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 @chaserrdad: Thank you Amanda Keener, @Nature & @SeegeneUSA for the great article about the powers of whole genome sequencing and our da….

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.

We propose that closer evaluation of structural variants containing highly-conserved lncRNAs in individuals with #RareDisease may identify additional genes essential for human development and disease in the vast and largely unexplored noncoding genome. 9/10.

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.

Increasing dosage of 𝘊𝘏𝘋2 was predicted to be damaging (i.e., “triplosensitive”) based on large-scale aggregated analysis of copy number variation in humans (h/t @TalkowskiLab), but hadn’t yet been demonstrated in a specific disorder. 6/10.

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….