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Contribution of Rare and Potentially Functionally Relevant Sequence Variants in Schizophrenia Risk-Locus Xq28,distal. 精神分裂症风险病灶 Xq28 远端罕见和潜在功能相关序列变异的贡献
IF 1.6 3区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-10-30 DOI: 10.1002/ajmg.b.33011
I Claus, S Sivalingam, A C Koller, A Weiß, C M Mathey, L Sindermann, D Klein, L Henschel, K U Ludwig, P Hoffmann, A Heimbach, S Heilmann-Heimbach, H Vedder, J Kammerer-Ciernioch, T Stürmer, F Streit, A Maaser-Hecker, I Nenadić, B T Baune, A M Hartmann, B Konte, I Giegling, U Heilbronner, M Wagner, A Philipsen, B Schmidt, D Rujescu, A Buness, T G Schulze, M Rietschel, A J Forstner, M M Nöthen, F Degenhardt

Duplications of the Xq28,distal locus have been described in male and female patients with schizophrenia (SCZ) or intellectual disability. The Xq28,distal locus spans eight protein-coding genes (F8, CMC4, MTCP1, BRCC3, VBP1, FUNDC2, CLIC2, and RAB39B) and is flanked by recurrent genomic breakpoints. Thus, the issue of which gene/s at this locus is/are relevant in terms of SCZ pathogenesis remains unclear. The aim of this study was to investigate the contribution of rare and potentially functionally relevant sequence variants within the Xq28,distal locus to SCZ risk using the single-molecule molecular inversion probes (smMIP) method. Targeted sequencing was performed in a cohort of 1935 patients with SCZ and 1905 controls of European ancestry. The consecutive statistical analysis addressed two main areas. On the level of the individual variants, allele counts in the patient and control cohort were systematically compared with a Fisher's exact test: (i) for the entire present study cohort; (ii) for patients and controls separated by sex; and (iii) in combination with data published by the Schizophrenia Exome Meta-Analysis (SCHEMA) consortium. On the gene-wise level, a burden analysis was performed using the X-chromosomal model of the Optimal Unified Sequence Kernel Association Test (SKAT-O), with adjustment for possible sex-specific effects. Targeted sequencing identified a total of 13 rare and potentially functional variants in four patients and 11 controls. However, neither at the level of individual rare and potentially functional variants nor at the level of the eight protein-coding genes at the Xq28,distal locus was a statistically significant enrichment in patients compared to controls observed. Although inconclusive, the present findings represent a step toward improved understanding of the contribution of X-chromosomal risk factors in neuropsychiatric disorder development, which is an underrepresented aspect of genetic studies in this field.

在患有精神分裂症(SCZ)或智力障碍的男性和女性患者中,都曾出现过 Xq28 远端位点的重复。Xq28远端位点横跨八个蛋白质编码基因(F8、CMC4、MTCP1、BRCC3、VBP1、FUNDC2、CLIC2和RAB39B),两侧是反复出现的基因组断点。因此,该基因位点上的哪些基因与 SCZ 发病机制相关的问题仍不清楚。本研究的目的是利用单分子分子反转探针(smMIP)方法,研究Xq28远端位点上罕见且可能与功能相关的序列变异对SCZ风险的贡献。对1935名SCZ患者和1905名欧洲血统的对照组进行了靶向测序。连续统计分析主要涉及两个方面。在单个变异的层面上,通过费雪精确检验系统地比较了患者和对照组的等位基因数:(i) 本研究的整个队列;(ii) 按性别区分的患者和对照组;(iii) 结合精神分裂症外显子组元分析(SCHEMA)联盟公布的数据。在基因层面,使用最优统一序列核关联检验(SKAT-O)的 X 染色体模型进行了负荷分析,并对可能的性别特异性效应进行了调整。在 4 名患者和 11 名对照组中,靶向测序共发现了 13 个罕见的潜在功能变异。然而,与对照组相比,无论是在单个罕见和潜在功能变异的水平上,还是在Xq28远端位点的八个蛋白编码基因的水平上,都没有观察到患者的罕见和潜在功能变异在统计学上有显著的富集。尽管尚无定论,但本研究结果标志着我们朝着更好地了解 X 染色体风险因素在神经精神疾病发展中的作用迈出了一步,而这正是该领域遗传研究中代表性不足的一个方面。
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引用次数: 0
Optimizing the Prediction of Depression Remission: A Longitudinal Machine Learning Approach. 优化抑郁症缓解预测:纵向机器学习方法。
IF 1.6 3区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-10-29 DOI: 10.1002/ajmg.b.33014
Ewan Carr, Marcella Rietschel, Ole Mors, Neven Henigsberg, Katherine J Aitchison, Wolfgang Maier, Rudolf Uher, Anne Farmer, Peter McGuffin, Raquel Iniesta

