Anne O'Donnell Luria / en Wed, 23 Oct 24 17:00:00 -0400 To help his daughter living with an ultra-rare disorder, this dad brought together a squad of genetic detectives /news/help-his-daughter-living-ultra-rare-disorder-dad-brought-together-squad-genetic-detectives <span class="field field--name-title field--type-string field--label-hidden"><h1>To help his daughter living with an ultra-rare disorder, this dad brought together a squad of genetic detectives</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Leah Eisenstadt</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-23T17:00:00-04:00" class="datetime">October 23, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>To help his daughter living with an ultra-rare disorder, this dad brought together a squad of genetic detectives</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>The ӳýbent family worked closely with scientists to discover the unique genetic cause of their daughter’s disease, highlighting the need to examine noncoding parts of the genome when diagnosing rare genetic disorders.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Leah Eisenstadt, ӳý Communications </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-23T17:00:00-04:00" title="Wednesday, October 23, 2024 - 17:00" class="datetime">October 23, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Chaserr_news_main_4.jpg?h=33b7f9e8&itok=qxuF4Nte 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Chaserr_news_main_4.jpg?h=33b7f9e8&itok=qxuF4Nte 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Chaserr_news_main_4.jpg?h=33b7f9e8&itok=GK9FUnkc 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"/> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Chaserr_news_main_4.jpg?h=33b7f9e8&itok=SlfFk4j8 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"/> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Chaserr_news_main_4.jpg?h=33b7f9e8&itok=CsgtP13T 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"/> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Chaserr_news_main_4.jpg?h=33b7f9e8&itok=9T6kNI7O 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"/> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/Chaserr_news_main_4.jpg?h=33b7f9e8&itok=9T6kNI7O" alt="Four members of a family pose together for a portrait outdoors between two buildings." title="Four members of a family pose together for a portrait outdoors between two buildings." typeof="foaf:Image" /> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Courtesy of the ӳýbent family </div> <div class="media-caption__description"> Brian and Julia ӳýbent are raising their daughters Claire, top left, and Emma, seated, who is the first person to be diagnosed with a rare genetic disorder caused by the long noncoding RNA CHASERR. The family was instrumental in the research that led to the discovery and her diagnosis. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous" /></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/2666/feed&title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#facebook" /> 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field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/patients-rare-disease-meet-their-matches" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/patients-rare-disease-meet-their-matches"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/longstory/Screen%20Shot%202023-01-10%20at%2012.51.21%20PM.png?itok=RztwnQ3N 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/longstory/Screen%20Shot%202023-01-10%20at%2012.51.21%20PM.png?itok=RztwnQ3N 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/longstory/Screen%20Shot%202023-01-10%20at%2012.51.21%20PM.png?itok=xtkbbHPB 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/longstory/Screen%20Shot%202023-01-10%20at%2012.51.21%20PM.png?itok=xtkbbHPB 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/longstory/Screen%20Shot%202023-01-10%20at%2012.51.21%20PM.png?itok=FaCr6E2d 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/longstory/Screen%20Shot%202023-01-10%20at%2012.51.21%20PM.png?itok=hkes4WGr 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"/> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/longstory/Screen%20Shot%202023-01-10%20at%2012.51.21%20PM.png?itok=hkes4WGr" alt="Matchmaker Exchange" title="Matchmaker Exchange" typeof="foaf:Image" /> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/patients-rare-disease-meet-their-matches" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Patients with rare disease meet their matches</span> </a> </div> </article> </div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related groups</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="https://www.curechd2.org/">Coalition to Cure CHD2</a></div> <div class="field__item"><a href="https://raregenomes.org/">ӳý Rare Genomes Project</a></div> <div class="field__item"><a href="https://odonnell-luria-lab.com/">O'Donnell-Luria Lab</a></div> <div class="field__item"><a href="https://sites.northwestern.edu/carvilllab/">Carvill Lab</a></div> <div class="field__item"><a href="https://www.weizmann.ac.il/dept/irb/igor-ulitsky/">Ulitsky Lab</a></div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Eight-year-old Emma ӳýbent 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. “When Emma’s feeling good she exudes this happiness to her, but she does have immense health challenges,” said her father, Brian ӳýbent, a digital marketing executive in Dallas, Texas, who’s raising Emma and her sister, Claire, with his wife, Julia.