Pathogenic variants identified using whole-exome sequencing in Chinese patients with primary ciliary dyskinesia.

The genetic factors contributing to primary ciliary dyskinesia (PCD), a rare autosomal recessive disorder, remain elusive for ~20%-35% of patients with complex and abnormal clinical phenotypes. Our study aimed to identify causative variants of PCD-associated pathogenic candidate genes using whole-exome sequencing (WES). All patients were diagnosed with PCD based on clinical phenotype or transmission electron microscopy images of cilia. WES and bioinformatic analysis were then conducted on patients with PCD. Identified candidate variants were validated by Sanger sequencing. Pathogenicity of candidate variants was then evaluated using in silico software and the American College of Medical Genetics and Genomics (ACMG) database. In total, 13 rare variants were identified in patients with PCD, among which were three homozygous causative variants (including one splicing variant) in the PCD-associated genes CCDC40 and DNAI1. Moreover, two stop-gain heterozygous variants of DNAAF3 and DNAH1 were classified as pathogenic variants based on the ACMG criteria. This study identified novel potential pathogenic genetic factors associated with PCD. Noteworthy, the patients with PCD carried multiple rare causative gene variants, thereby suggesting that known causative genes along with other functional genes should be considered for such heterogeneous genetic disorders.

Changed nocturnal levels of stress-related hormones couple with sleep-wake states in the patients with chronic insomnia disorder: A clinical pilot study.

OBJECTIVES: To explore the relationship between nocturnal levels of stress-related hormones and different sleep-wake states in chronic insomnia disorder (CID) patients. METHODS: Thirty-three CID patients and 34 good sleepers were enrolled and completed assessment of sleep log, Pittsburgh Sleep Quality Index and Insomnia Severity Index. During a-overnight polysomnography monitoring, the patients' vein bleeds were continually collected at different time points (pre-sleep, deep-sleep, 5-min or 30-min waking, and morning waking-up). The control subjects' bleeds were collected only at 22:00 and morning waking-up. The serum hormones were detected using enzyme-linked immunosorbent assay. RESULTS: Compared with at pre-sleep, the level of cortisol was significantly higher at morning waking-up respectively in two-group subjects (Ps < 0.001), with insignificant inter-group differences in cortisol, corticotropin releasing hormone and copeptin at the two time-points. In the patients, the nocturnal secretion curves of three hormones were similar, with the highest concentration at morning waking-up, followed by 30-min waking, 5-min waking, pre-sleep, and deep-sleep. The patients' cortisol (Z = 79.192, P < 0.001) and copeptin (Z = 12.333, P = 0.015) levels were statistically different at different time-points, with higher cortisol at morning waking-up relative to deep-sleep, pre-sleep and 5-min waking (Ps < 0.05), and at 30-min waking relative to deep-sleep and pre-sleep (Ps < 0.05), and higher copeptin at morning waking-up relative to deep-sleep (P < 0.05). CONCLUSIONS: In CID, the nocturnal wakes were instantaneously accompanied by high level, and deep sleep was accompanied by the lowest levels, of stress-related hormones, especially in cortisol, supporting the insomniac hypothesis of increased nocturnal pulse-release of cortisol.

[Progress in clinical research of REM-related obstructive sleep apnea].

REM-related obstructive sleep apnea （REM-OSA） refers to apneas and hypopneas in which most respiratory events occur during REM. The total AHI of REM-OSA is low compared to NREM-OSA, but the duration of apnea hypopnea events is longer and the oxygen saturation is lower. Only focusing on the total AHI value will miss the diagnosis of REM-OSA, and even some patients with severe hypoxemia cannot be effectively treated.REM-OSA may be an early manifestation of OSA, and active early recognition and intervention may benefit patients.The pathophysiology and mechanism of REM-OSA are still unclear. In this article, we reviewed the existing REM-OSA related research.

Changed signals of blood adenosine and cytokines are associated with parameters of sleep and/or cognition in the patients with chronic insomnia disorder.

OBJECTIVES: This study aimed to investigate whether plasma levels of adenosine, adenosine deaminase (ADA), and certain cytokines change in patients with chronic insomnia disorder (CID), and if so, whether these alterations are associated with poor sleep quality and cognitive dysfunction. METHODS: Fifty-five CID patients were selected for the study, along with fifty-five healthy controls (HC) matched to the patients according to their basic data. All subjects completed sleep, emotion, and cognition assessments, with some CID patients also completing an overnight polysomnography. The plasma level of adenosine was measured using liquid chromatography-tandem mass spectrometry, while ADA level was quantified using a quantitative sandwich enzyme-linked immunosorbent assay. Levels of cytokines, including IL-1ß, IL-2, IL-4, IL-6, IL-10, IL-12, TNF-α, and IFN-γ, were measured using Luminex liquid chip technology. RESULTS: CID patients had a lower adenosine level, and higher levels of ADA and some of the cytokines (IL-1ß, IL-2, IL-6, IL-10 and TNF-α) compared with controls. In the CID group, plasma concentrations of adenosine were negatively correlated with Pittsburgh Sleep Quality Index scores, while concentrations of IL-1ß, IL-6 and TNF-α were positively correlated with these scores. Concentrations of IL-1ß and TNF-α were negatively correlated with scores on the Chinese-Beijing Version of the Montreal Cognitive Assessment. Moreover, levels of IL-1ß, TNF-α, IL-6, and IL-2 were positively correlated with memory test errors by CID patients after controlling for confounding factors. CONCLUSIONS: The reduced adenosine and elevated cytokine levels of CID patients were associated with the severity of insomnia and/or cognitive dysfunction.