Leadership Blossoms in Parental Warmth: Positive Parenting Practices Shape Adolescent Leader Emergence via Intrapersonal and Interpersonal Mechanisms.

Developing leadership skills during adolescence is crucial for future career success. Previous studies have primarily focused on the impact of school settings, academic courses, and simulated team tasks on leader emergence, neglecting the significant role of parental influence in this process. Employing a mixed-methods approach, this research investigated the positive relationship between parental warmth and adolescent leader emergence and the underlying mechanisms of this relationship. The quantitative study (Study 1) collected multi-source data from 1255 adolescents (Mage = 14.2, SDage = 0.56, 48.2% male) and their parents, teachers and peers. Findings from Study 1 revealed a positive correlation between parental warmth and adolescent leader emergence. Structural equation modeling showed two mediating pathways: an intrapersonal pathway involving self-esteem and leader self-efficacy, and an interpersonal pathway involving empathy and prosocial behavior. Encouragement of independence, as an additional adolescents-focused parenting practice, strengthened the observed positive relationship. The qualitative study (Study 2) conducted in-depth interviews with adolescents to identify the parental practices that facilitate or hinder adolescent leader emergence for the triangulation of the central research question. Study 2 collected data from 32 adolescents (Mage = 15.16, SDage = 1.37, 50% male). Findings from Study 2 corroborated the significance of parental warmth and the encouragement of independence for adolescent leader emergence, elucidating specific parenting behaviors conducive to these positive parenting practices, such as providing companionship and communication, as well as encouraging adolescents to participate in household tasks. This mix-methods research prepositioned the stages of leadership development, advocating for the importance of the warmth and autonomy from parents as formative factors for cultivating the next generation of leaders.

Clinical value of screening prenatal ultrasound combined with chromosomal microarrays in prenatal diagnosis of chromosomal abnormalities.

OBJECTIVE: To evaluate the clinical value of ultrasound findings in the screening of fetal chromosomal abnormalities and the analysis of risk factors for chromosome microarray analysis (CMA) abnormalities. METHODS: We retrospectively analyzed the datasets of 15,899 pregnant women who underwent prenatal evaluations at Affiliated Maternity and Child Health Care Hospital of Nantong University between August 2018 and December 2022. Everyone underwent ultrasound screening, and those with abnormal findings underwent CMA to identify chromosomal abnormalities. RESULTS: The detection rates for isolated ultrasound anomalies and combined ultrasound and CMA anomalies were 11.81% (1877/15,899) and 2.40% (381/15,899), respectively. Among all ultrasound abnormalities, detection rates for isolated ultrasound soft marker anomalies, isolated structural abnormalities, and both ultrasound soft marker anomalies with structural abnormalities were 82.91% (1872/2258), 15.99% (361/2258), and 1.11% (25/2258), respectively. The detection rate of abnormal chromosomes in pregnant women with abnormal ultrasound results was 16.87% (381/2258). The detection rates were 13.33% in cases with two or more ultrasound soft markers anomalies, 47.37% for two or more structural anomalies, and 48.00% for concomitant ultrasound soft marker and structural anomalies. CONCLUSIONS: Enhanced detection rates of chromosomal anomalies in fetal malformations are achieved with specific ultrasound findings (NT thickening, cardiovascular abnormalities, and multiple soft markers) or when combined with high-risk factors (advanced maternal age, familial history, parental chromosomal anomalies, etc.). When the maternal age is over 35 and with ≥2 ultrasound soft marker anomalies accompanied with any high-risk factors, CMA testing can aid in the diagnosis of prenatal chromosomal abnormalities.

CELSR1 variants are associated with partial epilepsy of childhood.

