Network and gene tools help quickly identify new, rare genetic disease

September 29, 2016
DNA
Credit: NIH

The first patient was a mystery. Arriving at Duke six years ago at the age of three, the youngster had mild developmental delays and physical characteristics that included a large body and large head circumference. A genetic analysis showed mutation of a specific gene, known as ASXL2, which had never been singled out as causing disease.

The youngster's doctor, Vandana Shashi, a professor of pediatrics for the Division of Medical Genetics at Duke University School of Medicine, told his parents their son likely had a rare and yet-unidentified disease. And she promised to remain vigilant if any other cases popped up in the medical literature that might provide additional clues.

After none turned up, Shashi set out to see if the mystery case might be solved, instead, using the tools of the Undiagnosed Diseases Network (UDN) at the National Institutes of Health, which links Duke and six other medical teaching sites around the country. The participating centers pool information and innovations about diseases that are so rare they often stump the broader medical community.

Within just six weeks—connected to other UDN research labs and an international database of genes and disease characteristics called GeneMatcher—Shashi had a remarkable trove: Five additional children, all with the same physical features and the ASXL2 gene mutation.

"We can now definitively say this is a newly identified disease," Shashi said. "With just one case, we could not say the gene mutation was the underlying cause. But with six cases, all with the same ASXL2 mutation, it is definitive."

Shashi and colleagues from other UDN institutions published their findings online Sept. 29 in the American Journal of Human Genetics.

The new disease, which still has no name, does have similarities to two other arising from related genes. A condition called Bohring-Opitz syndrome is the result of a mutation of the ASXL1 gene, while Bainbridge-Ropers syndrome is caused by a flaw in the ASXL3 gene. Both conditions are also rare, and result in similar, but more severe impairments.

It's unknown how the ASXL2 genetic mutation arises, but Shashi said identifying the root cause of the children's condition is a first step, and could help drive new therapies and treatment approaches.

The immediate benefit is to the families of the children, who now have an answer to their most basic question.

"It has been wonderful to be connected to other families who share this genetic condition," said Teresa Locklear, whose son, Issac, was the first patient to present with the mutation at Duke. "When we started, we hoped we would find other families with children who were older than Isaac, to provide a sort of roadmap for what to expect. But it turns out, Isaac is the oldest and we are the ones sharing our experiences with parents of younger children, and that's been so rewarding."

Study co-author Loren del Mar Peña, assistant professor in the Department of Pediatrics at Duke, said reducing isolation for families with a rare disease has tremendous impact.

"These families feel truly alone when their child clearly has a disorder, and yet there is no name for it, and no community of people they can relate to with shared experiences," Peña said. "This will help them be able to connect with others and compare notes. That's a huge deal – to know you aren't the only one and there a five other children out there."

Explore further: Mutations in ASXL3 cause problems similar to Bohring-Opitz syndrome

Related Stories

Mutations in ASXL3 cause problems similar to Bohring-Opitz syndrome

February 4, 2013
Mutations which affect the gene ASXL3 cause a novel syndrome similar to Bohring-Opitz syndrome, finds a study published in BioMed Central's open access journal Genome Medicine. This molecular definition distinguishes these ...

Gene sleuths use social media to help map a new disease

March 21, 2014
(Medical Xpress)—By combining the modern tools of gene-sequencing and social media, a team of researchers has confirmed the identification of a new genetic disorder that causes severe impairments in children.

Unexplained developmental disorder linked to gene involved in essential cellular processes

August 18, 2016
A neurodevelopmental disorder for which there was no known cause has been linked to SON, a gene that is involved in essential mechanisms a cell uses to translate DNA into protein, as well as in DNA replication and cell division. ...

New genetic syndrome tied to defects in protein transport

July 28, 2016
An international team of researchers has discovered the mutation responsible for a rare, newly identified genetic disorder that causes craniofacial abnormalities and developmental delays. The mutation disrupts normal protein ...

Rare and common genetic variants combine to cause skull-fusion disorder

September 8, 2016
During the first year of life, the human brain doubles in size, and continues growing through adolescence. But sometimes, the loosely connected plates of a baby's skull fuse too early, a disorder known as craniosynostosis. ...

Sequencing works in clinical setting to help -- finally -- get a diagnosis

May 8, 2012
Advanced high-speed gene-sequencing has been used in the clinical setting to find diagnoses for seven children out of a dozen who were experiencing developmental delays and congenital abnormalities for mysterious reasons.

Recommended for you

An architect gene is involved in the assimilation of breast milk

October 17, 2017
A family of "architect" genes called Hox coordinates the formation of organs and limbs during embryonic life. Geneticists from the University of Geneva (UNIGE) and the Swiss Federal Institute of Technology in Lausanne (EPFL), ...

Study identifies genes responsible for diversity of human skin colors

October 12, 2017
Human populations feature a broad palette of skin tones. But until now, few genes have been shown to contribute to normal variation in skin color, and these had primarily been discovered through studies of European populations.

Genes critical for hearing identified

October 12, 2017
Fifty-two previously unidentified genes that are critical for hearing have been found by testing over 3,000 mouse genes. The newly discovered genes will provide insights into the causes of hearing loss in humans, say scientists ...

Team completes atlas of human DNA differences that influence gene expression

October 11, 2017
Researchers funded by the National Institutes of Health (NIH) have completed a detailed atlas documenting the stretches of human DNA that influence gene expression - a key way in which a person's genome gives rise to an observable ...

Genetic advance for male birth control

October 10, 2017
When it comes to birth control, many males turn to two options: condoms or vasectomies. While the two choices are effective, both methods merely focus on blocking the transportation of sperm.

Researchers uncover new congenital heart disease genes

October 9, 2017
Approximately one in every 100 babies is born with congenital heart disease (CHD), and CHD remains the leading cause of mortality from birth defects. Although advancements in surgery and care have improved rates of survival ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.