Expanding allelic and phenotypic spectrum of ZC4H2-related disorder: A novel hypomorphic variant and high prevalence of tethered cord

ZC4H2 (MIM# 300897) is a nuclear factor involved in various cellular processes including proliferation and differentiation of neural stem cells, ventral spinal patterning and osteogenic and myogenic processes. Pathogenic variants in ZC4H2 have been associated with Wieacker-Wolff syndrome (MIM# 314580), an X-linked neurodevelopmental disorder characterized by arthrogryposis, development delay, hypotonia, feeding difficulties, poor growth, skeletal abnormalities, and dysmorphic features. Zebrafish zc4h2 null mutants recapitulated the human phenotype, showed complete loss of vsx2 expression in brain, and exhibited abnormal swimming and balance problems. Here we report 7 new patients (four males and three females) with ZC4H2-related disorder from six unrelated families. Four of the 6 ZC4H2 variants are novel: three missense variants, designated as c.142T>A (p.Tyr48Asn), c.558G>A (p.Met186Ile) and c.602C>T (p.Pro201Leu), and a nonsense variant, c.618C>A (p.Cys206*). Two variants were previously reported : a nonsense variant c.199C>T (p.Arg67*) and a splice site variant (c.225+5G>A). Five patients were on the severe spectrum of clinical findings, two of whom had early death. The male patient harboring the p.Met186Ile variant and the female patient that carries the p.Pro201Leu variant have a relatively mild phenotype. Of note, 4/7 patients had a tethered cord that required a surgical repair. We also demonstrate and discuss previously under-recognized phenotypic features including sleep apnea, arrhythmia, hypoglycemia, and unexpected early death. To study the effect of the missense variants, we performed microinjection of human ZC4H2 wild-type or variant mRNAs into zc4h2 null mutant zebrafish embryos. The p.Met186Ile mRNA variant was able to partially rescue vsx2 expression while p.Tyr48Asn and p.Pro201Leu mRNA variants were not. However, swimming and balance problems could not be rescued by any of these variants. These results suggest that the p.Met186Ile is a hypomorphic allele. Our work expands the genotypes and phenotypes associated with ZC4H2-related disorder and demonstrates that the zebrafish system is a reliable method to determine the pathogenicity of ZC4H2 variants.     

妊高征患者与ACE基因缺失多态性研究

目的：探讨血管紧张素转换酶（ＡＣＥ）基因的缺失多态性与妊高征的关系。方法：对５２例妊高征患者（观察组）及１００例正常产妇,应用聚合酶链反应技术检测ＡＣＥ基因的缺失／插入多态性。结果：观察组的缺失型纯合子（ＤＤ型）ＡＣＥ基因占６５％,高于对照组的１６％;观察组的缺失型（Ｄ型）ＡＣＥ等位基因出现频率为７５％,亦高于对照组的３３％（Ｐ〈０．０１）。结论：妊高征的发病与ＡＣＥ基因的缺失多态性有关。     

难治性肾病的判别及危险因素分析

目的　产生激素敏感性肾病与难治性肾病的判别函数 ,了解引起肾病难治的危险因素。方法　使用SPSS软件包 ,对激素敏感与难治性肾病 2组患儿的临床资料进行了逐步判别分析和条件logistic逐步回归。结果　筛选出血尿 (blo)、水肿程度 (ede)、感染 (inf)、白蛋白输入 (per) 4个变量对 2类总体有显著贡献 ,其判别方程为 :X1=- 6 .16 18 5 .2 6 2 2blo 2 .5 86 0ede 0 .710 8inf 0 .5 6 86per,X2 =- 11.1970 6 .72 18blo 3.40 42ede 2 2 873inf 2 .75 0 3per。此判别函数的Wilks统计量为 0 .6 947,P <0 .0 1,回代判别总的准确率为 77.88%。由这些自变量组成的logistic线性方程为 :Y =- 5 .5 789 1.15 38blo 0 .8711ede 1.3714inf 1.5 72 3per,这 4个变量的条件危险比分别为 3.170 3、2 .3894、3.940 9和 4.8178。结论　血尿、高度水肿、感染、白蛋白输入是肾病综合征难治的危险因素     

维生素E和二甲亚砜对油酸型ARDS防治作用的研究

目的 研究氧化性肺损伤在成人呼吸窘迫综合征（ＡＲＤＳ）发病中的作用及维生素Ｅ和二甲亚砜的抗氧化保护作用。方法 将２８只大鼠随机分成４组：油酸组,ＶＥ组,ＤＭＳＯ组,正常对照组。油酸于尾静脉注入,维生素Ｅ和二甲亚砜由腹腔注射。注油酸后２ｈ观察肺系数,肺组织ＭＤＡ含量,ＰａＯ２及肺组织病理改变。结果 ＶＥ组和ＤＭＳＯ组较油酸组肺系数,ＭＤＡ含量降低,ＰａＯ２同,肺组织病理改变明显减轻。     