CELSR1 gene, encoding cadherin EGF LAG seven-pass G-type receptor 1, is mainly expressed in neural stem cells during the embryonic period. It plays an important role in neurodevelopment. However, the relationship between CELSR1 and disease of the central nervous system has not been defined. In this study, we performed trios-based whole-exome sequencing in a cohort of 356 unrelated cases with partial epilepsy without acquired causes and identified CELSR1 variants in six unrelated cases. The variants included one de novo heterozygous nonsense variant, one de novo heterozygous missense variant, and four compound heterozygous missense variants that had one variant was located in the extracellular region and the other in the cytoplasm. The patients with biallelic variants presented severe epileptic phenotypes, whereas those with heterozygous variants were associated with a mild epileptic phenotype of benign epilepsy with centrotemporal spikes (BECTS). These variants had no or low allele frequency in the gnomAD database. The frequencies of the CELSR1 variants in this cohort were significantly higher than those in the control populations. The evidence from ClinGen Clinical-Validity Framework suggested a strong association between CELSR1 variants and epilepsy. These findings provide evidence that CELSR1 is potentially a candidate pathogenic gene of partial epilepsy of childhood.

BCOR variants are associated with X-linked recessive partial epilepsy.

OBJECTIVE: BCOR gene, encoding a corepressor of BCL6, plays an important role in fetal development. BCOR mutations were previously associated with oculofaciocardiodental syndrome (OFCD or MCOPS2, OMIM# 300166). The BCOR protein is ubiquitously expressed in multiple areas, including the brain. However, the role of BCOR in neurological disorder remains elusive. METHODS: Trios-based whole-exome sequencing was performed in a cohort of 323 cases with partial epilepsy without acquired causes. RESULTS: Seven hemizygous missense BCOR variants, including c 0.103 G>C/p.Asp35His, c.1079 A>G/p.His360Arg, c 0.1097 C>T/p.Thr366Ile, c 0.3301 C>T/p.Pro1101Ser, c 0.3391 C>T/p.Arg1131Trp, c 0.4199 G>A/p.Arg1400Gln, and c 0.5254 G>A/p.Asp1752Asn, were identified in seven cases with partial epilepsy. Two patients presented partial seizures with generalized seizures and/or generalized discharges. One case showed cortical dysplasia in the right temporal-occipital area on MRI. Two cases presented mild developmental delay. However, all patients achieved seizure-free. The frequency of BCOR variants in the present cohort was significantly higher than that in the controls of healthy Chinese volunteers and all populations of Genome Aggregation Database (gnomAD). Computational modeling, including hydrogen bond and prediction of protein stability, implied that the variants lead to structural impairment. Previously, OFCD associated BCOR mutations were mostly destructive mutations in an X-linked dominant (XLD) pattern; in contrast, the BCOR variants identified in this study were all missense variants, which were associated with partial epilepsy in an X-linked recessive (XLR) pattern. The proportion of missense mutations in epilepsy was significantly higher than that in OFCD. CONCLUSIONS: BCOR was potentially a candidate pathogenic gene of partial epilepsy with or without developmental delay. The genotype-phenotype correlation helps understanding the mechanism underlying phenotypic variation.

ADGRV1 Variants in Febrile Seizures/Epilepsy With Antecedent Febrile Seizures and Their Associations With Audio-Visual Abnormalities.

Objective: ADGRV1 gene encodes adhesion G protein-coupled receptor-V1 that is involved in synaptic function. ADGRV1 mutations are associated with audio-visual disorders. Although previous experimental studies suggested that ADGRV1 variants were associated with epilepsy, clinical evidence is limited and the phenotype spectrum is to be defined. Methods: Trio-based targeting sequencing was performed in a cohort of 101 cases with febrile seizure (FS) and epilepsy with antecedent FS. Protein modeling was used to assess the damaging effects of variants. The genotype-phenotype correlations of the ADGRV1 variants in epilepsy and audio-visual disorders were analyzed. Results: ADGRV1 variants were identified in nine unrelated cases (8.91%), including two heterozygous frameshift variants, six heterozygous missense variants, and a pair of compound heterozygous variants. These variants presented a statistically higher frequency in this cohort than that in control populations. Most missense variants were located at CalX-ß motifs and changed the hydrogen bonds. These variants were inherited from the asymptomatic parents, indicating an incomplete penetrance. We also identified SCN1A variants in 25 unrelated cases (24.75%) and SCN9A variants in 3 unrelated cases (2.97%) in this cohort. Contrary to SCN1A variant-associated epilepsy that revealed seizure was aggravated by sodium channel blockers, ADGRV1 variants were associated with mild epilepsy with favorable responses to antiepileptic drugs. The patients denied problems with audio-visual-vestibular abilities in daily life. However, audio-visual tests revealed auditory and visual impairment in the patient with compound heterozygous variants, auditory or vestibular impairment in the patients with heterozygous frameshift, or hydrogen-bond changed missense variants but no abnormalities in the patients with missense variants without hydrogen-bond changes. Previously reported ADGRV1 variants that were associated with audio-visual disorders were mostly biallelic/destructive variants, which were significantly more frequent in the severe phenotype of audio-visual disorders (Usher syndrome 2) than in other mild phenotypes. In contrast, the variants identified in epilepsy were monoallelic, missense mainly located at CalX-ß, or affected isoforms VLGR1b/1c. Significance: ADGRV1 is potentially associated with FS-related epilepsy as a susceptibility gene. The genotype, submolecular implication, isoforms, and damaging severity of the variants explained the phenotypical variations. ADGRV1 variant-associated FS/epilepsy presented favorable responses to antiepileptic drugs, implying a clinical significance.

