or limbs, heart defects and/or vascular problems.

Dr. Patel, Dr. Lehman and their colleagues at two US institutions sequenced the genomes of 12 families who have AOS. They found that five of these families had mutations in a gene called NOTCH1, a gene that was previously not linked to AOS. Because these NOTCH1 mutations were not found in genomes from close to 10,000 other people, scientists are confident they’ve discovered a new cause of AOS.   

Scientists had previously identified mutations in four genes that can cause AOS; however, these mutations only explained AOS in a few families. Most patients with AOS don’t have changes in any of these genes.

NOTCH1 is the most common altered gene that has been linked to AOS to date. For patients living with unexplained symptoms, this discovery and its potential to improve testing for AOS, could speed diagnosis, prevent unnecessary testing, and help children get the care they need sooner.

“Many physicians aren’t familiar with this condition because it is so rare,” says Dr. Patel. “In many cases, children with AOS finally receive a correct diagnosis after their parents read about the disease on the internet.”

This discovery could also help doctors identify patients at risk for some of the most serious complications of AOS. Four of the five families in the study with the NOTCH1 mutation suffered from heart and vascular defects. The researchers say this isn’t a coincidence because other mutations in NOTCH1 have been tied to heart and vascular problems in both human and mice.

Although AOS is rare, these findings also contribute more broadly to our understanding of how babies develop. Researchers at the BC Cancer Agency are studying the key role NOTCH1 plays in the formation of the cardiovascular system in mice. “Our research builds on their results and extends the implications of their findings to humans,” says Dr. Patel. “We now know more about the function of NOTCH1 in the development of our hearts and blood vessels.”

Dr. Patel, Dr. Lehman and their colleagues are now undertaking further research to better understand how NOTCH1 mutations cause heart and vascular defects, with the aim of finding more effective therapies for these children. These scientists may also eventually contribute to new treatments for other conditions caused by NOTCH1 mutations such as life threatening heart valve defects.  

Scientists will also continue to mine AOS genome data for other mutations that cause the disease. “As the majority of people with AOS still don’t have a known genetic cause for their condition, this is one step of a long process,” says Dr. Patel.

Read more:

Stittrich AB, Lehman A, Patel MS, et al, “Mutations in NOTCH1 Cause Adams-Oliver Syndrome,” in American Journal of Human Genetics, August 12, 2014.