1例婴儿Lowe综合征临床特征和OCRL基因分析

目的:探讨Lowe综合征的临床、影像特点及基因特征。方法:分析1例10月大Lowe综合征患儿的临床资料,头颅核磁共振(MRI)特征及其致病基因OCRL突变检测结果。结果:患儿有先天性白内障、眼球震颤、精神运动发育落后、肌张力低下、蛋白尿及血尿等临床表现。头颅MRI提示患者脑白质髓鞘发育落后,双侧额颞叶发育不良,蛛网膜下腔增宽。OCRL基因检测发现一新发缺失突变NM_000276.3:c.1280-1281del TT(p.Cys428Hisfs*2),该突变未见文献报道。结论:Lowe综合征的诊断主要通过临床表现和OCRL基因检测,本研究发现的OCRL基因新突变丰富了该基因的致病突变谱。     

一个眼-脑-肾综合征家系的 OCRL基因变异研究

目的:探讨一个眼-脑-肾综合征(Lowe综合征)家系基因型与表型的关系,为遗传咨询提供依据。方法:应用全外显子测序(whole exome sequencing, WES)结合Sanger技术对先证者及其家系成员进行基因变异分析,对患者临床表型与以往文献比较。结果:先证者为一名3岁5个月男性患儿,临床表现为先天性白内障...     

一例Rotor综合征患儿的基因变异分析

目的探讨1例Rotor综合征患儿的遗传学病因。方法收集患儿的临床资料,应用高通量测序技术对患者行全外显子组测序并进行Sanger测序验证。用单管三引物PCR分析法检测SLCO1B3基因第5内含子长散布元件-1(long-interspersed element-1,LINE-1)的插入情况。结果高通量全外显子组测序发现患儿携带SLCO1B1基因c.1738C>T纯合无义变异。SLCO1B3基因第5内含子中LINE-1的纯合插入,导致第5外显子或第5~7外显子跳跃,并在SLCO1B3转录本中引入了终止密码子。结论SLCO1B1基因c.1738C>T纯合变异以及SLCO1B3基因第5内含子LINE-1的纯合插入可能是该Rotor综合征患儿的致病原因。     

Al Kaissi综合征1例患儿的基因变异分析及文献复习

目的探讨1例Al Kaissi综合征患儿的遗传学病因, 并为其家系提供产前诊断。方法选取2021年3月6日于河南省郑州大学第一附属医院就诊的1例Al Kaissi综合征患儿为研究对象。提取患儿基因组DNA, 应用拷贝数变异测序(CNV-seq)和全外显子组测序(WES)技术对患儿进行遗传变异筛查, 应用PCR-琼脂糖凝胶电泳和实时荧光定量PCR技术(qPCR)对筛查结果进行验证, 同时验证其父母以明确变异来源, 并对该家系的产前绒毛样本进行检测。结果患儿为6岁4个月男性, 具有低耳位、招风耳和三角脸等特殊面容, 语言和智力发育迟缓, 存在先天性室间隔缺损。CNV-seq结果未见明显异常, WES结果提示患儿CDK10基因第1、2外显子纯合缺失, PCR-琼脂糖凝胶电泳和qPCR结果进一步证实患儿父母均为CDK10基因第1、2外显子杂合缺失携带者。该家系产前绒毛样本提示胎儿为CDK10基因第1、2外显子杂合缺失携带者。结论结合临床表型, 上述患儿考虑为CDK10基因第1、2外显子纯合缺失所致的Al Kaissi综合征。     

TUBB2A基因新发变异导致癫痫伴发育迟缓及脑发育畸形一个家系的遗传学分析

目的探究1个癫痫伴发育迟缓及脑发育畸形家系的临床表现及致病基因变异情况。方法选取2022年7月2日于临沂市人民医院儿内科就诊的1个癫痫伴发育迟缓及脑发育异常家系为研究对象。收集患儿及其家系成员的临床资料, 应用高通量测序技术对患儿及其姐姐与父母进行基因检测, 采用Sanger测序法进行验证。结果患儿为6岁男性, 自幼全面生长发育迟缓, 间断抽搐4年余, 癫痫发作存在热敏感特点, 头颅影像学提示脑发育畸形, 视频脑电图提示异常放电。高通量测序结果显示患儿及其姐姐均携带TUBB2A基因c.5G>T(p.Arg2Leu)杂合变异, 其父母为野生型。根据美国医学遗传学与基因组学学会(ACMG)相关标准及指南, 该变异评定为致病性变异(PS2+PM2_Supporting+PM5+PP1+PP2+PP3)。结论 TUBB2A基因c.5G>T(p.Arg2Leu)杂合变异考虑是该家系的遗传学病因, 可能存在生殖腺细胞嵌合的情况。     