SHROOM4 Variants Are Associated With X-Linked Epilepsy With Features of Generalized Seizures or Generalized Discharges.

Objective: SHROOM4 gene encodes an actin-binding proteins, which plays an important role in cytoskeletal architecture, synaptogenesis, and maintaining gamma-aminobutyric acid receptors-mediated inhibition. SHROOM4 mutations were reported in patients with the Stocco dos Santos type of X-linked syndromic intellectual developmental disorder (SDSX; OMIM# 300434). In this study, we investigated the association between SHROOM4 and epilepsy. Methods: Trios-based whole-exome sequencing was performed in a cohort of 320 cases with idiopathic generalized epilepsy or idiopathic partial epilepsy. Protein modeling was used to assess the damaging effects of variations. Results: Six hemizygous missense SHROOM4 variants, including c.13C > A/p. Pro5Thr, c.3236C > T/p.Glu1079Ala, c.3581C > T/p.Ser1194Leu, c.4288C > T/p.Arg1430Cys, c.4303G > A/p.Val1435Met, c.4331C > T/p.Pro1444Leu, were identified in six cases with idiopathic epilepsy without intellectual disability. All patients presented with features of generalized seizures or generalized discharges. These hemizygous variants had no or extremely low allele frequencies in controls and showed statistically higher frequency in the case cohort than controls. All variants were predicted to alter hydrogen bond with surrounding amino acids or decreased protein stability. The SHROOM4 variants reported in patients with SDSX were mostly destructive or duplicative variants; in contrast, the SHROOM4 variants were all missense variants, suggesting a potential genotype-phenotype correlation. The two missense variants associated with SDSX were located in the middle of SHROOM4 protein, whereas variants associated with idiopathic epilepsy were located around the N-terminal PDZ domain and the C-terminal ASD2 domain. Significance: SHROOM4 was potentially a candidate pathogenic gene of idiopathic epilepsy without intellectual disability. The genotype-phenotype correlation and sub-regional effect helps understanding the mechanism underlying phenotypic variation.

CACNA1A Mutations Associated With Epilepsies and Their Molecular Sub-Regional Implications.