Decisions about when to change antidepressant treatment are complex and benefit from accurate prediction of treatment outcome. Prognostic accuracy can be enhanced by incorporating repeated assessments of symptom severity collected during treatment. Participants (n = 714) from the Genome-Based Therapeutic Drugs for Depression study received escitalopram or nortriptyline over 12 weeks. Remission was defined as scoring ≤ 7 on the Hamilton Rating Scale. Predictors included demographic, clinical, and genetic variables (at 0 weeks) and measures of symptom severity (at 0, 2, 4, and 6 weeks). Longitudinal descriptors extracted with growth curves and topological data analysis were used to inform prediction of remission. Repeated assessments produced gradual and drug-specific improvements in predictive performance. By Week 4, models' discrimination in all samples reached levels that might usefully inform treatment decisions (area under the receiver operating curve (AUC) = 0.777 for nortriptyline; AUC = 0.807 for escitalopram; AUC = 0.794 for combined sample). Decisions around switching or modifying treatments for depression can be informed by repeated symptom assessments collected during treatment, but not until 4 weeks after the start of treatment.

决定何时更换抗抑郁治疗方法是一项复杂的工作,需要对治疗结果进行准确预测。通过在治疗过程中对症状严重程度进行反复评估,可以提高预测的准确性。基于基因组的抑郁症治疗药物研究的参与者(n = 714)接受了为期 12 周的艾司西酞普兰或去甲替林治疗。汉密尔顿评分量表得分≤7分即为缓解。预测因素包括人口统计学、临床和遗传变异(0 周时)以及症状严重程度测量(0、2、4 和 6 周时)。利用生长曲线和拓扑数据分析提取的纵向描述符为缓解预测提供了依据。通过重复评估,预测性能逐步提高,并针对特定药物。到第4周时,所有样本中模型的辨别力都达到了可为治疗决策提供有用信息的水平(去甲替林的接收者工作曲线下面积(AUC)=0.777;艾司西酞普兰的接收者工作曲线下面积(AUC)=0.807;综合样本的接收者工作曲线下面积(AUC)=0.794)。在治疗过程中,可通过重复收集症状评估结果来决定是否更换或修改抑郁症治疗方法,但要等到治疗开始 4 周后。
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引用次数: 0
New Insights Into TRMT10A Syndrome: Case Report and Literature Review. 对 TRMT10A 综合征的新认识:病例报告和文献综述
IF 1.6 3区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-10-23 DOI: 10.1002/ajmg.b.33015
Graziana Ceraolo, Giulia Spoto, Ambra Butera, Maria Spanò, Mirella Vinci, Girolamo Aurelio Vitello, Antonino Musumeci, Francesco Calì, Antonio Gennaro Nicotera, Gabriella Di Rosa

