Genetic Spectrum Identified by Exome Sequencing in a Chinese Pediatric Cerebral Palsy Cohort.

OBJECTIVE: To explore the genetic spectrum of cerebral palsy (CP) in a Chinese pediatric cohort. STUDY DESIGN: This was a retrospective observational study of patients with CP from the Children's Hospital of Fudan University between June 2015 and December 2019. Their clinical data and exome sequencing data were collected and analyzed. RESULTS: A total of 217 patients with CP were enrolled, and genetic variants were identified in 78 subjects (35.9%): 65 patients with single-nucleotide variants (SNVs), 12 patients with copy number variants, and 1 patient with both an SNV and a copy number variant. The genetic diagnosis rates were significantly greater in patients without clinical risk factors than in patients with clinical risk factors (χ2 = 21.705, P = .000) and were significantly greater in patients with a family history than in those without a family history (χ2 = 4.493, P = .034). Variants in genes related to neurologic disorders were the most commonly detected variants, affecting 41 patients (62.1%, 41/66). Among the patients with SNVs detected, the top 12 genes were found to cover 62.1% (41/66) of cases, and 39.4% (26/66) of patients with SNVs had medically actionable genetic findings. CONCLUSIONS: The overall genetic diagnostic rate in this study was 35.9%, and patients without any clinical risk factors or with a family history were more likely to have genetic risk factors. The top 12 genes detected in this study as well as genes related to neurologic disorders or other medically actionable disorders should be noted in the analysis of genetic testing results in patients with CP.

Clinical and Genetic Etiologies of Neonatal Unconjugated Hyperbilirubinemia in the China Neonatal Genomes Project.

OBJECTIVE: To investigate the clinical and genetic causes of neonatal unconjugated hyperbilirubinemia. STUDY DESIGN: We included 1412 neonates diagnosed with unconjugated hyperbilirubinemia (total serum bilirubin >95 percentile for age), from the China Neonatal Genomes Project between August 2016 and September 2019, in the current study. Clinical data and targeted panel sequencing data on 2742 genes including known unconjugated hyperbilirubinemia genes were analyzed. RESULTS: Among the 1412 neonates with unconjugated hyperbilirubinemia, 37% had severe unconjugated hyperbilirubinemia, with total serum bilirubin levels that met the recommendations for exchange transfusion. Known clinical causes were identified for 68% of patients. The most common clinical cause in the mild unconjugated hyperbilirubinemia group was infection (17%) and in the severe group was combined factors (21%, with infection combined with extravascular hemorrhage the most common). A genetic variant was observed in 55 participants (4%), including 45 patients with variants in genes associated with unconjugated hyperbilirubinemia and 10 patients with variants that were regarded as additional genetic findings. Among the 45 patients identified with unconjugated hyperbilirubinemia-related variants, the genes were mainly associated with enzyme deficiencies, metabolic/biochemical disorders, and red blood cell membrane defects. G6PD and UGT1A1 variants, were detected in 34 of the 45 patients (76%). CONCLUSIONS: Known clinical causes, which varied with bilirubin levels, were identified in approximately two-thirds of the patients. Genetic findings were identified in 4% of the patients, including in patients with an identified clinical cause, with G6PD and UGT1A1 being the most common genes in which variants were detected.

Activating adenosine A1 receptor accelerates PC12 cell injury via ADORA1/PKC/KATP pathway after intermittent hypoxia exposure.

Obstructive sleep apnea hypopnea syndrome (OSAHS) is associated with the neurocognitive deficits as a result of the neuronal cell injury. Previous studies have shown that adenosine A1 receptor (ADORA1) played an important role against hypoxia exposure, such as controlling the metabolic recovery in rat hippocampal slices and increasing the resistance in the combined effects of hypoxia and hypercapnia. However, little is known about whether ADORA1 takes part in the course of neuronal cell injury after intermittent hypoxia exposure which was the main pathological characteristic of OSAHS. The present study is performed to explore the underlying mechanism of neuronal cell injury which was induced by intermittent hypoxia exposure in PC12 cells. In our research, we find that the stimulation of the ADORA1 by CCPA accelerated the injury of PC12 cells as well as upregulated the expression of PKC, inwardly rectifying potassium channel 6.2(Kir6.2) and sulfonylurea receptor 1(SUR1) while inhibition of the ADORA1 by DPCPX alleviated the injury of PC12 cells as well as downregulated the expression of PKC, Kir6.2, and SUR1. Moreover, inhibition of the PKC by CHE, also mitigated the injury of PC12 cells, suppressed the Kir6.2 and SUR1 expressions induced by PKC. Taken together, our findings indicate that ADORA1 accelerated PC12 cells injury after intermittent hypoxia exposure via ADORA1/PKC/KATP signaling pathway.