</p> <p>For years, the ӳýbents struggled to get an accurate genetic diagnosis for Emma, but they never gave up. They knew that discovering the genetic cause of her disorder would help them find other people like her, help get the condition formally recognized as a new disease, and help them better advocate for research into new treatments.</p> <p>The DNA change underlying Emma’s disorder is now known, thanks to years of work by an international team of scientists and physicians at the ӳý of MIT and Harvard, Northwestern University, University of Nantes, the Weizmann Institute of Science, and the Baylor College of Medicine. The research team also located two more children in France with the same condition, which helped them characterize this new neurodevelopmental disorder.</p> <p>Emma’s parents were instrumental in driving the work forward through a deep partnership they forged with her clinical and scientific teams. In fact, Brian is included as an author on the resulting research paper in the <a target="_blank" href="https://www.nejm.org/doi/full/10.1056/NEJMoa2400718"><em>New England Journal of Medicine</em></a>, acknowledging the family’s essential contributions to the discovery. “We’ve waited a long time for this diagnosis, and it’s given us hope, understanding, and something to press on with,” said Brian. “Now we can start thinking about a cure.”</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--image-text paragraph--view-mode--left"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-pt-image-text-left-right-"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/pt_image_text_left_right_laptop/public/2024-10/Chaserr_Emma.JPG?itok=SM5DcbT8 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="750" height="500"/> <source srcset="/files/styles/pt_image_text_left_right_laptop/public/2024-10/Chaserr_Emma.JPG?itok=SM5DcbT8 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="750" height="500"/> <source srcset="/files/styles/pt_image_text_left_right_laptop/public/2024-10/Chaserr_Emma.JPG?itok=SM5DcbT8 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="750" height="500"/> <source srcset="/files/styles/pt_image_text_left_right_laptop/public/2024-10/Chaserr_Emma.JPG?itok=SM5DcbT8 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="750" height="500"/> <source srcset="/files/styles/pt_image_text_left_right_phone/public/2024-10/Chaserr_Emma.JPG?itok=YjITZ63- 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="500" height="334"/> <source srcset="/files/styles/pt_image_text_left_right_phone/public/2024-10/Chaserr_Emma.JPG?itok=YjITZ63- 1x" media="all and (max-width: 539px)" type="image/jpeg" width="500" height="334"/> <img loading="lazy" width="500" height="334" src="/files/styles/pt_image_text_left_right_phone/public/2024-10/Chaserr_Emma.JPG?itok=YjITZ63-" alt="Photo of girl lying on blankets wearing hospital gown featuring cartoon characters." title="Photo of girl lying on blankets wearing hospital gown featuring cartoon characters." typeof="foaf:Image" /> </picture> <div class="media-caption">Emma ӳýbent is the first person to be diagnosed with a rare genetic disorder caused by changes to the CHASERR lncRNA gene. </div> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Courtesy of the ӳýbent family </div> <div class="media-caption__description"> Emma ӳýbent is the first person to be diagnosed with a rare genetic disorder caused by changes to the CHASERR lncRNA gene. </div> </div> </article> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>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 <em>CHASERR</em>. This gene is unlike a traditional gene, which encodes RNA that translates into a protein capable of performing various functions in the cell. Instead, <em>CHASERR</em> 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.</p> <p>In Emma’s case, having one broken copy of the <em>CHASERR</em> gene leads to an overabundance of the protein encoded by the gene immediately adjacent to <em>CHASERR</em>, called <em>CHD2</em>. This was an unusual finding, as <em>CHD2</em> 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 <em>CHASERR</em>) could also cause a human disease. This redefines <em>CHD2</em> as a “Goldilocks”-like gene — either too much or too little CHD2 disrupts typical human brain development and causes neurodevelopmental disorders.</p> <p>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 <em>CHASERR</em> abundance as a means to treat <em>CHASERR</em>- and <em>CHD2</em>-related disorders.</p> <p>“With three patients, we were able to finally classify this as a new disorder,” said co-senior author <a href="/node/214861">Anne O'Donnell-Luria</a>, co-director of the <a href="https://cmg.broadinstitute.org/">ӳý Center for Mendelian Genomics</a> and an institute member at the ӳý, 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.”</p> <p>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 <a target="_blank" href="https://sites.northwestern.edu/carvilllab/">Gemma Carvill</a>, an assistant professor of neurology, pharmacology, and pediatrics at Northwestern University Feinberg School of Medicine. “With the help of the ӳýbents, 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.”