TRMT10A is related to a syndrome characterized by early-onset diabetes mellitus, microcephaly, epilepsy, and intellectual disability. We report a case of a patient showing spastic-ataxic paraparesis and Dandy-Walker variant associated with a causative homozygous c.421-1G > A variant in the TRMT10A gene, affecting a canonical splicing site. This mutation disrupts the "SAM-dependent methyltransferase TRM10-type domain", which is implicated in methylation and S-adenosylmethionine metabolic biological processes, crucial for mitochondrial and glucose metabolism. The prominent neurological involvement of our patient enhances the implication of TRMT10A in the brain development, suggesting a potential association between TRMT10A variants and dominant neurological phenotypes. This case expands the clinical spectrum of TRMT10A syndrome highlighting the importance of considering this gene in the evaluation of patients with brain/cerebellar malformations and spastic-ataxic paraparesis. Further research is warranted to elucidate the underlying pathogenic mechanisms and potential therapeutic implications.

TRMT10A 与一种以早发糖尿病、小头畸形、癫痫和智力障碍为特征的综合征有关。我们报告了一例表现为痉挛性共济失调性截瘫和 Dandy-Walker 变异的患者,其病因与 TRMT10A 基因中的一个同源基因 c.421-1G > A 变异有关,该变异影响了一个典型的剪接位点。该基因突变破坏了 "SAM 依赖性甲基转移酶 TRM10 型结构域",而该结构域与甲基化和 S-腺苷蛋氨酸代谢生物过程有关,对线粒体和葡萄糖代谢至关重要。本例患者突出的神经系统受累增强了 TRMT10A 在大脑发育中的作用,提示 TRMT10A 变体与显性神经系统表型之间可能存在关联。该病例扩大了 TRMT10A 综合征的临床范围,强调了在评估脑/小脑畸形和痉挛性截瘫患者时考虑该基因的重要性。我们有必要开展进一步的研究,以阐明潜在的发病机制和潜在的治疗意义。
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引用次数: 0
Characterization of Two Novel PNKP Splice-Site Variants in a Proband With Microcephaly, Intellectual Disability, and Multiple Malformations. 一个患有小头畸形、智力障碍和多种畸形的婴儿体内两个新的 PNKP 片段位点变异的特征。
IF 1.6 3区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-10-17 DOI: 10.1002/ajmg.b.33013
Ugo Sorrentino, Elisa Baschiera, Maria Andrea Desbats, Orsetta Zuffardi, Leonardo Salviati, Matteo Cassina

Polynucleotide kinase phosphatase (PNKP), encoded by the PNKP gene, is a DNA processing enzyme involved in double-strand break and single-strand break repair pathways, which are essential for genome stability and for the correct development and maintenance of human nervous system. PNKP biallelic loss-of-function variants have been associated with a broad spectrum of neurological anomalies, ranging from congenital microcephaly with intellectual disability and seizures (MCSZ), to later onset forms of ataxia-oculomotor apraxia (AOA4) or peripheral neuropathy (CMT2B2). We report the atypical clinical manifestations of a patient with severe microcephaly, short stature, developmental delay, conductive hearing loss, and tracheoesophageal malformation, in the absence of seizures. Whole exome sequencing analysis identified two novel, compound heterozygous splice-site variants in the PNKP gene (NM_007254.4): c.1448+1G > A and c.199-8_199-5del. To demonstrate the effect of both variants on the splicing process and prove their pathogenicity, we performed a hybrid minigene assay, which successfully highlighted a deleterious impact on the transcript, particularly regarding the c.199-8_199-5del variant. The uncommon clinical features of the proband and the identification of two newly associated pathogenic variants add further evidence to the allelic and phenotypic heterogeneity of the PNKP locus.

