■Joubert综合征是一种罕见的遗传性疾病,其特征是中枢神经系统发育异常,大脑磁共振成像显示“磨牙征”,并伴有小脑疣发育不全,共济失调,低张力,和发育迟缓。圆锥角膜(KC)是一种遗传易感的眼病,其特征是中心或中心旁角膜锥形向前投射的扩张变薄,高度不规则散光,和严重的视力障碍。Klinefelter综合征是由男性患者的细胞中多余的X染色体引起的,主要表型为高个子和发育不良,具有第二性征。本研究旨在确定一个具有圆锥角膜和多器官受累的特定临床表现的汉族家庭的遗传病因并确定其临床诊断。
■对一名患者及其无症状的父母和兄弟进行了全面的眼部和相关的一般检查。通过外显子组测序测试致病基因。CNV-seq用于验证拷贝数变异,培养外周血进行核型分析。根据ACMG指南确定所鉴定的变体的致病性。获得NCBI数据库中圆锥角膜相关基因的基因表达综合(GEO)数据集,分析圆锥角膜组和正常对照组角膜组织中的差异表达基因,并进行了蛋白质-蛋白质相互作用网络(PPI)的分析。
■Proband,一个25岁的男性,左眼视力突然丧失1周。最佳矫正视力(BCVA):右眼0.5(-1.00DS/-5.00DC*29°),计算手指/40厘米的左眼。右眼裂隙灯显微镜检查显示角膜轻度前突,锥顶角膜变薄。左眼显示角膜中央区域明显变薄,呈锥状凸起的圆形水肿,上皮性大疱,基质的水肿和浑浊,和Descemet膜的膨胀。颅磁共振成像(MRI)显示中脑和小脑的变化,带有“磨牙符号”和“蝙蝠翅”脑室。一般检查:身高168厘米,四肢肌肉张力下降,引起膝跳,Babinski阴性体征,引起腹反射,手指到鼻子测试呈阳性,双手都有明显的故意震颤,肯定Romberg\'ssign,步态不稳定,一级智力残疾,不良的适应性行为,沟通障碍,牙齿所有的假牙,一个特殊的脸有眼睑萎缩,宽的内眼角距离,轻度下垂,严重的内胎膜阳性,高腭弓,外斜视,胡须和面部的毛发减退,不显眼的突出喉部,和短的上肢和下肢。外显子组测序检测到复合杂合移码变体M1:c.9279dup:p。His3094Thrfs*18和M2:c.6515_6522del:p。Lys2172Thrfs*37在患者的CPLANE1基因和X染色体上存在复制型CNV。Sanger测序显示,母亲和父亲携带M1和M2变体,分别,弟弟带着M2变体,这是一个新颖的变体。CNV-seq分析表明,在先证者的X染色体上存在约155Mb的复制型CNVXp22.33-Xq28(2757837-156030895),这是一个从头变种,父母都没有携带。根据ACMG指南,两种杂合移码变体和重复型CNV具有致病性。圆锥角膜相关基因的差异表达分析表明,与正常对照相比,圆锥角膜患者角膜组织中CPLANE1表达上调,差异有统计学意义(p=0.000515,<0.05)。PPI分析表明,CPLANE1-NPHP3复合蛋白充当纤毛和细胞外基质组织之间的桥梁。根据基因检测结果和临床表型分析,该家庭最终被诊断为Joubert综合征合并圆锥角膜和Klinefelter综合征.
■在这项研究中,我们报告了一个先证者,在一个汉族家庭中,患有Joubert综合征和X连锁Klinefelter综合征以及圆锥角膜,CPLANE1-Joubert综合征的表型谱可能会相应扩展。同时,外显子组测序的重要性在帮助复杂病例的临床诊断中得到了强调,这很难做到。
UNASSIGNED: Joubert syndrome a rare genetic disorder, is characterized by abnormalities in the development of the central nervous system with \"molar signs\" on magnetic resonance imaging of the brain and accompanied by cerebellar vermis hypoplasia, ataxia, hypotonia, and developmental delay. Keratoconus (KC) is a kind of genetically predisposed eye disease that causes blindness characterized by a dilated thinning of the central or paracentral cornea conically projected forward, highly irregular astigmatism, and severe visual impairment. Klinefelter syndrome is caused by an extra X chromosome in the cells of male patients, and the main phenotype is tall stature and dysplasia with secondary sex characteristics. This study was intended to identify the genetic etiology and determine the clinical diagnosis of one Han Chinese family with specific clinical manifestations of keratoconus and multiorgan involvement.