Purpose: Previously, mutations in the voltage-gated calcium channel subunit alpha1 A (CACNA1A) gene have been reported to be associated with paroxysmal disorders, typically as episodic ataxia type 2. To determine the relationship between CACNA1A and epilepsies and the role of molecular sub-regional on the phenotypic heterogeneity. Methods: Trio-based whole-exome sequencing was performed in 318 cases with partial epilepsy and 150 cases with generalized epilepsy. We then reviewed all previously reported CACNA1A mutations and analyzed the genotype-phenotype correlations with molecular sub-regional implications. Results: We identified 12 CACNA1A mutations in ten unrelated cases of epilepsy, including four de novo null mutations (c.2963_2964insG/p.Gly989Argfs*78, c.3089 + 1G > A, c.4755 + 1G > T, and c.6340-1G > A), four de novo missense mutations (c.203G > T/p.Arg68Leu, c.3965G > A/p.Gly1322Glu, c.5032C > T/p.Arg1678Cys, and c.5393C > T/p.Ser1798Leu), and two pairs of compound heterozygous missense mutations (c.4891A > G/p.Ile1631Val& c.5978C > T/p.Pro1993Leu and c.3233C > T/p.Ser1078Leu&c.6061G > A/p.Glu2021Lys). The eight de novo mutations were evaluated as pathogenic or likely pathogenic mutations according to the criteria of American College of Medical Genetics and Genomics (ACMG). The frequencies of the compound heterozygous CACNA1A mutations identified in this cohort were significantly higher than that in the controls of East Asian and all populations (P = 7.30 × 10-4, P = 2.53 × 10-4). All of the ten cases were ultimately seizure-free after antiepileptic treatment, although frequent epileptic seizures were observed in four cases. Further analysis revealed that episodic ataxia type 2 (EA2) had a tendency of higher frequency of null mutations than epilepsies. The missense mutations in severe epileptic phenotypes were more frequently located in the pore region than those in milder epileptic phenotypes (P = 1.67 × 10-4); de novo mutations in the epilepsy with intellectual disability (ID) had a higher percentage than those in the epilepsy without ID (P = 1.92 × 10-3). Conclusion: This study suggested that CACNA1A mutations were potentially associated with pure epilepsy and the spectrum of epileptic phenotypes potentially ranged from the mild form of epilepsies such as absence epilepsy or partial epilepsy, to the severe form of developmental epileptic encephalopathy. The clinical phenotypes variability is potentially associated with the molecular sub-regional of the mutations.

Autonomic Nervous System Response Patterns of Test-Anxious Individuals to Evaluative Stress.

Test anxiety is a widespread and primarily detrimental emotion in learning and achievement settings. This research aimed to explore the autonomic nervous system (ANS) response patterns of test-anxious individuals in response to evaluative stress. By presenting a standard interview task, an evaluative scenario was effectively induced. Heart rate variability (HRV), a biomarker that can accurately reflect the ANS activity, was used to reflect the physiological responses of 48 high test-anxious subjects and 49 low test-anxious subjects. Results indicate that: (1) both groups show a significantly increased emotional arousal in the evaluative scenario; (2) high test-anxious individuals show a significantly decreased emotional pleasantness in the evaluative scenario, whereas low test-anxious individuals show no significant changes; (3) both groups show a significantly increased low-frequency HRV; (4) high test-anxious individuals show a significantly decreased high-frequency HRV and root mean square of successive heartbeat interval differences (RMSSD), whereas low test-anxious individuals remain stable. These findings suggest that high test-anxious individuals display an increased sympathetic nervous system (SNS) activity and a decreased parasympathetic nervous system (PNS) activity in response to evaluative stress, while low-anxious individuals display an increased SNS activity and a stable PNS activity in response to evaluative stress.

Screening of Candidate Pathogenic Genes for Spontaneous Abortion Using Whole Exome Sequencing.

BACKGROUND: Spontaneous abortion is a common disease in obstetrics and reproduction. OBJECTIVES: This study aimed to screen candidate pathogenic genes for spontaneous abortion using whole-exome sequencing. METHODS: Genomic DNA was extracted from abortion tissues of spontaneous abortion patients and sequenced using the Illumina HiSeq2500 high-throughput sequencing platform. Whole exome sequencing was performed to select harmful mutations, including SNP and insertion and deletion sites, associated with spontaneous abortion. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and gene fusion analyses were performed. MUC3A and PDE4DIP were two novel mutation genes that were screened and verified by PCR in abortion tissues of patients. RESULTS: A total of 83,633 SNPs and 13,635 Indel mutations were detected, of which 29172 SNPs and 3093 Indels were screened as harmful mutations. The 7 GO-BP, 4 GO-CC, 9 GO-MF progress, and 3 KEGG pathways were enriched in GO and KEGG pathway analyses. A total of 746 gene fusion mutations were obtained, involving 492 genes. MUC3A and PDE4DIP were used for PCR verification because of their high number of mutation sites in all samples. CONCLUSION: There are extensive SNPs and Indel mutations in the genome of spontaneous abortion tissues, and the effect of these gene mutations on spontaneous abortion needs further experimental verification.

