To help his daughter living with an ultra-rare disorder, this dad brought together a squad of genetic detectives

The research team found that Emma and the two other children from unrelated families each lack a chunk of DNA in one copy of a gene called CHASERR. This gene is unlike a traditional gene, which encodes RNA that translates into a protein capable of performing various functions in the cell. Instead, CHASERR is a long noncoding RNA (lncRNA) that has a functional role in and of itself, without being translated into a protein. Since the discovery of lncRNAs 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.

In Emma’s case, having one broken copy of the CHASERR gene leads to an overabundance of the protein encoded by the gene immediately adjacent to CHASERR, called CHD2. This was an unusual finding, as CHD2 had been associated with brain development disorders, but only due to lower CHD2 abundance. Emma and the two other children identified in this study provided the genetic evidence that an excess of CHD2 (due to loss of a copy of CHASERR) could also cause a human disease. This redefines CHD2 as a “Goldilocks”-like gene — either too much or too little CHD2 disrupts typical human brain development and causes neurodevelopmental disorders.

This is the first human disease caused by loss of one copy of a lncRNA gene. The work highlights the importance of examining the often-ignored noncoding parts of the genome when diagnosing rare genetic disorders, and also points to possible future genetic therapies that fine-tune CHASERR abundance as a means to treat CHASERR- and CHD2-related disorders.

“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 Broad Center for Mendelian Genomics and an institute member at the Broad, clinical genetics physician at Boston Children’s Hospital, and an assistant professor of pediatrics at Harvard Medical School. “The unique mechanism we’ve identified here suggests that there are more lncRNAs underlying rare genetic disorders still to be found, which could potentially bring answers for some of the many families still waiting for a rare disease diagnosis.”

The study also shows the valuable role families can have in 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, an 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.”

A diagnostic journey

Emma’s challenges began immediately at birth, leading her to spend the first weeks of her life in intensive care. There, Julia recalled, an experienced doctor informed her and Brian that it appeared Emma was a unique case, and that it wouldn’t be easy or quick to get to the roots of it. “They told us that she likely had an extremely rare disorder, and that the more eyes we could get on her, the better,” said Julia.

Imaging tests soon revealed concerning abnormalities involving the white matter of Emma’s brain that hinted at a genetic disorder. After undergoing a battery of clinical tests for white matter disorders including an analysis of the protein-coding parts of her genome and meeting with experts at the Children’s Hospital of Philadelphia (CHOP), Emma’s family still had no leads for the genetic cause of her disorder. The team at CHOP suggested that answers could be discovered by sequencing her entire genome, so Brian and Julia enrolled Emma in the National Institutes of Health Undiagnosed Diseases Network (UDN) and the Rare Genomes Project (RGP) at the Broad Institute.

The UDN team analyzed all of Emma’s DNA and RNA and zeroed in initially on a variant in one copy of the CHD2 gene, which was known to cause a severe form of epilepsy. They also recommended the family connect with a scientific expert in CHD2 who could study the protein in Emma’s cells. The family quickly contacted Carvill at Northwestern University after finding her research on CHD2, including her work to establish it as a genetic cause of epilepsy. Emma’s parents were also able to connect with other families affected by CHD2-related disorders through a Facebook group. There, the Broadbents realized that Emma had more physical and mental disabilities and less severe seizures than children with disorders caused by CHD2 pathogenic variants, so they began to doubt the diagnosis.

Meanwhile, the Rare Genomes Project team at the Broad was still working on Emma’s case. The researchers found the same variant in CHD2 as the UDN had uncovered, but then decided to see if there were any other changes nearby in the genome. By taking a wider view, they observed that Emma’s CHD2 variant was incidental to a much larger genetic change nearby, a deletion of a segment of DNA that overlapped the CHASERR lncRNA gene, which sits next to the CHD2 gene in the genome.