</p> <h2>A diagnostic journey</h2> <p>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.</p> <p>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 <a target="_blank" href="https://raregenomes.org/">Rare Genomes Project</a> (RGP) at the ӳý.</p> <p>The UDN team analyzed all of Emma’s DNA and RNA and zeroed in initially on a variant in one copy of the <em>CHD2</em> 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 ӳýbents realized that Emma had more physical and mental disabilities and less severe seizures than children with disorders caused by <em>CHD2</em> pathogenic variants, so they began to doubt the diagnosis.</p> <p>Meanwhile, the Rare Genomes Project team at the ӳý was still working on Emma’s case. The researchers found the same variant in <em>CHD2</em> 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 <em>CHD2</em> variant was incidental to a much larger genetic change nearby, a deletion of a segment of DNA that overlapped the <em>CHASERR</em> lncRNA gene, which sits next to the <em>CHD2</em> gene in the genome.</p> <p>This was a puzzling finding because at that time neither <em>CHASERR</em>, 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 <em>CHASERR</em>. In early 2019, Ulitsky’s team at Weizmann shared a preliminary report of their discovery that mice with one copy of the <em>CHASERR</em> gene deleted had high levels of CHD2. Further, the Ulitsky lab showed that the excess CHD2 came from the DNA strand that lacked <em>CHASERR</em>. This prompted the ӳý RGP team to look more closely at Emma’s blood, which showed exactly what the Ulitsky lab saw in mice.</p> <p>Because little was known about <em>CHASERR</em>, 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 ӳý 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 <em>CHASERR</em> deficiency as the cause of her illness.</p> <h2>A new ultra-rare disorder</h2> <p>Although the ӳýbents 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.</p> <p>Through <a href="/node/1127321/">Matchmaker Exchange</a>, 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 <em>CHASERR</em> and too much CHD2. The research team eventually located a third, unrelated child in France with similar symptoms and a <em>CHASERR</em> deletion, and now all three families communicate regularly with each other.</p> <p> </p> <article class="media media--type-remote-video media--view-mode-default"> <div class="field field--name-field-media-oembed-video field--type-string field--label-hidden field__item"><iframe src="/media/oembed?url=https%3A//www.youtube.com/watch%3Fv%3D6X8bzEN9d2c&max_width=0&max_height=0&hash=vp71j3n6IG2BHYkz88eAToOYWlbEEMFcD9eaNU8jMq4" width="200" height="113" class="media-oembed-content" loading="eager" title="Emma's match: How connecting patients with ultra-rare disorders can uncover the roots of disease"></iframe> </div> </article> <p><em>In 2020, Emma ӳýbent received a presumptive diagnosis of a new ultra-rare disorder through the ӳý'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. </em></p> <p> </p> <p>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 <em>CHASERR</em>, how it works, and how it might open the door to a new treatment. Brian helps lead the <a target="_blank" href="https://www.curechd2.org/">Coalition to Cure CHD2</a>, a group of parents and experts focused on raising funds for research into CHD2-related conditions.</p> <p>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.</p> <p>In Carvill’s lab at Northwestern, she continues to study Emma’s cells to better understand <em>CHASERR’s</em> 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 <em>CHASERR</em> lncRNA to increase CHD2 levels. “It wasn’t until Emma that this possibility came on everyone’s radar,” said Carvill.</p> <p>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.”</p> <p>For the ӳýbent 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 <em>CHASERRs</em> 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.”</p> <p> </p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>This work was supported in part by the Mass General Brigham Training Program in Precision and Genomic Medicine, National Institutes of Health/NHGRI/NEI/NHLBI/NICHD/NINDS, the European Research Council, the 2025 French Genomic Medicine Initiative, the Nella and Leon Benoziyo Center for Neurological Diseases, CURE Epilepsy/the CURE Taking Flight Award, and the Chan Zuckerberg Initiative Donor-Advised Fund at the Silicon Valley Community Foundation.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Ganesh, VS et al. <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2400718" target="_blank">Neurodevelopmental disorder caused by deletion of CHASERR, a lncRNA gene</a>. <em>New England Journal of Medicine</em>. October 24, 2024. Vol. 391, No. 16.