多核苷酸激酶磷酸酶(PNKP)由 PNKP 基因编码,是一种 DNA 处理酶,参与双链断裂和单链断裂修复途径,对基因组稳定性以及人类神经系统的正确发育和维护至关重要。PNKP 双重功能缺失变异与多种神经系统异常有关,包括先天性小头畸形伴智力障碍和癫痫发作(MCSZ),以及迟发性共济失调-运动障碍(AOA4)或周围神经病变(CMT2B2)。我们报告了一名患者的非典型临床表现,该患者患有严重小头畸形、身材矮小、发育迟缓、传导性听力损失和气管食管畸形,但没有癫痫发作。全外显子组测序分析在PNKP基因(NM_007254.4)中发现了两个新型复合杂合剪接位点变异:c.1448+1G > A和c.199-8_199-5del。为了证明这两个变异位点对剪接过程的影响并证明其致病性,我们进行了杂交微型基因检测,结果成功地突出了对转录本的有害影响,尤其是对 c.199-8_199-5del 变异位点的影响。该患者不常见的临床特征和两个新发现的相关致病变异为 PNKP 基因座的等位基因和表型异质性提供了进一步的证据。
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引用次数: 0
Genetic Variants ε2 and ε4 of APOE Predict Mortality and Poor Outcome Independently in Spontaneous Intracerebral Hemorrhage Within the Chinese Han Population. APOE的遗传变异ε2和ε4可独立预测中国汉族人群自发性脑内出血的死亡率和不良预后。
IF 1.6 3区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-10-06 DOI: 10.1002/ajmg.b.33010
Chuyue Wu, Qinji Zhou, Yu Huang, Fei Yan, Zhenjie Yang, Lei He, Qian Li, Li Li

The heightened mortality and disability rates, coupled with restricted neurological recovery post intracerebral hemorrhage (ICH), have sparked considerable attention toward its treatment and results. Simultaneously, the influence of the APOE gene on ICH prognosis has been well-documented. This research aimed to explore the relationship between specific APOE alleles in the present cohort and the incidences of mortality, recurrence, and adverse prognosis, as determined by neurological function assessments in ICH patients. Data on patients diagnosed with ICH and hospitalized in the Department of Neurology at our institution from October 2021 to March 2022 were collected, including determining their APOE genotypes. A 1-year follow-up was conducted to evaluate mortality, ICH recurrence, and modified Rankin Scale (mRS) scores at 3 and 12 months. Poor prognosis was defined as an mRS score of ≥ 3. Initially, we analyzed the relationships between different APOE alleles and mortality, recurrence, and poor prognosis. Subsequently, we explored additional factors influencing each prognostic outcome and conducted multivariate analysis to identify independent risk factors. An analysis was conducted on 289 patients diagnosed with ICH. The presence of the ε2 allele was found to be a significant independent predictor for unfavorable outcomes at both 3 months (p = 0.022, OR = 2.138, 95% CI [2.041, 3.470]) and 1 year (p = 0.020, OR = 5.116, 95% CI [5.044, 5.307]). Moreover, the ε4 allele was established as an independent risk factor for ICH recurrence within 1 year (p = 0.025, OR = 2.326, 95% CI [1.163, 2.652]), as well as for mortality at 3 months (p = 0.037, OR = 4.250, 95% CI [4.068, 4.920]) and 1 year (p = 0.023, OR = 4.109, 95% CI [4.016, 4.739]). In conclusions, Both APOE ε2 and ε4 variants independently heighten mortality risk, recurrence, and poor prognosis after ICH. The substantial influence underscores the need for additional investigation into the impact of APOE genotype on ICH prognosis.