Advances of Antisense Oligonucleotide Technology in the Treatment of Hereditary Neurodegenerative Diseases.

Antisense nucleic acids are single-stranded oligonucleotides that have been specially chemically modified, which can bind to RNA expressed by target genes through base complementary pairing and affect protein synthesis at the level of posttranscriptional processing or protein translation. In recent years, the application of antisense nucleic acid technology in the treatment of neuromuscular diseases has made remarkable progress. In 2016, the US FDA approved two antisense nucleic acid drugs for the treatment of Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), and the development to treat other neurodegenerative diseases has also entered the clinical stage. Therefore, ASO represents a treatment with great potential. The article will summarize ASO therapies in terms of mechanism of action, chemical modification, and administration methods and analyze their role in several common neurodegenerative diseases, such as SMA, DMD, and amyotrophic lateral sclerosis (ALS). This article systematically summarizes the great potential of antisense nucleic acid technology in the treatment of hereditary neurodegenerative diseases.

HLA Risk Alleles in Aromatic Antiepileptic Drug-Induced Maculopapular Exanthema.

To characterize human leukocyte antigen (HLA) loci as risk factors in aromatic antiepileptic drug-induced maculopapular exanthema (AED-MPE). A case-control study was performed to investigate HLA loci involved in AED-MPE in a southern Han Chinese population. Between January 2007 and June 2019, 267 patients with carbamazepine (CBZ), oxcarbazepine (OXC), or lamotrigine (LTG) associated MPE and 387 matched drug-tolerant controls from six centers were enrolled. HLA-A/B/C/DRB1 genotypes were determined using sequence-based typing. Potential risk alleles were validated by meta-analysis using data from different populations and in silico analysis of protein-drug interactions. HLA-DRB1*04:06 was significantly associated with OXC-MPE (p = 0.002, p c = 0.04). HLA-B*38:02 was associated with CBZ-MPE (p = 0.03). When pooled, HLA-A*24:02, HLA-A*30:01, and HLA-B*35:01 additionally revealed significant association with AED-MPE. Logistic regression analysis showed a multiplicative interaction between HLA-A*24:02 and HLA-B*38:02 in CBZ-MPE. Meta-analysis of data from different populations revealed that HLA-24*:02 and HLA-A*30:01 were associated with AED-MPE (p = 0.02 and p = 0.04, respectively). In silico analysis of protein-drug interaction demonstrated that HLA-A*24:02 and HLA-A*30:01 had higher affinities with the three aromatic AEDs than the risk-free HLA-A allele. HLA-DRB1*04:06 showed relatively specific high affinity with S-monohydroxy derivative of OXC. HLA-DRB1*04:06 is a specific risk allele for OXC-induced MPE in the Southern Han Chinese. HLA-A*24:02, possibly HLA-A*30:01, are common risk factors for AED-MPE. The multiplicative risk potential between HLA-A*24:02 and HLA-B*38:02 suggests that patients with two risk alleles are at greater risk than those with one risk allele. Inclusion of these HLA alleles in pre-treatment screening would help estimating the risk of AED-MPE.

UNC13B variants associated with partial epilepsy with favourable outcome.

The unc-13 homolog B (UNC13B) gene encodes a presynaptic protein, mammalian uncoordinated 13-2 (Munc13-2), which is highly expressed in the brain-predominantly in the cerebral cortex-and plays an essential role in synaptic vesicle priming and fusion, potentially affecting neuronal excitability. However, the functional significance of the UNC13B mutation in human disease is not known. In this study, we screened for novel genetic variants in a cohort of 446 unrelated cases (families) with partial epilepsy without acquired causes by trio-based whole-exome sequencing. UNC13B variants were identified in 12 individuals affected by partial epilepsy and/or febrile seizures from eight unrelated families. The eight probands all had focal seizures and focal discharges in EEG recordings, including two patients who experienced frequent daily seizures and one who showed abnormalities in the hippocampus by brain MRI; however, all of the patients showed a favourable outcome without intellectual or developmental abnormalities. The identified UNC13B variants included one nonsense variant, two variants at or around a splice site, one compound heterozygous missense variant and four missense variants that cosegregated in the families. The frequency of UNC13B variants identified in the present study was significantly higher than that in a control cohort of Han Chinese and controls of the East Asian and all populations in the Genome Aggregation Database (gnomAD). Computational modelling, including hydrogen bond and docking analyses, suggested that the variants lead to functional impairment. In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila. Electrophysiological recordings showed that excitatory neurons in Unc13b-deficient flies exhibited increased excitability. These results indicate that UNC13B is potentially associated with epilepsy. The frequent daily seizures and hippocampal abnormalities but ultimately favourable outcome under anti-epileptic therapy in our patients indicate that partial epilepsy caused by UNC13B variant is a clinically manageable condition.

