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RICTOR is a key component of the mTORC2 signaling complex which is involved in the regulation of cell growth, proliferation and survival. RICTOR is highly expressed in neurons and is necessary for brain development. Here, we report eight unrelated patients presenting with intellectual disability and/or development delay and carrying variants in the RICTORgene. The phenotypic presentation is diverse with associated features including growth failure, feeding difficulties, abnormal behavior, seizure, hypertonia, brain anomalies and various other congenital organ and skeletal malformations. All patients carried de novo or heterozygous variants inherited from one affected parent, including three missense variants, four loss-of-function variants and one 3 kb deletion encompassing RICTOR. The mTORC2 pathway was hyperactivated in a patient’s fibroblasts carrying a missense variant, while the expression of RICTOR remained unchanged, indicating a gain-of-function mechanism. RNA sequencing on RICTORknock-out mouse embryonic fibroblasts confirmed the potential role of RICTORin neuronal cell development.

Traumatic brain injury (TBI) is an invisible injury of war that has been identified as the 'signature injury' of Operations Iraqi Freedom (OIF) and Enduring Freedom (OEF). (1-8) Between 2000 [...]

One challenge clinicians face is determining when a military Service Member (SM) can return to duty after an injury that affects the postural control. The gold standard to measure postural control is the Sensory Organization Test (SOT). This test measures the amount of sway present in an individual's static stance that may be used to examine range of function and monitor recovery from injury. Normative values currently available were developed using a sample of clinically normal adults from the general population (i.e., civilian non-aviator). Previous research suggests that these values should not be used as a comparative cohort for high-performing populations in the military. However, normative values, specific to military SMs, do not exist. The aim of this study was to develop a normative clinical database for functional balance (i.e., the SOT) for military-trained aviators, an occupational specialty that may consist of high performers.

PurposeThe study aimed at widening the clinical and genetic spectrum and assessing genotype–phenotype associations in FOXG1 syndrome due to FOXG1 variants.MethodsWe compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher’s exact test and a nonparametric multivariate test.ResultsAmong the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype–phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.ConclusionsThese data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.