脑内出血(ICH)后死亡率和致残率升高,加上神经功能恢复受限,引发了人们对其治疗和结果的极大关注。与此同时,APOE 基因对 ICH 预后的影响也已得到充分证实。本研究旨在探讨本研究队列中特定 APOE 等位基因与 ICH 患者死亡率、复发率和不良预后发生率之间的关系,并通过神经功能评估加以确定。我们收集了 2021 年 10 月至 2022 年 3 月期间本院神经内科确诊为 ICH 并住院的患者数据,包括确定他们的 APOE 基因型。随访1年,评估死亡率、ICH复发情况以及3个月和12个月时的改良Rankin量表(mRS)评分。预后不良的定义是 mRS 评分≥ 3。我们首先分析了不同 APOE 等位基因与死亡率、复发和预后不良之间的关系。随后,我们探讨了影响每种预后结果的其他因素,并进行了多变量分析,以确定独立的风险因素。我们对 289 例确诊为 ICH 的患者进行了分析。结果发现,ε2 等位基因的存在是 3 个月(p = 0.022,OR = 2.138,95% CI [2.041,3.470])和 1 年(p = 0.020,OR = 5.116,95% CI [5.044,5.307])不利预后的重要独立预测因素。此外,ε4 等位基因被确定为 1 年内 ICH 复发(p = 0.025,OR = 2.326,95% CI [1.163,2.652])以及 3 个月内死亡率(p = 0.037,OR = 4.250,95% CI [4.068,4.920])和 1 年内死亡率(p = 0.023,OR = 4.109,95% CI [4.016,4.739])的独立危险因素。总之,APOE ε2和ε4变异均可独立增加ICH后的死亡风险、复发和不良预后。这种重大影响突出表明,有必要进一步研究 APOE 基因型对 ICH 预后的影响。
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引用次数: 0
Causal Relationship Between Autism Spectrum Disorder and Inflammatory Bowel Disease: A Bidirectional Mendelian Randomization Study. 自闭症谱系障碍与炎症性肠病之间的因果关系:双向孟德尔随机化研究
IF 1.6 3区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-10-01 DOI: 10.1002/ajmg.b.33012
Weilin Li, Xiaoyu He, Chao Tan, Tao Zhang

Patients with autism spectrum disorder (ASD) are often accompanied by inflammatory bowel disease (IBD) in observational research; however, the potential causal link between the two conditions remains unknown. In this study, we used a two-sample bidirectional Mendelian randomization (MR) approach to assess the causal relationship between ASD and IBD and its main subtypes, Crohn's disease (CD), and ulcerative colitis (UC). Independent genetic instruments from a genome-wide association study (GWAS) for IBD (25,042 cases and 34,915 controls) were used to investigate the association of IBD with ASD data obtained from the PGC and the iPSYCH consortia (N = 46,351). The primary analysis employed the random effects inverse variance weighting (IVW) method. Horizontal pleiotropy was detected using the MR Egger regression and the MR-pleiotropy residual sum and outlier (MR-PRESSO) analysis while heterogeneity was detected using Cochran's Q. The IVW method indicated a positive causal relationship of IBD with ASD (odds ratio (OR) = 1.028, 95% confidence interval (CI) = 1.001-1.056, p = 0.042). In subtype analyses, CD was positively related to ASD (OR = 1.036; 95% CI = 1.004-1.069; p = 0.02); however, UC showed no relationship (OR = 1.021; 95% CI = 0.999-1.044; p = 0.065). In contrast, no evidence of a causal relationship between ASD and IBD or its subtypes (p > 0.05) was found. Our findings provided evidence in support of potential causal associations between IBD/CD and ASD.

在观察性研究中,自闭症谱系障碍(ASD)患者通常伴有炎症性肠病(IBD);然而,这两种疾病之间的潜在因果关系仍然未知。在这项研究中,我们采用了双样本双向孟德尔随机化(MR)方法来评估 ASD 与 IBD 及其主要亚型克罗恩病(CD)和溃疡性结肠炎(UC)之间的因果关系。IBD全基因组关联研究(GWAS)的独立遗传工具(25,042例病例和34,915例对照)被用来研究IBD与ASD的关联,这些数据来自PGC和iPSYCH联盟(N = 46,351)。主要分析采用随机效应逆方差加权法(IVW)。IVW 方法表明,IBD 与 ASD 存在正向因果关系(比值比 (OR) = 1.028,95% 置信区间 (CI) = 1.001-1.056,P = 0.042)。在亚型分析中,CD 与 ASD 呈正相关(OR = 1.036;95% CI = 1.004-1.069;p = 0.02);但 UC 与 ASD 没有关系(OR = 1.021;95% CI = 0.999-1.044;p = 0.065)。相比之下,没有证据表明 ASD 与 IBD 或其亚型之间存在因果关系(p > 0.05)。我们的研究结果为 IBD/CD 与 ASD 之间的潜在因果关系提供了证据支持。
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引用次数: 0
Sex Differences in Cortical Thickness and Neuropsychiatric Symptom Burden Based on APOE4 Homozygosity in Alzheimer's Disease. 基于阿尔茨海默病 APOE4 基因同源性的皮质厚度和神经精神症状负担的性别差异。
IF 1.6 3区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-09-30 DOI: 10.1002/ajmg.b.33008
Marc A Khoury, Mila Valcic, Nathan W Churchill, Alex Di Battista, Vincenzo De Luca, Luis R Fornazzari, David G Munoz, Corinne E Fischer, Tom A Schweizer