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/medical-and-population-genetics" hreflang="en">Medical and Population Genetics Program</a></div> <div class="field__item"><a href="/broad-tags/rare-disease" hreflang="en">Rare Disease</a></div> <div class="field__item"><a href="/broad-tags/clinical-genomics" hreflang="en">Clinical genomics</a></div> <div class="field__item"><a href="/broad-tags/anne-odonnell-luria" hreflang="en">Anne O'Donnell Luria</a></div> </div> </div> </div> </div> </div> Wed, 23 Oct 2024 21:00:00 +0000 leah@broadinstitute.org 5557616 at Patients with rare disease meet their matches /patients-rare-disease-meet-their-matches <span class="field field--name-title field--type-string field--label-hidden"><h1>To help his daughter living with an ultra-rare disorder, this dad brought together a squad of genetic detectives</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Leah Eisenstadt</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-23T17:00:00-04:00" class="datetime">October 23, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>To help his daughter living with an ultra-rare disorder, this dad brought together a squad of genetic detectives</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>The ӳýbent family worked closely with scientists to discover the unique genetic cause of their daughter’s disease, highlighting the need to examine noncoding parts of the genome when diagnosing rare genetic disorders.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Leah Eisenstadt, ӳý Communications </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-10-23T17:00:00-04:00" title="Wednesday, October 23, 2024 - 17:00" class="datetime">October 23, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Chaserr_news_main_4.jpg?h=33b7f9e8&itok=qxuF4Nte 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Chaserr_news_main_4.jpg?h=33b7f9e8&itok=qxuF4Nte 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Chaserr_news_main_4.jpg?h=33b7f9e8&itok=GK9FUnkc 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"/> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Chaserr_news_main_4.jpg?h=33b7f9e8&itok=SlfFk4j8 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"/> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Chaserr_news_main_4.jpg?h=33b7f9e8&itok=CsgtP13T 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"/> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Chaserr_news_main_4.jpg?h=33b7f9e8&itok=9T6kNI7O 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"/> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/Chaserr_news_main_4.jpg?h=33b7f9e8&itok=9T6kNI7O" alt="Four members of a family pose together for a portrait outdoors between two buildings." title="Four members of a family pose together for a portrait outdoors between two buildings." typeof="foaf:Image" /> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Courtesy of the ӳýbent family </div> <div class="media-caption__description"> Brian and Julia ӳýbent are raising their daughters Claire, top left, and Emma, seated, who is the first person to be diagnosed with a rare genetic disorder caused by the long noncoding RNA CHASERR. The family was instrumental in the research that led to the discovery and her diagnosis. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous" /></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/2666/feed&title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg#facebook" /> 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field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/patients-rare-disease-meet-their-matches" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/patients-rare-disease-meet-their-matches"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/longstory/Screen%20Shot%202023-01-10%20at%2012.51.21%20PM.png?itok=RztwnQ3N 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/longstory/Screen%20Shot%202023-01-10%20at%2012.51.21%20PM.png?itok=RztwnQ3N 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/longstory/Screen%20Shot%202023-01-10%20at%2012.51.21%20PM.png?itok=xtkbbHPB 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/longstory/Screen%20Shot%202023-01-10%20at%2012.51.21%20PM.png?itok=xtkbbHPB 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/longstory/Screen%20Shot%202023-01-10%20at%2012.51.21%20PM.png?itok=FaCr6E2d 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"/> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/longstory/Screen%20Shot%202023-01-10%20at%2012.51.21%20PM.png?itok=hkes4WGr 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"/> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/longstory/Screen%20Shot%202023-01-10%20at%2012.51.21%20PM.png?itok=hkes4WGr" alt="Matchmaker Exchange" title="Matchmaker Exchange" typeof="foaf:Image" /> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/patients-rare-disease-meet-their-matches" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Patients with rare disease meet their matches</span> </a> </div> </article> </div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related groups</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="https://www.curechd2.org/">Coalition to Cure CHD2</a></div> <div class="field__item"><a href="https://raregenomes.org/">ӳý Rare Genomes Project</a></div> <div class="field__item"><a href="https://odonnell-luria-lab.com/">O'Donnell-Luria Lab</a></div> <div class="field__item"><a href="https://sites.northwestern.edu/carvilllab/">Carvill Lab</a></div> <div class="field__item"><a href="https://www.weizmann.ac.il/dept/irb/igor-ulitsky/">Ulitsky Lab</a></div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Eight-year-old Emma ӳýbent 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. “When Emma’s feeling good she exudes this happiness to her, but she does have immense health challenges,” said her father, Brian ӳýbent, a digital marketing executive in Dallas, Texas, who’s raising Emma and her sister, Claire, with his wife, Julia.