Functional Differences Between Two Kv1.1 RNA Editing Isoforms: a Comparative Study on Neuronal Overexpression in Mouse Prefrontal Cortex.

The Shaker-related potassium channel Kv1.1 subunit has important implications for controlling neuronal excitabilities. A particular recoding by A-to-I RNA editing at I400 of Kv1.1 mRNA is an underestimated mechanism for fine-tuning the properties of Kv1.1-containing channels. Knowledge about functional differences between edited (I400V) and non-edited Kv1.1 isoforms is insufficient, especially in neurons. To understand their different roles, the two Kv1.1 isoforms were overexpressed in the prefrontal cortex via local adeno-associated virus-mediated gene delivery. The I400V isoform showed a higher competitiveness in membrane translocalization, but failed to reduce current-evoked discharges and showed weaker impact on spiking-frequency adaptation in the transduced neurons. The non-edited Kv1.1 overexpression led to slight elevations in both fast- and non-inactivating current components of macroscopic potassium current. By contrast, the I400V overexpression did not impact the fast-inactivating current component. Further isolation of Kv1.1-specific current by its specific blocker dendrotoxin-κ showed that both isoforms did result in significant increases in current amplitude, whereas the I400V was less efficient in contributing the fast-inactivating current component. Voltage-dependent properties of the fast-inactivating current component did not alter for both isoforms. For recovery kinetics, the I400V showed a significant acceleration of recovery from fast inactivation. The gene delivery of the I400V rather than the wild type exhibited anxiolytic activities, which was assessed by an open field test. These results suggest that the Kv1.1 RNA editing isoforms have different properties and outcomes, reflecting the functional and phenotypic significance of the Kv1.1 RNA editing in neurons.

Heterozygous PGM3 Variants Are Associated With Idiopathic Focal Epilepsy With Incomplete Penetrance.

INTRODUCTION: Idiopathic focal epilepsy (IFE) is a group of self-limited epilepsies. The etiology for the majority of the patients with IFE remains elusive. We thus screened disease-causing variants in the patients with IFE. METHODS: Whole-exome sequencing was performed in a cohort of 323 patients with IFE. Protein modeling was performed to predict the effects of missense variants. The genotype-phenotype correlation of the newly defined causative gene was analyzed. RESULTS: Four novel heterozygous variants in PGM3, including two de novo variants, were identified in four unrelated individuals with IFE. The variants included one truncating variant (c.1432C > T/p.Q478X) and three missense variants (c.478C > T/p.P160S, c.1239C > G/p.N413K, and c.1659T > A/p.N553K), which had no allele frequency in the gnomAD database. The missense variants were predicted to be damaging and affect hydrogen bonds with surrounding amino acids. Mutations Q478X, P160S, and N413K were associated with benign childhood epilepsy with centrotemporal electroencephalograph (EEG) spikes. P160S and N413K were located in the inner side of the enzyme active center. Mutation N553K was associated with benign occipital epilepsy with incomplete penetrance, located in the C-terminal of Domain 4. Further analysis demonstrated that previously reported biallelic PGM3 mutations were associated with severe immunodeficiency and/or congenital disorder of glycosylation, commonly accompanied by neurodevelopmental abnormalities, while monoallelic mutations were associated with milder symptoms like IFE. CONCLUSION: The genetic and molecular evidence from the present study implies that the PGM3 variants identified in IFE patients lead to defects of the PGM3 gene, suggesting that the PGM3 gene is potentially associated with epilepsy. The genotype-phenotype relationship of PGM3 mutations suggested a quantitative correlation between genetic impairment and phenotypic severity, which helps explain the mild symptoms and incomplete penetrance in individuals with IFE.