一例由 PPP2R5D基因变异引起的神经发育迟缓

目的使用全外显子组测序技术对一例发育迟缓的婴儿进行基因检测, 查明该患儿致病原因。方法应用全外显子组测序技术对其进行致病基因筛查, 结合临床表型资料, 锁定候选基因致病位点, 利用Sanger测序技术对先证者及其家系成员完成致病变异验证。结果发现先证者存在PPP2R5D基因c.592G>A(p.E198K)杂合变异, 该变异为已知致病变异, 根据相关文献报道及患儿临床症状, 诊断该患儿的致病原因为PPP2R5D基因c.592G>A变异引起的。结论 Jordan综合征是一种罕见的遗传疾病, 应用全外显子组测序技术能够快速发现PPP2R5D基因变异, 有助于该疾病的临床诊断和辅助治疗及该家系的遗传咨询及产前诊断。     

一例Lowe综合征患儿的临床特征和致病变异分析

目的旨在分析一例Lowe综合征患者的临床症状和致病变异, 为家系提供遗传咨询。方法收集患者临床资料, 抽取外周血样并提取基因组DNA;应用全外显子组测序对患者进行检测;通过生物信息学分析确定变异位点, 并在家系中用Sanger测序验证。结果 Sanger测序结果表明患者存在OCRL基因第18外显子c.2083C>T(p.Arg695*)无义变异, 该变异已被证实为致病性变异, 但尚未在国内患者中报道。结论 Lowe综合征的确诊主要通过临床表现和基因检测, 本研究为家系的遗传咨询和产前基因诊断奠定基础。     

一例先天性角化不良患儿的基因变异研究

目的对一例疑似为先天性角化不良的患儿进行临床和遗传学分析。方法对患儿进行临床检查,提取患儿及其父母基因组DNA,采用新一代外显子目标区域捕获测序技术对患儿进行基因变异分析,并对疑似致病性变异对患儿及其父母进行Sanger测序验证及生物信息学预测。结果患儿临床主要表现为指趾甲营养不良、皮肤色素沉着、口腔黏膜白斑,贫血、血小板减少、粒细胞减少。测序结果显示,患儿DKC1基因第12外显子的c.1213A>C变异(p.T405P),患儿母亲为同一位点的杂合变异。同时检测到患儿TERT基因中第12外显子的c.2915G>A变异(p.R972H),患儿父亲为c.2915G>A杂合变异携带者。结论DKC1基因第12外显子的c.1213A>C变异和TERT基因中第12外显子的c.2915G>A变异可能是导致该患儿先天性角化不良发病的分子病因。     

一个肌-眼-脑病家系的临床表型和POMGNT1基因突变分析

目的 分析并确立1个肌-眼-脑病( muscle-eye-brain disease,MEB)家系的临床表型及POMGNT1基因突变的类型.方法 收集肌-眼-脑病患儿及父母的临床资料,提取患儿及其父母外周血基因组DNA,用聚合酶链反应(polymerase chain reaction,PCR)扩增POMGNT1基因的外显子,以琼脂糖凝胶电泳鉴定PCR产物,PCR产物纯化后DNA直接测序,确定基因突变的类型,分析基因型和表型的关系.结果 该患儿诊断为松软儿,生后起病,智力运动发育落后,肌病面容,肌酶中度升高,头颅MRI提示前头部多小脑回,后头部无脑回畸形,脑白质异常信号,脑干、小脑发育不良及小脑囊肿,临床诊断为先天性肌营养不良伴眼脑病变.基因检测显示患儿POMGNT1基因第22外显子5′端前第1个碱基发生了改变(c.1896-1 G＞C),推测该突变可能导致剪切错误;而在第16外显子也发生了c.1319T＞G,p.L440R错义突变.其父母分别为此位点杂合突变.结论 通过分子遗传学分析发现该患儿为POMGNT1基因的复合杂合突变,其突变基因分别来自父母,符合肌-眼-脑病常染色体隐性遗传的规律,可确诊为肌-眼-脑病.     