</p> <p>For years, the ӳýbents struggled to get an accurate genetic diagnosis for Emma, but they never gave up. They knew that discovering the genetic cause of her disorder would help them find other people like her, help get the condition formally recognized as a new disease, and help them better advocate for research into new treatments.</p> <p>The DNA change underlying Emma’s disorder is now known, thanks to years of work by an international team of scientists and physicians at the ӳý of MIT and Harvard, Northwestern University, University of Nantes, the Weizmann Institute of Science, and the Baylor College of Medicine. The research team also located two more children in France with the same condition, which helped them characterize this new neurodevelopmental disorder.</p> <p>Emma’s parents were instrumental in driving the work forward through a deep partnership they forged with her clinical and scientific teams. In fact, Brian is included as an author on the resulting research paper in the <a target="_blank" href="https://www.nejm.org/doi/full/10.1056/NEJMoa2400718"><em>New England Journal of Medicine</em></a>, acknowledging the family’s essential contributions to the discovery. “We’ve waited a long time for this diagnosis, and it’s given us hope, understanding, and something to press on with,” said Brian. “Now we can start thinking about a cure.”</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--image-text paragraph--view-mode--left"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-pt-image-text-left-right-"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/pt_image_text_left_right_laptop/public/2024-10/Chaserr_Emma.JPG?itok=SM5DcbT8 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="750" height="500"/> <source srcset="/files/styles/pt_image_text_left_right_laptop/public/2024-10/Chaserr_Emma.JPG?itok=SM5DcbT8 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="750" height="500"/> <source srcset="/files/styles/pt_image_text_left_right_laptop/public/2024-10/Chaserr_Emma.JPG?itok=SM5DcbT8 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="750" height="500"/> <source srcset="/files/styles/pt_image_text_left_right_laptop/public/2024-10/Chaserr_Emma.JPG?itok=SM5DcbT8 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="750" height="500"/> <source srcset="/files/styles/pt_image_text_left_right_phone/public/2024-10/Chaserr_Emma.JPG?itok=YjITZ63- 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="500" height="334"/> <source srcset="/files/styles/pt_image_text_left_right_phone/public/2024-10/Chaserr_Emma.JPG?itok=YjITZ63- 1x" media="all and (max-width: 539px)" type="image/jpeg" width="500" height="334"/> <img loading="lazy" width="500" height="334" src="/files/styles/pt_image_text_left_right_phone/public/2024-10/Chaserr_Emma.JPG?itok=YjITZ63-" alt="Photo of girl lying on blankets wearing hospital gown featuring cartoon characters." title="Photo of girl lying on blankets wearing hospital gown featuring cartoon characters." typeof="foaf:Image" /> </picture> <div class="media-caption">Emma ӳýbent is the first person to be diagnosed with a rare genetic disorder caused by changes to the CHASERR lncRNA gene. </div> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Courtesy of the ӳýbent family </div> <div class="media-caption__description"> Emma ӳýbent is the first person to be diagnosed with a rare genetic disorder caused by changes to the CHASERR lncRNA gene. </div> </div> </article> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>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 <em>CHASERR</em>. This gene is unlike a traditional gene, which encodes RNA that translates into a protein capable of performing various functions in the cell. Instead, <em>CHASERR</em> 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.</p> <p>In Emma’s case, having one broken copy of the <em>CHASERR</em> gene leads to an overabundance of the protein encoded by the gene immediately adjacent to <em>CHASERR</em>, called <em>CHD2</em>. This was an unusual finding, as <em>CHD2</em> 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 <em>CHASERR</em>) could also cause a human disease. This redefines <em>CHD2</em> as a “Goldilocks”-like gene — either too much or too little CHD2 disrupts typical human brain development and causes neurodevelopmental disorders.</p> <p>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 <em>CHASERR</em> abundance as a means to treat <em>CHASERR</em>- and <em>CHD2</em>-related disorders.</p> <p>“With three patients, we were able to finally classify this as a new disorder,” said co-senior author <a href="/node/214861">Anne O'Donnell-Luria</a>, co-director of the <a href="https://cmg.broadinstitute.org/">ӳý Center for Mendelian Genomics</a> and an institute member at the ӳý, 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.”</p> <p>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 <a target="_blank" href="https://sites.northwestern.edu/carvilllab/">Gemma Carvill</a>, an assistant professor of neurology, pharmacology, and pediatrics at Northwestern University Feinberg School of Medicine. “With the help of the ӳýbents, 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.”