Genetic Basis for Congenital Heart Disease: Revisited: A Scientific Statement From the American Heart Association

First Cases Of New Neurology Syndrome Identified

Three unrelated children with deletions of CHASERR, a long non-coding RNA, had a severe neurological disorder not previously identified.

The CHASERR deletions and the resulting increased expression of a nearby coding gene -- CHD2 -- caused an unnamed, early-onset syndrome of severe encephalopathy with cortical atrophy, cerebral hypomyelination, and facial dysmorphism, reported Gemma Carvill, PhD, of Northwestern University Feinberg School of Medicine in Chicago, and co-authors in a New England Journal of Medicine brief report.

The three children with CHASERR deletions had greater impairment than even the most severely affected persons with CHD2 haploinsufficiency, the researchers said. This presents a "Goldilocks" problem because too little CHD2 is bad -- and too much also is bad, they noted.

Emma Broadbent is the patient in whom Carvill and colleagues first identified the CHASERR deletion that was not present in either of her parents. She is wheelchair-bound, non-verbal, uses a feeding tube, and has severe intellectual delays.

"Because of Emma's very profound neurological presentation, her physicians suspected there was a genetic cause," Carvill told MedPage Today. "Typically, in patients who present like Emma, our first genetic test would be to do an exome, looking for a de novo mutation. Because her physicians were pretty convinced she had something genetic, they did a follow-up genome -- not just looking at the exome, but the overwhelming majority of the genome -- sequencing the 1% coding, as well as the 99% non-coding."

Only 1% of the human genome codes for proteins. Long non-coding RNAs don't make proteins but are needed to regulate gene expression.

CHASERR lies immediately upstream of CHD2, a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. The deletion of CHASERR resulted in a corresponding increase in CHD2 transcription and protein abundance that were specifically due to the upregulation of the CHD2 allele, Carvill and colleagues wrote.

"With one patient, it was very difficult to make any sweeping conclusions," Carvill said. "We spent the last 3 or 4 years looking for more patients." They found them through word-of-mouth, including one patient through a group of French researchers they met at a poster presentation during a conference.

"With three patients, we were able to finally classify this as a new disorder," noted co-author Anne O'Donnell-Luria, MD, PhD, of Boston Children's Hospital. The mechanism in this study suggests there are more long non-coding RNAs underlying rare genetic disorders still to be found, she added.

"We really should be looking at the non-coding genome, the other 3.6 billion base pairs in the genome," Carvill said. "We need to start building new tools to understand what the other 99% of the genome actually does, and which parts are important for human disease."

The present study suggests that CHASERR acts like a brake to control how much or how little CHD2 protein is produced, Carvill observed.

"For the longest time, we didn't know what CHASERR did," she said. "There was some evidence in mice that it affected how much CHD2 protein was made but we didn't know if the same thing happened in humans."

About 40% of long non-coding RNAs that have been identified are expressed in the brain, and there's some support that at least a few of them contribute to neuronal disease, noted Ling-Ling Chen, PhD, of the Chinese Academy of Sciences in Shanghai, in an accompanying essay. "For example, BACE1-AS was shown to facilitate amyloid-beta plaque formation, and its expression is elevated in persons with Alzheimer's disease," she wrote.

Researchers have reported dysregulated long non-coding RNAs in schizophrenia, autism spectrum disorder, and Parkinson's disease, she pointed out.

"However, because of the poor conservation of long non-coding RNAs across species -- only approximately 20% of human long non-coding RNAs have homologues in mice -- evaluating their pathophysiological roles in vivo has been challenging," Chen noted.

Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer's, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson's, ALS, concussion, CTE, sleep, pain, and more. Follow

Disclosures

This study was supported by the National Human Genome Research Institute, the Chan Zuckerberg Initiative Donor-Advised Fund at the Silicon Valley Community Foundation the 2025 French Genomic Medicine Initiative, the National Institute of Neurological Disorders and Stroke, and the CURE Taking Flight Award.

Carvill reported relationships with BridgeBio, CURE Epilepsy, NIH, and Northwestern University.

Co-authors reported relationships with academic institutions, non-profit groups, and industry.

Chen had no disclosures.

Primary Source

New England Journal of Medicine

Source Reference: Ganesh VS, et al "Neurodevelopmental disorder caused by deletion of CHASERR, a lncRNA gene" N Engl J Med 2024; DOI: 10.1056/NEJMoa2400718.

