Using exome sequencing data from ~10k patients with severe developmental disorders (DD) from the DDD project we decipher 3 distinct mechanisms through which ‘non-coding’ variants cause MEF2C loss-of-function medrxiv.org/content/10.110… 1/10
Two 5’UTR SNVs create upstream start codons (uAUGs) that are out-of-frame with the coding sequence (CDS) and reduce normal translation of MEF2C. This effect is dependent on the Kozak consensus of the uAUG, with even partial reduction of MEF2C leading to DD @nickquaife1 2/10
Feb 28, 2019 • 5 tweets • 3 min read
Introducing the next gnomAD pre-print - in collaboration with @23andMeResearch we use highly curated genomic and phenotypic data from >4 million individuals to characterise the effects of life-long LRRK2 reduction in 1,358 loss-of-function carriers: biorxiv.org/content/10.110… 1/5
Motivation: Gain-of-kinase function variants in LRRK2 are a frequent cause of Parkinson's disease, suggesting targeting LRRK2 as a promising therapeutic. Early studies in model organisms, however, show inconsistent phenotypes and raised concerns about toxicity 2/5
Aug 6, 2018 • 5 tweets • 2 min read
Earlier this year a paper by Shah et al. in AJHG suggested that our allele frequency filtering approach “may be prone to removing pathogenic variants”. In this response, we show that this is incorrect, and demonstrate that our approach is robust biorxiv.org/content/early/… 1/5
Shah et al. reported 15 ClinVar variants that are ‘inappropriately filtered’ by our approach. We show that these are either (a) incorrect use of our approach e.g. filtering founder variants or singletons, (b) not high-confidence pathogenic alleles, or (c) very low penetrance. 2/5