一例母系嵌合的Nicolaides-Baraitser综合征患儿的临床特征及基因变异分析

目的探讨1例表现为全面发育迟缓、肝功能异常、先天性心脏病、大脑畸形的患儿的基因检测结果, 并分析候选变异的致病性。方法采集患儿及父母外周血标本, 提取基因组DNA, 进行全外显子组高通量测序, 对候选变异进行Sanger测序验证及生物信息学分析。结果基因检测结果提示患儿SMARCA2基因存在c.2002G>T(p.Glu668Ter)杂合变异, 生物信息学分析提示可能致病变异, 患儿母亲的外周血基因组DNA中, 检测到低比例的嵌合变异, 高精度定点检测示变异比例为0.054(246/4 549)。结论该患者被诊断为SMARCA2基因变异引起的Nicolaides-Baraitser综合征, 其母存在低比例的嵌合变异。     

OCRL localizes to the primary cilium: a new role for cilia in Lowe syndrome

Oculocerebral renal syndrome of Lowe (OCRL or Lowe syndrome), a severe X-linked congenital disorder characterized by congenital cataracts and glaucoma, mental retardation and kidney dysfunction, is caused by mutations in the OCRL gene. OCRL is a phosphoinositide 5-phosphatase that interacts with small GTPases and is involved in intracellular trafficking. Despite extensive studies, it is unclear how OCRL mutations result in a myriad of phenotypes found in Lowe syndrome. Our results show that OCRL localizes to the primary cilium of retinal pigment epithelial cells, fibroblasts and kidney tubular cells. Lowe syndrome-associated mutations in OCRL result in shortened cilia and this phenotype can be rescued by the introduction of wild-type OCRL; in vivo, knockdown of ocrl in zebrafish embryos results in defective cilia formation in Kupffer vesicles and cilia-dependent phenotypes. Cumulatively, our data provide evidence for a role of OCRL in cilia maintenance and suggest the involvement of ciliary dysfunction in the manifestation of Lowe syndrome.     

Oculo-cerebro-renal Lowe syndrome: clinical, biochemical and molecular studies in a Moroccan patient

The oculo-cerebro-renal syndrome of Lowe is a rare X-linked disorder, caused by the inositol biphosphate 5-phosphatase deficiency, localized to the Golgi complex. Several mutations were reported in patient's OCRL gene leading to enzyme deficiency. We report a Moroccan case of OCRL syndrome of Lowe with a neo mutation in exon 10. The patient aged of 19 months was referred to our medical centre because of a psychomotor retardation. He had a medical history of eye abnormalities including cataract and bilateral glaucoma, diagnosed when he was 5 weeks old. Cataract has been treated after chirurgical therapy but ocular hypertonia persisted. Physical examination revealed an axial hypotonia and walking difficulties. Laboratory tests revealed a moderate acidosis (20 mmol/L), a slight decrease of serum phosphate level (24 mg/L) and an increased serum phosphatase activity. Further studies showed mild proteinuria, urinary bicarbonates loosing and generalised hyperaminoaciduria. Based on both clinical and biological data, Lowe syndrome has been suggested. In this context, molecular investigation has been performed using dHPLC/sequencing techniques which allow identifying an original mutation c.776T>C (p.Phe259Ser), localized on the exon 10 of the OCRL gene. The mutation was not found in the probant's mother suggesting a neo mutation. Lowe syndrome is a rare hereditary X-linked disorder resulting from a variety of heterogeneous mutations of OCRL gene. Indeed, numerous mutations have been reported, variations were noted concerning their localization as well as their type. To our knowledge, this is the first report of the neo mutation c.776T>C of OCRL gene and the first published case report of the Lowe syndrome in a Moroccan patient.     

