De novo variants in QRICH1 has recently been reported in 11 individuals with intellectual disability. The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, the authors present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals with QRICH1 variants. Additional findings included poor weight gain, short stature, autism spectrum disorder, seizures and scoliosis. Truncating or splice variants were found in 28 individuals and 10 had missense variants. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity.

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Disturbances of the early stages of neurogenesis lead to irreversible changes in the structure of the mature brain and its functional impairment, including increased excitability, which may be the basis for drug-resistant epilepsy. The range of possible clinical symptoms is as wide as the different stages of disturbed neurogenesis may be. In this study, the authors used a quadruple model of brain dysplasia by comparing structural and functional disorders in animals whose neurogenesis was disturbed with a single dose of 1 Gy of gamma rays at one of the four stages of neurogenesis, i.e. Thereafter, pilocarpine was administered and significant differences in susceptibility to seizure behavioral symptoms were detected depending on the degree of brain dysplasia. Before, during and after the seizures significant correlations were found between the density of parvalbumin-immunopositive neurons located in the cerebral cortex and the intensity of behavioral seizure symptoms or increases in the power of particular EEG bands. Neurons expressing calretinin or NPY showed also dysplasia-related increases without, however, correlations with parameters of seizure intensity. The results point to significant roles of parvalbumin-expressing interneurons, and also to expression of NPY - an endogenous anticonvulsant and neuroprotectant reducing susceptibility to seizures and supporting neuronal survival. This article is protected by copyright. All rights reserved.

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