Inarguably the most important human genetics paper of the year, and a landmark moment in the history of neurodevelopmental disorder (NDD) genetics. Mutations in RNU4-2, encoding a small nuclear RNA (snRNA) are among the most frequent genetic causes of NDD, explaining up to 0.4% of all cases. Yet, these variants have not been found all these years, despite the big advancements in genome sequencing in the past years. The mind-blowing part: just a region of 18 base pairs that encode a critical part of the snRNA holds all the NDD mutations, a majority of them are insertion mutations. A 18bp noncoding region explaining 0.4% of all NDDs is really huge. This knowledge will solve (already solving) genetic diagnoses of thousands of NDD patients around the world. The 18-bp region is highly constrained. Natural selection is actively removing the mutations from the population, yet the region keeps mutating again and again and again. The next important follow up will be to find what drives such a high mutation rate in this region, particularly insertion mutations. The authors add a new twist to the story: the majority of the maternally inherited. This is surprising, as the origins of NDDs are typically paternally biased. The mechanism is going to be absolutely mind-blowing. Congrats Nicky and team on this remarkable work. This is one of the biggest success stories of 100k genomes project by Genomics England. Whole genome sequencing is already making a big impact in the rare disease space! https://bird.makeup/@nickywhiffin/1811420535580201037
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