Unusual renal features of Lowe syndrome in a mildly affected boy

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by congenital cataracts, mental retardation, and renal tubular dysfunction. The gene responsible for OCRL was identified by positional cloning and encodes a lipid phosphatase, phosphatidylinositol 4,5, bisphosphate [PtdIns(4,5)P2]5-phosphatase, which localizes to the Golgi apparatus and is suspected to play a role in Golgi vesicular transport [Suchy et al., 1995]. In addition to the ocular and renal manifestations, most boys with OCRL have cognitive problems and maladaptive behaviors including tantrums and stereotypies. We report a boy with a history of congenital cataracts and mild developmental delay who was also found to have hematuria with proteinuria but minimal signs of renal tubular dysfunction. Subsequent renal biopsy was compatible with a diagnosis of a noncomplement fixating chronic glomerulonephritis. Despite the atypical renal findings, skin fibroblast analysis for PtdIns (4,5)P2 5-phosphatase was performed, and enzyme activity was low, consistent with the diagnosis of OCRL. Western blot analysis from cell lysates showed the ocrl protein was decreased in size and amount. Our report shows atypical renal features of OCRL in a mildly affected boy. The possibility of OCRL should be considered in boys with cataracts and glomerular disease, even in the absence of renal tubular defects and frank mental retardation usually associated with the syndrome. Am. J. Med. Genet. 95:461-466, 2000. Published Wiley-Liss, Inc.     

Identification of a novel deletion of the entire OCRL1 gene detected by FISH analysis in a family with Lowe syndrome

The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked multisystem disorder affecting the lens, kidney and brain. The gene involved (OCRL1) has been identified and is known to encode a phosphatidylinositol 4,5-bisphosphate 5-phosphatase. Mutations in OCRL1 have been shown to be causative of OCRL. To date, most of the mutations identified have consisted of simple or point mutations and there is one report of a 1.4-kb deletion. We investigated the OCRL1 gene in a male patient with OCRL by the polymerase chain reaction and found that the entire OCRL1 gene was deleted. Fluorescence in situ hybridisation analysis (FISH), with cosmid probes that span the entire OCRL1 gene, was used to confirm this deletion and subsequently identify it in the proband's mother. This is the first report of a whole gene deletion of OCRL1 and thus expands the range of mutations that give rise to OCRL. The use of the FISH technique facilitated carrier and prenatal testing for the deletion in the family.     

Autosomal XX sex reversal caused by duplication of SOX9

SOX9 is one of the genes that play critical roles in male sexual differentiation. Mutations of SOX9 leading to haploinsufficiency can cause campomelic dysplasia and XY sex reversal. We report here evidence supporting that SOX9 duplication can cause XX sex reversal. A newborn infant was referred for genetic evaluation because of abnormal male external genitalia. The infant had severe penile/scrotal hypospadias. Gonads were palpable. Cytogenetic analysis demonstrated a de novo mosaic 46,XX,dup(17)(q23.1q24.3)/46, XX karyotype. Fluorescent in situ hybridization (FISH) with a BAC clone containing the SOX9 gene demonstrated that the SOX9 gene is duplicated on the rearranged chromosome 17. The presence of SRY was ruled out by FISH with a probe containing the SRY gene and polymerase chain reaction with SRY-specific primers. Microsatellite analysis with 13 markers on 17q23-24 determined that the duplication is maternal in origin and defined the boundary of the duplication to be approximately 12 centimorgans (cM) proximal and 4 cM distal to the SOX9 gene. Thus, SOX9 duplication is the most likely cause for the sex reversal in this case because it plays an important role in male sex determination and differentiation. This study suggests that extra dose of SOX9 is sufficient to initiate testis differentiation in the absence of SRY. Other SRY-negative XX sex-reversed individuals deserve thorough investigation of SOX9 gene.     

