Genetic Detectives Diagnose Child With Ultra-Rare Disorder

Work highlights need to examine noncoding parts of genome in rare diseases

By LEAH EISENSTADT | Broad Institute Research

2 min read

Photo of a young girl lying on blankets wearing a hospital gown featuring cartoon characters.

Emma Broadbent is the first person diagnosed with a rare genetic disorder caused by changes to the CHASERR gene. Image: Courtesy of the Broadbent family

Eight-year-old Emma Broadbent of Dallas, Texas, lives with an ultra-rare disorder that has caused severe delays in brain development, led to hundreds of days in the hospital, and left her functioning as a 3- to 5-month-old.

For years, her parents struggled to obtain an accurate genetic diagnosis. They knew doing so would help them get the condition formally recognized as a new disease, find other people like Emma, and better advocate for research into new treatments.

The DNA change underlying Emma’s disorder has now been revealed, thanks to years of work by an international team co-led by Harvard Medical School physician-scientists.

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The team reported Oct. 23 in the New England Journal of Medicine that Emma and two other children from unrelated families in France each lack a chunk of DNA in one copy of a gene called CHASERR.

“With three patients, we were able to finally classify this as a new disorder,” said co-senior author Anne O’Donnell-Luria, co-director of the Center for Mendelian Genomics at the Broad Institute of Harvard and MIT, assistant professor of pediatrics at HMS, and clinical genetics physician at Boston Children’s Hospital.

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CHASERR is unlike traditional genes, which are used as blueprints for making messenger RNA and proteins that perform various functions in cells. Instead, CHASERR codes for a long noncoding RNA, or lncRNA, that has a functional role itself, without being translated into a protein.

The researchers found that having one broken copy of the CHASERR gene leads to an overabundance of the protein encoded by the gene next to CHASERR, called CHD2. CHD2 had previously been associated with neurodevelopmental disorders, but because of low, not high, CHD2 protein levels. The new work shows that excess CHD2 can also disrupt brain development.

Emma’s disorder is the first known to be caused by loss of one copy of a lncRNA gene. Since lncRNAs were discovered in the 1990s, several thousand have been found throughout the human genome, yet very little is known about their function or their significance to human disease.

The work highlights the importance of examining the often-ignored noncoding parts of the genome when diagnosing rare genetic disorders, the study authors said.

“The unique mechanism we’ve identified here suggests that there are more lncRNAs underlying rare genetic disorders still to be found, which could bring answers for some of the many families still waiting for a rare disease diagnosis,” said O’Donnell-Luria.

The findings also point to possible future genetic therapies that fine-tune CHASERR abundance to treat diseases involving CHASERR and CHD2.

In addition, the study shows the value of collaboration among families, scientists, and clinicians in advancing rare disease research.

“This discovery speaks to the power of parents who won’t take ‘no’ for an answer,” said co-senior author Gemma Carvill, assistant professor of neurology, pharmacology, and pediatrics at Northwestern University Feinberg School of Medicine. “With the help of the Broadbents, multiple institutions came together to end one rare diagnostic journey and begin another — to learn how this information can one day help patients and design new therapies.”

“We’ve waited a long time for this diagnosis, and it’s given us hope, understanding, and something to press on with,” said Emma’s father, Brian Broadbent, who is a co-author of the study and, together with his wife Julia, was instrumental in driving this research effort. “Now we can start thinking about a cure.”

Adapted from a Broad Institute news story.