Sex differences in patterns of cortical thickness and neuropsychiatric symptom (NPS) burden were examined among individuals with Alzheimer's disease (AD) and two copies (homozygote carriers) of the e4 allele of the apolipoprotein gene (APOE). A total of 752 participants with a clinical etiologic diagnosis of AD were selected from the National Alzheimer's Coordinating Center (NACC) database. Bayesian multilevel regression was used to examine both the within- and between-sex differences in gray-matter cortical thickness and total NPS burden associated with APOE homozygosity. Female homozygote carriers displayed a high probability of having reduced cortical thickness primarily in medial-lateral temporal regions and a greater burden of NPS, relative to both non-homozygous females and homozygous males. These findings support the notion that APOE4 status affects cortical thickness and symptom burden in men and women with AD differentially, with females showing more pronounced effects in brain areas known to be vulnerable in early AD. Future investigations should attempt to elucidate the proposed pattern of decline longitudinally.

我们研究了阿尔茨海默病(AD)患者和脂蛋白基因(APOE)e4等位基因两个拷贝携带者(同基因携带者)在皮层厚度和神经精神症状(NPS)负担模式方面的性别差异。研究人员从美国国家阿尔茨海默病协调中心(NACC)数据库中选取了 752 名临床病因诊断为阿尔茨海默病的患者。该研究采用贝叶斯多层次回归法,考察了与APOE同基因相关的灰质皮层厚度和NPS总负荷的性别内和性别间差异。与非同源基因女性和同源基因男性相比,女性同源基因携带者的皮质厚度主要在颞叶内外侧区域降低的概率较高,且NPS负担较重。这些发现支持这样一种观点,即APOE4状态对男性和女性AD患者的皮层厚度和症状负担的影响是不同的,女性对已知在AD早期易受影响的脑区的影响更为明显。未来的研究应尝试纵向阐明所提出的衰退模式。
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引用次数: 0
Parenting Stress Index in Caregivers of Individuals With Noonan Syndrome. 努南综合征患者照顾者的养育压力指数。
IF 1.6 3区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-09-27 DOI: 10.1002/ajmg.b.33009
Lucrezia Perri, Germana Viscogliosi, Valentina Trevisan, Claudia Brogna, Daniela Pia Rosaria Chieffo, Ilaria Contaldo, Paolo Alfieri, Nicolo' Lentini, Roberta Pastorino, Giuseppe Zampino, Chiara Leoni

Medical professionals frequently underestimate stress level of parents/caregivers of patients with rare disorders as RASopathies, the latter might experience elevated stress levels, with their own health frequently overlooked despite significant responsibilities and hurdles encountered. The aim of this study is to assess the stress experienced by parents of individuals with Noonan syndrome and related conditions. Forty-eight parents (20 fathers; 28 mothers), among the 31 recruited families, completed the Italian version of the Parenting Stress Index-Short Form. Our study shows abnormally elevated scores (≥ 85° percentile) in 35.4% of parents. Data retrieved from subscales reveal a perception of a difficult child in 25% of cases, a dysfunctional parental-child interaction in 20.8%, a general parental distress in 10.4% of cases, and an elevated overall stress in 18.8% of parents. Questionnaires as the Parenting Stress Index-Short Form are valuable tools to evaluate stress in parents/caregivers of children with RASopathies. Evaluation by professionals is fundamental to support parents and caregivers in managing stressors and to enhance their quality of life and relationships. To prevent stress escalation and parents' burnout, an early assessment to tailor a timely treatment should be introduced as soon as possible as good clinical practice.