Relationship between genetic mutations and clinical phenotypes in patients with Wilson disease.

To study the relationship between genotype and clinical phenotype of major gene mutation sites in patients with Wilson disease (WD).Clinical and laboratory data were collected from 40 children with WD admitted to the hospital by high-pass sequencing. The basic clinical data of patients included the following: age, sex, first symptom, K-F ring, clinical classification, serum Ceruloplasmin (CP), 24 hours urine copper. High Frequency Mutations were identified in WD patients: Exon 8, Ar9778Leu, and study the relationship between high frequency mutation and clinical phenotype.The mutation frequency of 2333G>T(Arg778Leu) in Exon 8 was the highest (48%). The mutation frequency of Exon 13 at 2975C>T site was 29%. The age (t = 0.296, P = .768), sex (χ = 0.005, P = .944), first symptom (χ = 0.480, P = .449), K-F ring (χ = 0.321, P = .17), clinical classification (χ = 20.064, P > .969), serum CP levels (t = 0.007, P = .897) had no significant difference between Arg778Leu mutation group and non-Arg778Leu mutation group. Twenty-four-hour urinary copper levels (t = 12.134, P < .001,) in the Arg778Leu mutation group were higher than those in the Arg778Leu mutation group.Arg778Leu mutation is associated with 24 hours urinary copper. The study of the association between the type of gene mutation and the clinical phenotype has important implications for the occurrence regularity, pathogenesis, and disease progression in patients with WD.

Homozygous missense TPP1 mutation associated with mild late infantile neuronal ceroid lipofuscinosis and the genotype-phenotype correlation.

PURPOSE: TPP1 mutations have been identified in patients with variable phenotypes such as late infantile neuronal ceroid lipofuscinosis (LINCL), juvenile neuronal ceroid lipofuscinosis (JNCL), and spinocerebellar ataxia 7. However, the mechanism underlying phenotype variation is unknown. We screened TPP1 mutations in patients with epilepsies and analyzed the genotype-phenotype correlation to explain the phenotypic variations. METHODS: We performed targeted next-generation sequencing in a cohort of 330 patients with epilepsies. All previously reported TPP1 mutations were systematically retrieved from the PubMed and NCL Mutation Database. RESULTS: The homozygous missense TPP1 mutation c.646 G > A/ p.Val216Met was identified in a family with two affected siblings. The proband presented with seizures from three years of age, while no ataxia, cognitive regression, or visual abnormalities were observed. Further analysis of all reported TPP1 mutations revealed that the LINCL group had a significantly higher frequency of truncating and invariant splice-site mutations than the JNCL group. In contrast, the JNCL group had a higher frequency of variant splice-site mutations than LINCL. There was a significant correlation between phenotype severity and the frequency of destructive mutation. CONCLUSION: This study suggested that the phenotype of mainly epilepsy can be included in the phenotypic spectrum of TPP1 mutations, which are candidate targets for genetic screening in patients with epilepsy. With the development of therapy techniques, early genetic diagnosis may enable the improvement of etiology-targeted treatments. The relationship between phenotype severity and the genotype of TPP1 mutations may help explain the phenotypic variations.

LCK rs10914542-G allele associates with type 1 diabetes in children via T cell hyporesponsiveness.

