Whole-exome sequencing identified five novel de novo variants in patients with unexplained intellectual disability.

BACKGROUND: Intellectual disability (ID) represents a neurodevelopmental disorder, which is characterized by marked defects in the intellectual function and adaptive behavior, with an onset during the developmental period. ID is mainly caused by genetic factors, and it is extremely genetically heterogeneous. This study aims to identify the genetic cause of ID using trio-WES analysis. METHODS: We recruited four pediatric patients with unexplained ID from non-consanguineous families, who presented at the Department of Pediatrics, Guizhou Provincial People's Hospital. Whole-exome sequencing (WES) and Sanger sequencing validation were performed in the patients and their unaffected parents. Furthermore, conservative analysis and protein structural and functional prediction were performed on the identified pathogenic variants. RESULTS: We identified five novel de novo mutations from four known ID-causing genes in the four included patients, namely COL4A1 (c.2786T>A, p.V929D and c.2797G>A, p.G933S), TBR1 (c.1639_1640insCCCGCAGTCC, p.Y553Sfs*124), CHD7 (c.7013A>T, p.Q2338L), and TUBA1A (c.1350del, p.E450Dfs*34). These mutations were all predicted to be deleterious and were located at highly conserved domains that might affect the structure and function of these proteins. CONCLUSION: Our findings contribute to expanding the mutational spectrum of ID-related genes and help to deepen the understanding of the genetic causes and heterogeneity of ID.

Quantitative Study of the Changes in Cerebral Blood Flow and Iron Deposition During Progression of Alzheimer's Disease.

BACKGROUND: Advanced Alzheimer's disease (AD) has no effective treatment, and identifying early diagnosis markers can provide a time window for treatment. OBJECTIVE: To quantify the changes in cerebral blood flow (CBF) and iron deposition during progression of AD. METHODS: 94 subjects underwent brain imaging on a 3.0-T MRI scanner with techniques of three-dimensional arterial spin labeling (3D-ASL) and quantitative susceptibility mapping (QSM). The subjects included 22 patients with probable AD, 22 patients with mild cognitive impairment (MCI), 25 patients with subjective cognitive decline (SCD), and 25 normal controls (NC). The CBF and QSM values were obtained using a standardized brain region method based on the Brainnetome Atlas. The differences in CBF and QSM values were analyzed between and within groups using variance analysis and correlation analysis. RESULTS: CBF and QSM identified several abnormal brain regions of interest (ROIs) at different stages of AD (p < 0.05). Regionally, the CBF values in several ROIs of the AD and MCI subjects were lower than for NC subjects (p < 0.001). Higher QSM values were observed in the globus pallidus. The CBF and QSM values in multiple ROI were negatively correlated, while the putamen was the common ROI of the three study groups (p < 0.05). The CBF and QSM values in hippocampus were cross-correlated with scale scores during the progression of AD (p < 0.05). CONCLUSION: Iron deposition in the basal ganglia and reduction in blood perfusion in multiple regions existed during the progression of AD. The QSM values in putamen can be used as an imaging biomarker for early diagnosis of AD.