Interference with particular spliceosome components, including small nuclear RNAs, cause reproducible uniquely distributed phenotypic and transcript-specific effects, making this an important category of disease-associated mutation. Our approach to differential expression analysis of minor intron-containing genes is applicable to other diseases involving altered transcriptome processing. ANN NEUROL 2017;81:68-78.

Following the presentation of radiation-induced skin effects by three patients who had undergone glue embolisation of intracranial arteriovenous malformation (AVM), measurements were made of absorbed dose to the skin of patients undergoing other interventional neuroradiological procedures that involve long fluoroscopy times. The maximum absorbed dose to the skin measured by thermoluminescent dosemeters during these procedures was 4 Gy. From these measurements and from records of fluoroscopy time and the number of digital runs acquired, estimates of the maximum absorbed skin dose were made for the AVM patients. The best estimate of maximum absorbed dose to the skin received by any of the AVM patients during a procedure was 5 Gy, which is consistent with the skin effects presented by the AVM patients, that is temporary epilation and main erythema. Maximum absorbed dose to the skull was estimated to be 45 Gy and to the outer table of the skull 55 Gy. Although it is unlikely that the AVM patients will suffer serious effects from these skin doses, there remains some uncertainty over the risk of long-term effects to the skull. Examination of the fluoroscopy unit showed that the image intensifier was not performing optimally in terms of entrance dose rate and resolution. Replacement of the unit with modern X-ray equipment designed for interventional radiology was prioritized. Operators should be aware of the potential risks to patients from complex interventional neuroradiology procedures and should optimize their procedures to minimize such risks. Patients undergoing prolonged and complex procedures should be counselled regarding the symptoms and risks of large doses of radiation.

Sotos syndrome, characterized by intellectual disability and characteristic facial features, is caused by haploinsufficiency in the NSD1 gene. We conducted an etiological study on two siblings with Sotos features without mutations in NSD1 and detected a homozygous frameshift mutation in the APC2 gene by whole-exome sequencing, which resulted in the loss of function of cytoskeletal regulation in neurons. Apc2-deficient (Apc2) mice exhibited impaired learning and memory abilities along with an abnormal head shape. Endogenous Apc2 expression was downregulated by the knockdown of Nsd1, indicating that APC2 is a downstream effector of NSD1 in neurons. Nsd1 knockdown in embryonic mouse brains impaired the migration and laminar positioning of cortical neurons, as observed in Apc2 mice, and this defect was rescued by the forced expression of Apc2. Thus, APC2 is a crucial target of NSD1, which provides an explanation for the intellectual disability associated with Sotos syndrome.

The results provide new insight into the functional role of WDR73 in brain development and show that perturbation of its function in an inherited disorder in humans is associated with cerebellar hypoplasia as well as nephrotic disease, consistent with Galloway-Mowat Syndrome.