Excited to report our study in @NEJM on the discovery of deletions in a long noncoding RNA gene 🧬 (𝘊𝘏𝘈𝘚𝘌𝘙𝘙) as the cause of a newly defined human neurodevelopmental disorder 🧠. 🧵1/10

RT @maggiet_arriaga: What if one variant can cause splicing outliers transcriptome-wide? Our preprint shows how examining transcriptome-wid…

RT @doctorveera: Spliceopathies are a group of rare diseases caused by inborn errors in RNA splicing mechanisms. The causative mutations co…

RT @RM2Akiki: Check out our latest publication in Science describing a novel molecular mechanism involved in emotional experience dependent…

RT @HeidiRehm: We are delighted to announce this year's call for applications for the NHGRI-funded MGB T32 Postdoctoral Training Program in…

RT @TalkowskiLab: Congrats @Philip_M_Boone on receiving the ASHG Award for Outstanding Early Career Publication! He's a clinical geneticis…

Thank you to Prof. Ling-Ling Chen and the illustrators and editors at @NEJM for nicely summarizing our study and its implications. 🙏

This work would not be possible without collaboration with the families (@chaserrdad), federated genomic data sharing networks (@MatchMExchange), experts in 𝘊𝘏𝘋2 (@CarvillLab) and 𝘊𝘏𝘈𝘚𝘌𝘙𝘙 (@IgorUlitsky), @broadinstitute, @dgmacarthur, and my mentor @AnneOtation. 10/10

Our data suggest that the mechanism of these 𝘊𝘏𝘈𝘚𝘌𝘙𝘙 deletions is Alu-Alu mediated DNA recombination, so we anticipate that additional cases can likely be uncovered by reanalysis of genome sequencing in large cohorts of undiagnosed neurodevelopmental disorders. 8/10

Serendipitously, @IgorUlitsky, a lncRNA expert at @WeizmannScience, recently published a study showing that a deletion of one copy of Chaserr resulted in a severe developmental disease in mice, via increased abundance of Chd2, matching our findings. 7/10

Loss-of-function variants in 𝘊𝘏𝘋2 were previously discovered (by @CarvillLab and @hcmefford) to cause a different neurodevelopmental disorder (with normal brain MRI, more prominent epilepsy, and less severe developmental impairments than the individuals in our study). 5/10

We collaborated with @CarvillLab at @NorthwesternMed who generated induced pluripotent stem cells from these individuals with deletions of 𝘊𝘏𝘈𝘚𝘌𝘙𝘙. The iPSCs showed an increased abundance of 𝘊𝘏𝘋2, a protein-coding gene immediately adjacent to 𝘊𝘏𝘈𝘚𝘌𝘙𝘙. 4/10

Together with researchers in France (@NantesUniv, @Inserm), @NIH Undiagnosed Diseases Network (@UDNConnect), and our team at @BroadInstitute, we identified deletions of 𝘊𝘏𝘈𝘚𝘌𝘙𝘙 in two additional unrelated children with similar facial and neurological features. 3/10

This was an 8 year odyssey for @ChaserrDad whose daughter has severe developmental delay, epilepsy, and brain atrophy with cerebral hypomyelination. She lacked a genetic diagnosis despite extensive testing, an all too common problem for individuals with #RareDisease 2/10

RT @nickywhiffin: So excited that our paper “De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome” is out toda…

Thank you @BrighamMedRes for inviting me to this CPC, and to our coauthors @sonyardavey, Drs. Sun, Amato, and Loscalzo. We hope you learn through this patient’s rare disease how to structure an evaluation of common symptoms at the interface of medicine and neurology.

RT @nickywhiffin: Would you believe me if I told you that a single variant in a non-coding RNA explains ~0.5% of all undiagnosed individual…

@LeandrosBoukas Elegant work by @IgorUlitsky’s lab in 2019, comparing CRISPR/Cas9 mESC clones that removed promoter+exon 1 of Chaserr vs. the rest of the gene, and ASOs or LNA Gapmers knocking down Chaserr, showed the cis regulation is likely by the lncRNA not an enhancer