医疗专业人员经常低估罕见疾病(如 RASopathies)患者的父母/照护者的压力水平,后者可能会经历更高的压力水平,尽管面临重大责任和障碍,他们自身的健康却经常被忽视。本研究旨在评估努南综合征及相关疾病患者父母所承受的压力。在招募的 31 个家庭中,有 48 位父母(20 位父亲;28 位母亲)完成了意大利语版的养育压力指数简表。我们的研究显示,35.4% 的父母得分异常升高(≥ 85° 百分位数)。从分量表中获取的数据显示,25%的父母认为自己的孩子很难管,20.8%的父母认为自己与孩子的互动不正常,10.4%的父母认为自己很苦恼,18.8%的父母认为自己的整体压力增大。育儿压力指数(Parenting Stress Index-Short Form)调查表是评估 RAS 病患儿父母/照顾者压力的重要工具。专业人员的评估对于支持家长和照顾者管理压力、提高生活质量和改善人际关系至关重要。为防止压力升级和家长的职业倦怠,作为良好的临床实践,应尽早进行早期评估,以便及时调整治疗方案。
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引用次数: 0
Cognitive, Social, and Emotional-Behavioral Outcomes in Children and Adolescents With Beckwith-Wiedemann Syndrome. 贝克维茨-韦德曼综合症儿童和青少年的认知、社交和情感行为结果。
IF 1.6 3区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-09-25 DOI: 10.1002/ajmg.b.33006
Niccolò Butti, Cosimo Urgesi, Alessandro Mussa, Rosario Montirosso

Although Beckwith-Wiedemann syndrome spectrum (BWSp) is not usually associated with intellectual disability, recent evidences calls for further investigation of cognitive development and academic skills in children with BWSp. Moreover, research has documented social difficulties and emotional-behavioral problems associated with BWSp. Nevertheless, a full characterization of socio-emotional development in BWSp is still lacking. In the current study, cognitive and socio-emotional development was assessed in 29 children with BWSp aged 5-18 years, using a test of nonverbal intelligence, a neuropsychological battery covering multiple domains, academic skills tests, and questionnaires evaluating autistic traits and emotional-behavioral problems. As expected, most participants showed adequate performance in cognitive tests. However, the findings also highlighted greater difficulties in language than visuospatial processing, strengths in social perception, as well as slowness in reading and mental calculation. The assessment of emotional-behavioral difficulties indicated a prevalent phenotype characterized by increased anxiety, low self-esteem, social withdrawal and a tendency to control externalizing reactions, but no associations with autistic traits, cognitive outcomes, and the clinical score proposed by the recent Consensus statement. Increased social perception and internalization problems likely result from coping strategies with social and care-related stress. Overall, the findings of this study inform clinical management and genetic counseling for children and adolescents with BWSp.