This was a puzzling finding because at that time neither CHASERR, nor any other lncRNA gene, had been definitively linked to a human disease. An important clue came from study co-author and lncRNA expert Igor Ulitsky of the Weizmann Institute of Science in Israel, whose own postdoctoral research at the Whitehead Institute of MIT had led to the discovery of CHASERR. In early 2019, Ulitsky’s team at Weizmann shared a preliminary report of their discovery that mice with one copy of the CHASERR gene deleted had high levels of CHD2. Further, the Ulitsky lab showed that the excess CHD2 came from the DNA strand that lacked CHASERR. This prompted the Broad RGP team to look more closely at Emma’s blood, which showed exactly what the Ulitsky lab saw in mice.

Because little was known about CHASERR, additional studies were required to confirm that the results seen in mice aligned with Emma’s condition. Brian connected Carvill to the UDN team, who already had a sample of Emma’s skin cells in the lab at Baylor. Carvill obtained some of these cells and, in her lab at Northwestern, she began growing stem cells generated from them. In collaboration with the Broad RGP team, Carvill found that Emma’s cells were churning out too much CHD2, unlike other children with CHD2 disorders, who have too little. Together with the findings of too much CHD2 in Emma’s blood, this evidence strongly implicated CHASERR deficiency as the cause of her illness.

A new ultra-rare disorder

Although the Broadbents now knew the genetic cause of Emma’s disorder, she was still the only patient in the world to be diagnosed with it. To be sure of her diagnosis, they wanted to find more patients like her.

Through Matchmaker Exchange, a rare disease research network, the team found a patient in France with similar symptoms and brain and genetic changes as Emma. In that child’s cells, Carvill saw the same pattern they’d seen in Emma’s — too little CHASERR and too much CHD2. The research team eventually located a third, unrelated child in France with similar symptoms and a CHASERR deletion, and now all three families communicate regularly with each other.

In 2020, Emma Broadbent received a presumptive diagnosis of a new ultra-rare disorder through the Broad's Rare Genomes Project. After a year in the Matchmaker Exchange rare disease research network, her case was matched with another patient overseas, only the second to be diagnosed with the new CHASERR-related illness. 

With a confirmed genetic diagnosis and knowing that there are three people with this disorder, with likely more yet to be diagnosed, Brian and Julia are now pushing for more research into CHASERR, how it works, and how it might open the door to a new treatment. Brian helps lead the Coalition to Cure CHD2, a group of parents and experts focused on raising funds for research into CHD2-related conditions.

The scientists credit Brian and Julia for driving this years-long research collaboration that was so crucial for finding answers. Brian brought researchers together and attended the scientific team’s monthly meetings. “He wasn't just there to get updates,” said O’Donnell-Luria. “He was developing hypotheses, asking questions, and pushing us to think deeper. He was a huge driver in the scientific process on this.” Carvill recalled, “Brian was really the one that made sure that we all got in the same room and collaborated.” He even arranged a virtual meeting with one of the patient families in France that yielded key clinical details that the scientists hadn’t been able to obtain. “Even though it was over Zoom and we needed a translator, it was really moving to finally meet another family going through the same struggles,” said Julia.

In Carvill’s lab at Northwestern, she continues to study Emma’s cells to better understand CHASERR’s impact and she is developing cellular models that could help evaluate future treatments. The discovery has also opened the door to one day possibly treating people who have too little CHD2 by dampening the CHASERR lncRNA to increase CHD2 levels. “It wasn’t until Emma that this possibility came on everyone’s radar,” said Carvill.

Now, the researchers are encouraging their colleagues to examine noncoding genetic elements like lncRNAs when trying to diagnose patients with rare diseases. “This work highlights a regulatory mechanism that’s baked into the genome, for genes that need to be precisely expressed,” said study co-first author Vijay Ganesh, a senior postdoctoral fellow in the O’Donnell-Luria lab and a neurologist at Brigham and Women’s Hospital. “They’re clearly quite active, but they remain hidden to us without the right data and analysis, so there’s a lot of room for progress.”

For the Broadbent family, their journey isn’t over, but this research finding is an important milestone. “Emma might not be able to walk or talk, but she has changed the world by helping unlock a whole new class of genetic disease,” said Brian. “We know there are more CHASERRs out there. Julia and I want to push this forward as far as possible for Emma and to create a roadmap for future discoveries like hers.”