临床活体部分小肠移植术移植肠的处理

目的 报告我国首例活体小肠移植术的移植肠处理体会。方法 为１例１８岁男性超短肠综合征患放行了活体部分小肠移植术,供肠来自患的父亲（４４岁）,切取供体回肠１５０ｃｍ,ＵＷ液灌洗血管,将移植肠动、静脉车受体腹主动及及下腔静脉而吻合,移植肠近端与受体空肠近端行端端吻合,远端与受体空肠远端行侧端吻合,末端造口,术后给子抗排斥,抗感染,抗凝及营养支持等治疗。结果 术后管出现贫血,单纯疱疹病感染和急性排斥     

肾综合征出血热患者血液透析前后的血液流变性及甲襞微循环变化

目的 探讨肾综合征出血热（ＨＦＲＳ）合并争性肾功衰竭（ＡＲＦ）患者血液透析（ＨＤ）前后的血液流变性及甲臂微循环的变化规律。方法 采用瑞曲Ｇａｍｂｒｏ公司生产的ＡＫ－１０型血液透析机治疗患者４５型,血液流变学及甲臂微循环指标分别采用成都仪器厂的ＮＸＥ－１型锥板式粘度计和徐州光学仪器厂的ＭＸ－７５３Ｂ微循环显微镜检测,所得数据按田牛氏综合定量评价方法,计算综合加权积分值。结果 ＨＤ前后患者血中ＢＵＮ,     

GM-CSF-producing CCR2+CCR6+ Th17 cells are pathogenic in dextran sodium sulfate-induced colitis model in mice

Although excessive immune responses by Th17 cells, a helper T cell subset, are implicated in the pathogenesis of inflammatory bowel disease (IBD), the mechanism by which its localization in an inflamed colon is regulated remains unclear. Chemokines and their receptors are involved in the pathogenesis of IBD, however, the relative significance of each receptor on Th17 cells remains unknown. We generated C–C motif chemokine receptor 2 (CCR2) knockout (KO) and CCR6 KO mice in the syngeneic background using the CRISPR/Cas9 system and found that the phenotypes of experimental colitis worsened in both mutant mice. Surprisingly, the phenotype of colitis in CCR2/CCR6-double knockout (CCR2/6 DKO) mice was opposite to that of the single-deficient mice, with significantly milder experimental colitis (p < .05). The same was true for the symptoms in CCR6 KO mice, but not in wild type mice treated with a CCR2 inhibitor, propagermanium. Colonic CCR2⁺CCR6⁺ Th17 cells produced a potentially pathogenic cytokine GM-CSF whose levels in the gut were significantly reduced in CCR2/6 DKO mice (p < .05). These results suggest that GM-CSF-producing CCR2⁺CCR6⁺ Th17 cells are pathogenic and are attracted to the inflamed colon by either CCR2 or CCR6 gradient, which subsequently exacerbates experimental colitis in mice.     

1p36 deletion syndrome: Review and mapping with further characterization of the phenotype,a new cohort of 86 patients

Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second-largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype–phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow-up of patients.     

Comprehensive genetic screening for vascular Ehlers–Danlos syndrome through an amplification-based next-generation sequencing system

Vascular Ehlers–Danlos syndrome (vEDS) is a hereditary connective tissue disorder (HCTD) characterized by arterial dissection/aneurysm/rupture, sigmoid colon rupture, or uterine rupture. Diagnosis is confirmed by detecting heterozygous variants in COL3A1. This is the largest Asian case series and the first to apply an amplification-based next-generation sequencing through custom panels of causative genes for HCTDs, including a specific method of evaluating copy number variations. Among 429 patients with suspected HCTDs analyzed, 101 were suspected to have vEDS, and 33 of them (32.4%) were found to have COL3A1 variants. Two patients with a clinical diagnosis of Loeys–Dietz syndrome and/or familial thoracic aortic aneurysm and dissection were also found to have COL3A1 variants. Twenty cases (57.1%) had missense variants leading to glycine (Gly) substitutions in the triple helical domain, one (2.9%) had a missense variant leading to non-Gly substitution in this domain, eight (22.9%) had splice site alterations, three (8.6%) had nonsense variants, two (5.7%) had in-frame deletions, and one (2.9%) had a multi-exon deletion, including two deceased patients analyzed with formalin-fixed and paraffin-embedded samples. This is a clinically useful system to detect a wide spectrum of variants from various types of samples.