</p> <h2>A diagnostic journey</h2> <p>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.</p> <p>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 <a target="_blank" href="https://raregenomes.org/">Rare Genomes Project</a> (RGP) at the ӳý.</p> <p>The UDN team analyzed all of Emma’s DNA and RNA and zeroed in initially on a variant in one copy of the <em>CHD2</em> 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 ӳýbents realized that Emma had more physical and mental disabilities and less severe seizures than children with disorders caused by <em>CHD2</em> pathogenic variants, so they began to doubt the diagnosis.</p> <p>Meanwhile, the Rare Genomes Project team at the ӳý was still working on Emma’s case. The researchers found the same variant in <em>CHD2</em> 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 <em>CHD2</em> variant was incidental to a much larger genetic change nearby, a deletion of a segment of DNA that overlapped the <em>CHASERR</em> lncRNA gene, which sits next to the <em>CHD2</em> gene in the genome.</p> <p>This was a puzzling finding because at that time neither <em>CHASERR</em>, 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 <em>CHASERR</em>. In early 2019, Ulitsky’s team at Weizmann shared a preliminary report of their discovery that mice with one copy of the <em>CHASERR</em> gene deleted had high levels of CHD2. Further, the Ulitsky lab showed that the excess CHD2 came from the DNA strand that lacked <em>CHASERR</em>. This prompted the ӳý RGP team to look more closely at Emma’s blood, which showed exactly what the Ulitsky lab saw in mice.</p> <p>Because little was known about <em>CHASERR</em>, 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 ӳý 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 <em>CHASERR</em> deficiency as the cause of her illness.</p> <h2>A new ultra-rare disorder</h2> <p>Although the ӳýbents 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.</p> <p>Through <a href="/node/1127321/">Matchmaker Exchange</a>, 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 <em>CHASERR</em> and too much CHD2. The research team eventually located a third, unrelated child in France with similar symptoms and a <em>CHASERR</em> deletion, and now all three families communicate regularly with each other.</p> <p> </p> <article class="media media--type-remote-video media--view-mode-default"> <div class="field field--name-field-media-oembed-video field--type-string field--label-hidden field__item"><iframe src="/media/oembed?url=https%3A//www.youtube.com/watch%3Fv%3D6X8bzEN9d2c&max_width=0&max_height=0&hash=vp71j3n6IG2BHYkz88eAToOYWlbEEMFcD9eaNU8jMq4" width="200" height="113" class="media-oembed-content" loading="eager" title="Emma's match: How connecting patients with ultra-rare disorders can uncover the roots of disease"></iframe> </div> </article> <p><em>In 2020, Emma ӳýbent received a presumptive diagnosis of a new ultra-rare disorder through the ӳý'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. </em></p> <p> </p> <p>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 <em>CHASERR</em>, how it works, and how it might open the door to a new treatment. Brian helps lead the <a target="_blank" href="https://www.curechd2.org/">Coalition to Cure CHD2</a>, a group of parents and experts focused on raising funds for research into CHD2-related conditions.</p> <p>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.</p> <p>In Carvill’s lab at Northwestern, she continues to study Emma’s cells to better understand <em>CHASERR’s</em> 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 <em>CHASERR</em> lncRNA to increase CHD2 levels. “It wasn’t until Emma that this possibility came on everyone’s radar,” said Carvill.</p> <p>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.”</p> <p>For the ӳýbent 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 <em>CHASERRs</em> 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.”</p> <p> </p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>This work was supported in part by the Mass General Brigham Training Program in Precision and Genomic Medicine, National Institutes of Health/NHGRI/NEI/NHLBI/NICHD/NINDS, the European Research Council, the 2025 French Genomic Medicine Initiative, the Nella and Leon Benoziyo Center for Neurological Diseases, CURE Epilepsy/the CURE Taking Flight Award, and the Chan Zuckerberg Initiative Donor-Advised Fund at the Silicon Valley Community Foundation.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Ganesh, VS et al. <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2400718" target="_blank">Neurodevelopmental disorder caused by deletion of CHASERR, a lncRNA gene</a>. <em>New England Journal of Medicine</em>. October 24, 2024. Vol. 391, No. 16.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/medical-and-population-genetics" hreflang="en">Medical and Population Genetics Program</a></div> <div class="field__item"><a href="/broad-tags/rare-disease" hreflang="en">Rare Disease</a></div> <div class="field__item"><a href="/broad-tags/clinical-genomics" hreflang="en">Clinical genomics</a></div> <div class="field__item"><a href="/broad-tags/anne-odonnell-luria" hreflang="en">Anne O'Donnell Luria</a></div> </div> </div> </div> </div> </div> Mon, 28 Feb 2022 10:00:16 +0000 leah@broadinstitute.org 1127321 at