Molecular Genetic Analysis of Newborns with Congenital Microcephaly.

INTRODUCTION: Data on the genetic landscape of congenital microcephaly (CM) in China are scarce, and the incidence of CM caused by the most commonly mutated gene ASPM in China remains unknown. METHODS: Sixty-one neonates with CM who were hospitalized in the Children's Hospital of Fudan University between August 1, 2016, and August 31, 2020, were enrolled, and the clinical data and clinical exome-sequencing data were analyzed. An additional 18,103 parental data entries from the Chinese Children's Genetic Testing Clinical Collaboration System database were collected to estimate the incidence of ASPM-related congenital microcephaly (ASPM-CM) in East China by analyzing the carrier frequency of ASPM mutations. RESULTS: Among the 61 neonates with CM, 35 (57.4%) patients were identified with genetic findings, including 24 patients with single nucleotide variants (SNVs) and 11 patients with copy number variations (CNVs). ASPM was the most common gene with detrimental SNVs detected in 3 patients. Patients with genetic findings showed a significantly higher incidence of developmental delay (91.3%, 21/23) than those without genetic findings (60%, 9/15) (p = 0.04). All the 3 decreased patients had genetic findings. The estimated ASPM-CM incidence in East China was 1/1,295,044. CONCLUSION: Comprehensive genetic testing, detecting both SNVs and CNVs, is recommended for newborns with CM. Patients with genetic findings should be aware of the potential for developmental delay. ASPM gene defect was the most common genetic cause of CM in this study. The estimation of the incidence of ASPM-CM in East China might provide a reference for analyzing overall incidence.

Aetiology and outcomes of prolonged neonatal jaundice in tertiary centres: data from the China Neonatal Genome Project.

OBJECTIVE: To investigate the distribution of aetiologies and outcomes in neonates with prolonged neonatal jaundice. DESIGN: An observational study. SETTING: Multiple tertiary centres from the China Neonatal Genome Project. PATIENTS: Term infants with jaundice lasting more than 14 days or preterm infants with jaundice lasting more than 21 days were recruited between 1 June 2016 and 30 June 2020. MAIN OUTCOME MEASURES: Aetiology and outcomes were recorded from neonates with prolonged unconjugated hyperbilirubinaemia (PUCHB) and prolonged conjugated hyperbilirubinaemia (PCHB). RESULTS: A total of 939 neonates were enrolled, and known aetiologies were identified in 84.1% of neonates (790 of 939). Among 411 neonates with PCHB, genetic disorders (27.2%, 112 of 411) were the leading aetiologies. There were 8 deceased neonates, 19 neonates with liver failure and 12 with neurodevelopmental delay. Among 528 neonates with PUCHB, a genetic aetiology was identified in 2 of 219 neonates (0.9%) who showed disappearance of jaundice within 4 weeks of age and in 32 of 309 neonates (10.4%) with persistent jaundice after 4 weeks of age. A total of 96 of 181 neonates (53.0%) who received genetic diagnoses had their clinical diagnosis modified as a result of the genetic diagnoses. CONCLUSION: Known aetiologies were identified in approximately 80% of neonates in our cohort, and their overall outcomes were favourable. Genetic aetiology should be considered a priority in neonates with PCHB or the persistence of jaundice after 4 weeks of age. Moreover, genetic data can modify the clinical diagnosis and guide disease management, potentially improving outcomes.

Genetic etiologies associated with infantile hydrocephalus in a Chinese infantile cohort.

BACKGROUND: Infantile hydrocephalus (IHC) is commonly related to other central nervous system diseases, which may have adverse effects on prognosis. The causes of IHC are heterogeneous, and the genetic etiologies are not fully understood. This study aimed to analyze the genetic etiologies of an IHC cohort. METHODS: The data for 110 IHC patients who had received exome sequencing at the Clinical Genetic Center of the Children's Hospital of Fudan University between 2016 and 2019 were reviewed and analyzed retrospectively. An exome-wide association analysis (EWAS) was performed within this cohort using IHC as the study phenotype. RESULTS: Of the 110 IHC patients, a pathogenic or likely pathogenic variant was identified in 16 (15%) patients, spanning 13 genes. The genes were mainly associated with metabolic disorders, brain abnormalities, and genetic syndromes. IHC patients who had unclear clinical etiology were more likely to possess a genetic etiology. Based on previous studies and on our EWAS results, ZEB1, SBF2, and GNAI2 were over-represented among IHC patients and might affect the signaling pathways involved in IHC formation. CONCLUSIONS: Our study showed heterogeneous genetic etiologies in an IHC cohort. It is essential to perform genetic testing on IHC patients who have unclear clinical etiology, and genes associated with metabolic disorders, brain abnormalities, and genetic syndromes should be noted. In addition, when aiming to discover IHC susceptibility genes, genes that might influence the signaling pathways involved in IHC formation should be prioritized.

