Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-

The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.

Prader-Willi syndrome (PWS) is a genetic disorder which is characterized by severe hypotonia and feeding problems in early infancy. In later childhood and adolescence, this is followed by hyperphagia and extreme obesity if the diet is not strictly controlled. Data on physical health problems in adults with PWS are scarce. We report on the prevalence of physical health problems in a Dutch cohort of adults with PWS in relation to age, BMI, and genetic subtype. Participants (n = 102) were retrieved via the Dutch Prader-Willi Parent Association and through physicians specializing in persons with intellectual disabilities (ID). Details regarding physical health problem spanning the participants' lifespan were collected from caretakers through semi-structured interviews. Cardiovascular problems included diabetes mellitus, hypertension, and cerebrovascular accidents. Respiratory infections were frequent in adulthood. In males, cryptorchidism was almost universal, for which 28/48 males had a history of surgery, mostly orchidopexy. None of the women had a regular menstrual cycle. Sixteen individuals had a diagnosis of osteoporosis. Spinal deformation, hip dysplasia, and foot abnormalities were common. Skinpicking, leg edema, and erysipelas were frequent dermatological problems. The findings in our group support the notion that the prevalence of physical health problems is underestimated. This underscores the importance of developing monitoring programs which would help to recognize physical health problems at an early stage.