Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.

MDEST compared favorably with radiologist estimates of percentage density and is more reproducible than radiologist estimates when qualitative BI-RADS density categories are used. Qualitative and quantitative BI-RADS density assessments differed markedly.

Objective• To detail the 9-year experience of renal trauma at a modern Level 1 trauma centre and report on patterns of injury, management and complications. Patients and methods• We analysed 338 patients with renal injuries who presented to our institution over a 9-year period.• Data on demographics, clinical presentation, management and complications were recorded. Results• Males comprised 74.9% of patients with renal injuries and the highest incidence was amongst those aged 20-24 years.• Blunt injuries comprised 96.2% (n = 325) of all the renal injuries, with road trauma being the predominant mechanism accounting for 72.5% of injuries.• The distribution of injury grade was; 21.6% grade 1 (n = 73), 24.3% grade 2 (n = 82), 24.9% grade 3 (n = 84), 16.6% grade 4 (n = 56), and 12.7% grade 5 (n = 43).• Conservative management was successful in all grade 1 and 2 renal injuries, and 94.9%, 90.7% and 35.1% of grade 3, 4 and 5 injuries respectively. • All but one of the 13 patients with penetrating injuries were successfully managed conservatively. Conclusions• Road trauma is the greatest cause of renal injury.• Most haemodynamically stable patients are successfully managed conservatively.

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