[Clinical value of portable sleep testing in children with obstructive sleep apnea syndrome].

OBJECTIVE: To determine the clinical value of portable sleep testing by Watch-PAT (PAT) in children with obstructive sleep apnea syndrome (OSAS). METHOD: Fifty cases of snoring children aged 3-11 years were randomly selected to undergo the polysomnography (PSG) and PAT simultaneously at the same night. The consistency of sleep parameters in OSAS and non - OSAS children were compared with PSG as reference standard, and ROC curve analysis was performed to assess the sensitivity and specificity in the diagnosis of OSAS with PAT portable sleep monitor. RESULT: Fourteen cases were diagnosed as OSAS in 6-11 years group by PAT and PSG. But in 3-5 years group, only six children were diagnosed as OSAS, there was significant difference between PAT and PSG (P < 0.05). Among those 6-11 years old children, compared with non-OSAS, PAT study showed that III+IV stage sleep ((30.5 ± 2.4)% vs. (38.2 ± 2.3)%, χ(2)=4.31, P<0.05), REM sleep duration ((8.9 ± 2.5)% vs. (18.3 ± 2.1)%, χ² =4.31, P<0.05), TST ((458 ± 78) min vs. (522 ± 56) min, t=4.85, P<0.05) and sleep efficiency ((83.5 ± 3.1)% vs. (93.5 ± 3.5)%, t=3.75, P<0.05) decreased, I+II stage sleep ((61.5 ± 4.4)% vs. (44.1 ± 3.5)%, χ² =6.07, P<0.05), arousal index ((29.5 ± 8.2)/h vs. (10.6 ± 5.6)/h, t=3.70, P<0.05), AHI ((7.6 ± 5.3)/h vs. (2.1 ± 2.0)/h, t=2.40, P<0.05), RDI((18.2 ± 5.1)/h vs. (6.5 ± 3.9)/h, t=3.85, P<0.05) increased in OSAS children. Furthermore, the total sleep time (TST) ((458 ± 78) min vs. (430 ± 76) min, t=2.90, P<0.05) and sleep efficiency ((83.5 ± 3.1) % vs. (81.9 ± 4.3) %, t=2.45, P<0.05) were higher by PAT than scored by PSG. ROC curve analysis showed the best threshold selection of AHI 5.0, the sensitivity was 0.952, the specificity was 0.858. AHI 7.0, the sensitivity was 0.968, the specificity was 0.985. AHI 10, the sensitivity was 0.985 and the specificity was 0.99, but AHI 1.0, the sensitivity was 0.852 and the specificity was 0.785. CONCLUSION: PAT can be used at home in school age children due to the high consistency with PSG and the high compliance.

Endoplasmic reticulum stress plays critical role in brain damage after chronic intermittent hypoxia in growing rats.

Obstructive sleep apnea hypopnea syndrome (OSAHS) in children is associated with multiple system morbidities. Cognitive dysfunction as a result of central nervous system complication has been reported in children with OSAHS. However, the underlying mechanisms are poorly understood. Endoplasmic reticulum stress (ERS)-related apoptosis plays an important role in various diseases of the central nervous system, but very little is known about the role of ERS in mediating pathophysiological reactions to cognitive dysfunction in OSAHS. Chronic intermittent hypoxia (CIH) exposures, modeling OSAHS, across 2 and 4weeks in growing rats made more reference memory errors, working memory errors and total memory errors in the 8-Arm radial maze task, increased significantly TUNEL positive cells, upregulated the unfolded protein response in the hippocampus and prefrontal cortex as evidenced by increased phosphorylation of PKR-like endoplasmic reticulum kinase, inositol-requiring enzyme l and some downstream products. A selective inhibitor of eukaryotic initiation factor-2a dephosphorylation, salubrinal, prevented C/EBP-homologous protein activation in the hippocampus and prefrontal cortex throughout hypoxia/reoxygenation exposure. Our findings suggest that ERS mediated cell apoptosis may be one of the underlying mechanisms of cognitive dysfunction in OSAHS children. Further, a specific ERS inhibitor Salubrinal should be tested for neuroprotection against CIH-induced injury.