Prestigious New England Journal of Medicine Publishes Study of CHD2-Adjacent Gene, CHASERR

“Neurodevelopmental Disorder Caused by Deletion of CHASERR, a lncRNA Gene” in the New England Journal of Medicine explains that three children in the world who have been identified with a change in the CHASERR gene produce too much CHD2 protein rather than too little, as is seen in people with changes in the CHD2 gene itself. This discovery may help us understand how to better regulate CHD2. This work was spearheaded by CHASERR father, Brian Broadbent, Co-President of the Coalition to Cure CHD2, along with 22 researchers who contributed to the study. The article caused a lot of buzz in the research community. Congratulation to Brian and team!

Summary of the Paper

CHASERR encodes a human long noncoding RNA (lncRNA) adjacent to CHD2, a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. Here, we report our findings in three unrelated children with a syndromic, early-onset neurodevelopmental disorder, each of whom had a de novo deletion in the CHASERR locus. The children had severe encephalopathy, shared facial dysmorphisms, cortical atrophy, and cerebral hypomyelination — a phenotype that is distinct from the phenotypes of patients with CHD2 haploinsufficiency. We found that the CHASERR deletion results in increased CHD2 protein abundance in patient-derived cell lines and increased expression of the CHD2 transcript in cis. These findings indicate that CHD2 has bidirectional dosage sensitivity in human disease, and we recommend that other lncRNA-encoding genes be evaluated, particularly those upstream of genes associated with mendelian disorders. (Funded by the National Human Genome Research Institute and others.)

Full Article: https://www.nejm.org/doi/full/10.1056/NEJMoa2400718

Video about Brian's search for a cure for Emma: https://youtu.be/Lu3-Rkgb37g

Article from the Broad Insitute: https://www.broadinstitute.org/news/help-his-daughter-living-ultra-rare-disorder-dad-brought-together-squad-genetic-detectives