UNASSIGNED: A comprehensive ocular and related general examination was performed on one patient and his asymptomatic parents and brother. Pathogenic genes were tested by exome sequencing. CNV-seq was used to verify the copy number variation, and peripheral blood was cultured for karyotype analysis. The pathogenicity of the identified variant was determined subject to ACMG guidelines. The Gene Expression Omnibus (GEO) dataset of keratoconus-related genes in the NCBI database was obtained to analyze the differentially expressed genes in corneal tissues of the keratoconus group and the normal control group, and analysis of protein-protein interaction networks (PPI) was performed.
UNASSIGNED: Proband, a 25-year-old male, had sudden loss of vision in the left eye for 1 week. Best corrected visual acuity (BCVA): 0.5 (-1.00DS/-5.00DC*29°) in the right eye, counting fingers/40 cm in the left eye. Slit-lamp microscopy of the right eye showed mild anterior protrusion of the cornea and thinning of the cone-topped cornea. The left eye showed marked thinning of the central region of the cornea, rounded edema in the form of a cone-like bulge, epithelial bullae, edema and turbidity of the stroma, and bulging of the Descemet\'s membrane. Cranial magnetic resonance imaging (MRI) revealed changes in the midbrain and cerebellum, with a \"molar sign\" and a \"bat-winged\" ventriculus quartus cerebri. General check-up: 168 cm in height, decreased muscle tone in all four limbs, knee jerk elicited, negative Babinski sign, abdominal reflexes elicited, finger-to-nose test positive, intentional tremor evident in both hands, positive Romberg\'s sign, instability of gait, level I intellectual disability, poor adaptive behavior, communication disorders, teeth all dentures, a peculiar face with blepharophimosis, wide inner canthus distance, mild ptosis, severe positive epicanthus, high palatal arches, exotropia, hypotrichosis of beard and face, inconspicuous prominentia laryngea, and short upper and lower limbs. Exome sequencing detected compound heterozygous frameshift variants M1:c.9279dup:p.His3094Thrfs*18 and M2:c.6515_6522del:p.Lys2172Thrfs*37 in the patient\'s CPLANE1 gene and the presence of duplication-type CNV on the X chromosome. Sanger sequencing showed that the mother and father carried the M1 and M2 variants, respectively, and the younger brother carried the M2 variant, which was a novel variant. CNV-seq analysis showed the presence of a duplication-type CNV Xp22.33-Xq28 (2757837-156030895) of approximately 155 Mb on the X chromosome of the proband, which was a de novo variant and carried by neither of the parents. The two heterozygous frameshift variants and duplication-type CNV were pathogenic according to the ACMG guidelines. Differential expression analysis of keratoconus-related genes showed that CPLANE1 was upregulated in the corneal tissues of keratoconus patients compared with normal controls, and such a difference was statistically significant (p = 0.000515, <0.05). PPI analysis showed that the CPLANE1-NPHP3 complex protein acted as a bridge between cilia and extracellular matrix tissue. According to the genetic test results and clinical phenotype analysis, the family was finally diagnosed with Joubert syndrome combined with Keratoconus and Klinefelter syndrome.
UNASSIGNED: In this study, we report a proband in a Han Chinese family with both Joubert syndrome and X-linked Klinefelter syndrome as well as keratoconus, and the phenotype spectrum of CPLANE1-Joubert syndrome may be expanded accordingly. Meanwhile, the significance of exome sequencing was emphasized in aiding the clinical diagnosis of complex cases, which is difficult to make.