BACKGROUND: Abnormal lymphocyte-specific protein tyrosine kinase (LCK)-related T cell hyporesponsiveness was discovered in type 1 diabetes (T1D). This study aims to investigate the potential associations between LCK single-nucleotide polymorphisms (SNPs) and the susceptibility of T1D. METHODS: DNAs were extracted from blood samples of 589 T1D patients and 596 healthy controls to genotype seven SNPs of the LCK gene using PCR and Sanger sequencing. Associations of these SNPs with the susceptibility of T1D were determined by χ2 test. LCKs were knocked out in peripheral blood mononuclear cells (PBMCs) using CRISPR-Cas9 to investigate the role of LCK SNP in T-lymphocyte activation in T1D. RESULTS: SNP rs10914542 but not the other six SNPs of the LCK gene was significantly associated with (C vs. G, odds ratio (OR) = 0.581, 95% confidence interval (CI) = 0.470-0.718, P value = 4.13E - 7) the susceptibility of T1D. Peripheral T-lymphocyte activation in response to T cell receptor (TCR)/CD3 stimulation is significantly lower in the rs10914542-G-allele group than in the C-allele group. In vitro experiments revealed that rs10914542 G allele impaired the TCR/CD3-mediated T-cell activation in PBMCs. CONCLUSIONS: This study reveals that the G allele of SNP rs10914542 of LCK impairs the TCR/CD3-mediated T-cell activation and increases the risk of T1D.

[Genetic analysis of 10 children with cerebral palsy].

OBJECTIVE: To explore the genetic basis of cerebral palsy (CP). METHODS: A pair of twins with cerebral palsy and different phenotypes were subjected to whole genome sequencing, and other 8 children with CP were subjected to whole exome sequencing. Genetic variations were screened by a self-designed filtration process in order to explore the CP-related biological pathways and genes. RESULTS: Three biological pathways related to CP were identified, which included axon guiding, transmission across chemical synapses and protein-protein interactions at synapses, and 25 susceptibility genes for CP were identified. CONCLUSION: The molecular mechanism of CP has been explored, which may provide clues for development of new treatment for CP.

Identification of pathways and genes associated with cerebral palsy.

Cerebral palsy (CP) is a non-progressive neurological disease, of which susceptibility is linked to genetic and environmental risk factors. More and more studies have shown that CP might be caused by multiple genetic factors, similar to other neurodevelopmental disorders. Due to the high genetic heterogeneity of CP, we focused on investigating related molecular pathways. Ten children with CP were collected for whole-exome sequencing by next-generation sequencing (NGS) technology. Customized processes were used to identify potential pathogenic pathways and variants. Three pathways (axon guidance, transmission across chemical synapses, protein-protein interactions at synapses) with twenty-three genes were identified to be highly correlated with CP. This study showed that the three pathways associated with CP might be the molecular mechanism of pathogenesis. These findings could provide useful clues for developing pathway-based pharmacotherapies. Further studies are required to confirm potential roles for these pathways in the pathogenesis of CP.

Few individuals with Lennox-Gastaut syndrome have autism spectrum disorder: a comparison with Dravet syndrome.

BACKGROUND: Autism spectrum disorder (ASD) in epilepsy has been a topic of increasing interest, which in general occurs in 15-35% of the patients with epilepsy, more frequently in those with intellectual disability (ID). Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) are two typical forms of intractable epileptic encephalopathy associated with ID. We previously reported that ASD was diagnosed in 24.3% of patients with DS, higher in those with profound ID. Given the severe epilepsy and high frequency of ID in LGS, it is necessary to know whether ASD is a common psychomotor co-morbidity of LGS. This study evaluated the autistic behaviors and intelligence in patients with LGS and further compared that between LGS and DS, aiming to understand the complex pathogenesis of epilepsy-ASD-ID triad. METHODS: A total of 50 patients with LGS and 45 patients with DS were enrolled and followed up for at least 3 years. The clinical characteristics were analyzed, and evaluations of ASD and ID were performed. RESULTS: No patients with LGS fully met the diagnostic criteria for ASD, but three of them exhibited more or less autistic behaviors. Majority (86%) of LGS patients presented ID, among which moderate to severe ID was the most common. Early onset age and symptomatic etiology were risk predictors for ID. The prevalence of ASD in LGS was significantly lower than that in DS (0/50 vs. 10/45, p < 0.001), while the prevalence and severity of ID showed no significant difference between the two forms of epileptic encephalopathy. CONCLUSIONS: This study demonstrated a significant difference in the co-morbidity of ASD between LGS and DS, although they had a similar prevalence and severity of ID, refuting the proposal that the prevalence of ASD in epilepsy is accounted for by ID. These findings suggest that the co-morbidity of ASD, ID, and epilepsy may result from multifaceted pathogenic mechanisms.