虽然贝克维茨-韦德曼综合征谱系(BWSp)通常与智力障碍无关,但最近的证据表明,需要进一步研究贝克维茨-韦德曼综合征谱系儿童的认知发展和学习技能。此外,研究还记录了与 BWSp 相关的社交困难和情绪行为问题。然而,目前仍缺乏对 BWSp 儿童社会情感发展的全面描述。在本研究中,我们使用非语言智力测验、涵盖多个领域的神经心理测试、学习技能测试以及评估自闭症特征和情绪行为问题的问卷,对 29 名 5-18 岁的 BWSp 儿童的认知和社会情感发展进行了评估。不出所料,大多数参与者在认知测试中都表现出了足够的能力。然而,研究结果也突出表明,语言方面的困难大于视觉空间处理能力,社会感知能力较强,阅读和心算能力较慢。对情绪行为障碍的评估表明,自闭症患者普遍存在焦虑增加、自卑、社交退缩和倾向于控制外化反应等表型,但与自闭症特征、认知结果和近期共识声明提出的临床评分没有关联。社交感知和内化问题的增加可能是应对社交和护理相关压力的策略所致。总之,本研究的结果可为 BWSp 儿童和青少年的临床管理和遗传咨询提供参考。
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引用次数: 0
Circadian Rhythms Correlated in DNA Methylation and Gene Expression Identified in Human Blood and Implicated in Psychiatric Disorders. 在人体血液中发现与 DNA 甲基化和基因表达相关的昼夜节律,并与精神疾病有关。
IF 1.6 3区 医学 Q3 GENETICS & HEREDITY Pub Date : 2024-09-25 DOI: 10.1002/ajmg.b.33005
Haiyan Tang, Shanshan Chen, Liu Yi, Sheng Xu, Huihui Yang, Zongchang Li, Ying He, Yanhui Liao, Xiaogang Chen, Chunyu Liu, Lin Gu, Ning Yuan, Chao Chen, Jinsong Tang

Circadian rhythms modulate the biology of many human tissues and are driven by a nearly 24-h transcriptional feedback loop. Dynamic DNA methylation may play a role in driving 24-h rhythms of gene expression in the human brain. However, little is known about the degree of circadian regulation between the DNA methylation and the gene expression in the peripheral tissues, including human blood. We hypothesized that 24-h rhythms of DNA methylation play a role in driving 24-h RNA expression in human blood. To test this hypothesis, we analyzed DNA methylation levels and RNA expression in blood samples collected from eight healthy males at six-time points over 24 h. We assessed 442,703 genome-wide CpG sites in methylation and 12,364 genes in expression for 24-h rhythmicity using the cosine model. Our analysis revealed significant rhythmic patterns in 6345 CpG sites and 21 genes. Next, we investigated the relationship between methylation and expression using powerful circadian signals. We found a modest negative correlation (ρ = -0.83, p = 0.06) between the expression of gene TXNDC5 and the methylation at the nearby CpG site (cg19116172). We also observed that circadian CpGs significantly overlapped with genetic risk loci of schizophrenia and autism spectrum disorders. Notably, one gene, TXNDC5, showed a significant correlation between circadian methylation and expression and has been reported to be association with neuropsychiatric diseases.

昼夜节律调节许多人体组织的生物学特性,并由一个近 24 小时的转录反馈回路驱动。动态 DNA 甲基化可能在驱动人脑基因表达的 24 小时节律中发挥作用。然而,人们对包括人体血液在内的外周组织中 DNA 甲基化与基因表达之间的昼夜节律调节程度知之甚少。我们假设 DNA 甲基化的 24 小时节律在驱动人体血液中 24 小时 RNA 表达方面发挥作用。为了验证这一假设,我们分析了从 8 名健康男性血液样本中采集的 24 小时内 6 个时间点的 DNA 甲基化水平和 RNA 表达。分析结果显示,6345 个 CpG 位点和 21 个基因存在明显的节律模式。接下来,我们利用强大的昼夜节律信号研究了甲基化与表达之间的关系。我们发现基因 TXNDC5 的表达与附近 CpG 位点(cg19116172)的甲基化之间存在适度的负相关(ρ = -0.83,p = 0.06)。我们还观察到,昼夜节律CpGs与精神分裂症和自闭症谱系障碍的遗传风险位点明显重叠。值得注意的是,有一个基因 TXNDC5 的昼夜节律甲基化与表达之间存在明显的相关性,并且有报道称该基因与神经精神疾病有关。
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引用次数: 0
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American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
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