Germline mosaic transmission of a novel duplication of PXDN and MYT1L to two male half-siblings with autism

Autism is a neurodevelopmental disorder with a strong genetic component to susceptibility. In this study, we report the molecular characterization of an apparent de-novo 281 kb duplication of chromosome 2p25.3 in two male half-siblings with autism. The 2p25.3 duplication was first identified through a low-density microarray, validated with fluorescent in-situ hybridization, and duplication breakpoints were delineated using an Affymetrix 6.0 single-nucleotide polymorphism microarray. The fluorescent in-situ hybridization results validated the novel copy number variant and revealed the mother to be mosaic, with ～33% of her lymphoblast cells carrying the duplication. Therefore, the duplication was transmitted through the mechanism of germline mosaicism. In addition, duplication breakpoints were refined and showed that PXDN is fully duplicated, whereas seven exons of the terminal portion of the 25 exon gene MYT1L are within the duplicated region. MYT1L, a gene predominately expressed in the brain, has recently been linked with other neuropsychiatric illness such as schizophrenia and depression. Results from this study indicate that the 2p25.3 duplication disrupting PXDN and MYT1L is a potential autism-causing variant in the pedigree reported here and should receive further consideration as a candidate for autism.     

Identification of two novel mutations in the OCRLI gene in Japanese families with Lowe syndrome

Kubota T, Sakurai A, Arakawa K, Shimazu M, Wakui K, Furihata K, Fukushima Y. Identification of two novel mutations in the OCRL1 gene in Japanese families with Lowe syndrome. Clin Genet 1998: 54: 199–202. 0 Munksgaard, 1998
The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked disorder with features of congenital cataracts. Fanconi syndrome of the renal tubule, and mental retardation. The OCRLI gene has been positionally cloned and shown to encode a phosphatidylinositol 4.5–biphos-phate-5–phosphatase. OCRL is thus thought to be an inborn error of inositol polyphosphate metabolism. We analyzed the gene in two Japanese OCRL patients and their families by DNA sequencing and mismatch polymerase chain reaction (PCR) followed by restriction digestion. A novel nonsense mutation (C1399T) replacing the glutamine of codon 391 (Gln 391 Stop) was identified in exon 12 in 1 patient and also in his mother. A novel missense mutation (C1743G) was identified in exon 15 in the second patient, his mother and maternal grandmother. The missense mutation predicts a substitution of serine for arginine (Ser 505 Arg) in a domain highly conserved among the inosi-tol-5–phosphatase family. Our observations expand the range of OCRLI mutations that cause Lowe syndrome. and will be useful for genetic counseling in these two Fdmilies.     

Carrier assessment in families with lowe oculocerebrorenal syndrome: novel mutations in the OCRL1 gene and correlation of direct DNA diagnosis with ocular examination

Lowe oculocerebrorenal syndrome (OCRL) (MIM 309000) is a rare X-linked multisystem disorder characterized by congenital cataracts, muscular hypotonia, areflexia, mental retardation, maladaptive behavior, renal tubular dysfunction, vitamin-D-resistant rickets, and scoliosis. The underlying gene OCRL1 is located on chromosome Xq25-q26 and contains 24 exons. It encodes a 105-kDa phosphatidylinositol 4,5-bisphosphate (PtdIns[4,5]P(2)) 5-phosphatase that is localized to the Golgi complex. To confirm the clinical diagnosis and to assess the carrier state of female relatives for genetic counseling we examined 6 independent patients and their families (a total of 23 individuals) using an improved mutation screening strategy for the OCRL1 gene by sequencing of large PCR amplicons. Four novel and two known mutations were identified: three premature terminations caused by either frameshift mutations (1899insT in exon 17 and 2104-2105delGT in exon 18) or a nonsense mutation (1399C > T in exon 12), two missense mutations (1676G > A and 1754C > T in exon 15), and a 6-bp deletion (1609-1614delAAGTAT in exon 14). An ophthalmological examination was performed in all patients and 14 female relatives. All genotypically proven carrier females showed characteristic lenticular opacities, while all proven noncarriers were lacking this phenotypic finding. The results confirm that ophthalmological evaluation is an apparently reliable first-line method to ascertain the carrier state in Lowe oculocerebrorenal syndrome. The high expressivity of lenticular symptoms in OCRL1 gene carriers is consistent with the hypothesis that (PtdIns[4,5]P(2)) 5-phosphatase activity has low functional reserve capacity for maintaining a balanced homeostasis of lenticular metabolism.