Secondary Source

New England Journal of Medicine

Source Reference: Chen L "Linking a neurodevelopmental disorder with a lncRNA deletion" N Engl J Med 2024; DOI: 10.1056/NEJMe2411291

Please enable JavaScript to view the comments

Mack Shearn: Official Hornet

By Chelsea Boling

Football is a way of life in the Shearn household. For Hayden, Graham, and Mack Shearn, the sport isn't just a passion—it's a family legacy. As third-generation Hornets, football pulses through their veins. Hayden, wearing #1, is a senior while his younger brother Graham, #2, is a sophomore. And then there's Mack, their 8-year-old little brother, who may not be able to physically suit up, but holds a title that's just as important—Hornet Foot ball's number one fan.

Recently, Mack had the opportunity of a lifetime, thanks to Head Coach Bobby Eu banks. Mack was invited to serve as an honorary team captain at a Hornet Football game, joining his brothers and his father, Kirk Shearn, who serves as an assistant coach. As Mack proudly walked onto the field hand in hand with Hayden and Graham, alongside his dad, the crowd felt the magnitude of the moment.

What made this even more special is what Mack's mom shared with me. "Mack will physically and mentally never be able to play sports, so it meant the world to us that he could experience being on the field with both of his brothers before Hayden graduates." Mack was born with 3p Deletion Syndrome, a rare genetic disorder where part of the short arm of chromosome 3 is missing. This condition brings with it significant challenges, including intellectual disabilities, developmental delays, and physical symptoms such as con genital heart defects, seizure disorders, and low muscle tone.

Despite these hurdles, Mack's enthusiasm for the game remains unparalleled. His love for the Friday night lights rivals that of any athlete, and his presence in the stands is a source of pride for the Shearn family and the entire Hornet community. Mack may never don a helmet, but his role as the team's number one fan is vital, reminding us all how important fans are to the game. After all, what would sports be without the roar of the crowd? That exhilarating moment when a last-second touchdown is scored wouldn't be the same without the thunderous cheers of those watching.

We all have a part to play—on the field and off. While some roles may seem more import ant, they are all essential to the team's spirit. For Mack, his position in the Hornet family is just as meaningful as his brothers' on the field. His journey and his joy remind us of the strength in this community and the power of inclusion.

The Shearn family would like to extend their deepest gratitude to Coach Bobby Eubanks and the entire coaching staff for making this unforgettable moment possible, showing that true team spirit goes far beyond the game.

Education Transport Fight Left Me 'angry'

A woman has said the fight to get transport funding for her brother who has special educational needs had left her "angry and frustrated".

Ben Miller,19, has Smith-Magenis syndrome and has been entitled to transport to get him to a place of education in Leeds.

However, his move to assisted living accommodation in Wakefield led to confusion over which council should cover the cost.

Leeds City Council said it has have revisited his application and confirmed Mr Milller will receive transport assistance they are also reimbursing him for the cost of his travel to and from college since the start of term.

Mr Miller was born in Leeds and has chromosome 17 deletion which is also known as Smith–Magenis syndrome.

His sister Vicky said it means he has behavioural issues, sleeping and eating issues, global development delay which impacts his speech and physical health.

She said he was "funny and witty and a cracking lad".

He had lived with his mother and attended a specialist school in Leeds, with the council paying for taxis for him.

Ben Miller has 'Smith–Magenis syndrome' and his family said there had been confusion over which council should pay for his transport to college. [BBC]

Mr Miller's mother was taken to hospital for a number of months last year and his sisters secured him a place in assisted living accommodation in Wakefield.

Leeds City Council continued covering the cost of taxi's from Wakefield to Mr Miller school until July when he moved to college.

However, his transport was stopped when he went to college due to confusion over his main home address.

Ms Miller said it has had a huge impact on her brother's quality of life.

She said he needs a lot of care and they had been spending all his weekly Personal Independent Payments on taxis to college.

She said it meant he was unable to go out and "experience life".

"All his money is being used for taxis due to no transport.

"He wants to go out and go to the united shop and buy united shirts, go bowling, go to pub on Thursday for a quiz night and learn those vital life skills but that has had to stop so he can go to college."

Mr Miller said it had left them feeling "angry and frustrated".

"So many families are facing or going to face many difficulties when it comes to their young adult receiving much needed transport to access education".

A spokesperson for Leeds City Council said ater the case was brought to tehir attention they checked their records and discovered the application for transport assistance gave a Wakefield home adderss but did not mention is was assisted accommodation.

"The application was therefore assessed on the basis that Ben was a Wakefield resident and, as a result, his request for assistance was turned down. Our decision was not queried or appealed by Ben and his family.

"As we have been informed that Ben's family home is in fact in Leeds, we have revisited his application and are pleased to confirm that he will now receive transport assistance."

Listen to highlights from West Yorkshire on BBC Sounds, catch up with the latest episode of Look North or tell us a story you think we should be covering here.

View comments

---