一例Xp22.12微重复胎儿的产前诊断及遗传学分析

目的应用单核苷酸多态性微阵列(single nucleotide polymorphism array,SNP-array)技术为1例携带染色体平衡易位的孕妇提供产前诊断。方法采用常规G显带染色体分析和SNP-array对胎儿及其父母进行分析。结果 SNP-array检测结果显示胎儿染色体Xp22.12区存在496.3 kb的片段重复,临床意义不明;表型正常的母亲染色体Xp22.12区相同位置存在505.8 kb的重复,父亲检测结果未见异常。胎儿足月经剖宫产出生,随访未见异常。结论 Xp22.12微重复区包含RPS6KA3基因的部分区段,因而表现为不同程度的Coffin-Lowry综合征症状,少部分Xp22.12微重复女性可因X染色体失活而成为无症状的携带者,本研究为Xp22.12微重复表型与基因型的关联提供了一定的依据。     

Crouzon综合征基因突变检测

目的 研究1个Crouzon综合征家系及1例散发的Crouzon综合征患者的成纤维生长因子受体2(fibroblast growth factors receptor 2,FGFR2)基因突变情况.方法 在1个Crouzon综合征家系的10名成员,和另一例散发者的外周血提取基因组DNA,PCR扩增FGFR2基因的第8和10外显子(部分家族成员仅扩增第8外显子),产物纯化后直接进行DNA测序检测突变.结果 家系中3名成员及另1例散发者FGFR2基因第8外显子的833位核苷酸发生G→T的转换突变,该突变为错义突变,使该位点所编码的氨基酸由半胱氨酸变为苯丙氨酸(C278F).该突变为杂合子突变.结论 FGFR2基因突变是Crouzon综合征致病原因.     

NOTCH2信号通路及其基因突变相关疾病

NOTCH2是NOTCH受体家族的重要一员,在器官发育中起着重要作用.胚系NOTCH2基因突变可导致两种罕见的多系统遗传疾病,Alagille综合症与Hajdu-Cheney综合症.而NOTCH2受体及其配体的异常表达也与多种肿瘤的发生或抑制密切相关.文章通过回顾文献,对NOTCH2信号通路的组成与活化,NOTCH2基...     

国内首例Costello综合征患儿HRAS基因突变分析

目的 通过对1例临床疑似Costello 综合征的患者进行HRAS基因分析并确诊。方法 提取患者及其父母的基因组DNA,PCR扩增HRAS基因的第2～5个编码外显子并直接测序。Pubmed检索Costello综合征的临床表现、实验室检查和治疗干预方法。结果 在HRAS基因第2外显子34位碱基序列处发现一个已知错义突变c.34G>A,p.Gly12Ser。患者父母DNA未检测到相同突变。结论 Costello 综合征是一种罕见的常染色体显性遗传病,患者有特征性面容、极度喂养困难史和生长发育落后等,确诊有赖于HRAS基因突变分析。     

Waardenburg综合征家系基因突变分析

目的 分析1个Waardenburg综合征1型家系成员的临床表型和基因突变.方法 收集1个Waardenburg综合征患者家系的临床资料,采用Sanger测序法对家系成员进行了Waardenburg综合征相关基因的外显子测序分析.结果 家系中共有1名患者,先证者有Waardenburg综合征1型的先天性感音神经性耳聋和...     

RT-PCR检测柯萨奇B3病毒易感人群的分布及意义

目的检测出CoxB3易感染的人群分布。方法采用逆转录聚合链式反应（RT-PCR）检测技术对1120例疑似CoxB3感染的患者静脉血进行检测。结果 1120例样本中,210例阳性扩增结果,并通过测序,BLAST确定病毒的类型;210例阳性扩增结果中,来自于儿科、新生儿病房共141例（阳性率67.2%）,来自于其他疾病科室的共计69例（阳性率32.8%）,（P目的检测出CoxB3易感染的人群分布。方法采用逆转录聚合链式反应(RT-PCR)检测技术对1120例疑似CoxB3感染的患者静脉血进行检测。结果 1120例样本中,210例阳性扩增结果,并通过测序,BLAST确定病毒的类型;210例阳性扩增结果中,来自于儿科、新生儿病房共141例(阳性率67.2%),来自于其他疾病科室的共计69例(阳性率32.8%),(P$0.05)。结论新生儿、儿童是CoxB3的易感人群,因此要对于易感人群增加一定的预防措施。     

ALDH3A2基因突变导致Sjogren-Larsson综合征2例报道

目的 研究2例Sjogren-Larsson综合征（SLS）患儿的临床表型和基因型特点,提高对SLS致病基因及其临床表型的认识。方法 对河南中医药大学第一附属医院儿科医学院收治的2个SLS患儿进行临床研究及ALDH3A2基因突变分析,并复习国内文献,为早期诊断提供理论依据。结果 本研究2例SLS患儿均有典型鱼鳞病样皮损,存在运动发育障碍,合并智能障碍与言语发育落后。基因检测结果显示1例患儿为ALDH3A2基因纯合型突变（实际为半合子状态）,1例患儿为ALDH3A2基因复合杂合型突变。结论 临床上对SLS可疑患儿进行ALDH3A2基因检测,对早期诊断更具有指导意义。     

云南省两种G6PD基因突变的检测

红细胞葡萄糖 - 6 -磷酸脱氢酶 (glucose- 6 - phosphatedehydrogenase,G6 PD) ,是磷酸戊糖旁路中产生还原型辅酶 (reduced nicotinamide adenine dinucleotide phosphate,NADPH)的关键酶。G6 PD的缺陷可导致蚕豆病、药物性溶血、新生儿高胆红素血症乃至核黄疸、感染性溶血及非球形细胞溶血性贫血等 ,G6 PD缺乏症是一种常见的人类遗传性酶缺陷疾病。G6 PD基因突变是导致 G6 PD缺乏症的主要分子基础 ,目前已发现 DNA突变类型 78种 ,其中在中国人中发现了 13种[1 ] 。云南是 G6 PD缺乏症高发区 ,部分少数民族地区该病发生率达16 .…     

软骨发育不全1例基因突变检测

目的对1例临床诊断为软骨发育不全（achondroplasia,ACH）的患者及其父母的成纤维细胞生长因子受体3（fibroblastgrowthfactorreceptor3,FGFR3）进行基因突变检测。方法提取患者及其父母外周血DNA,对FGFR3基因的第10外显子区设计引物,进行PCR扩增,并对扩增产物进行限制性内切酶酶切分析。结果与父母及正常对照相比,此例患儿FGFR3基因第10外显子发生了第1138位G到A的点突变。结论FGFR3基因第10外显子G1138A杂合突变可能为该例软骨发育不全患者的主要病因。该检测结果与国内外研究结果一致,进一步说明该突变为热点突变。     

Apert综合征患儿FGFR2基因突变分析

目的研究Apert综合征患儿成纤维细胞生长因子受体2（FGFR2）基因突变以及临床特点。方法采集1例Apert综合征患儿及其父母的外周血,提取基因组DNA,应用PCR扩增FGFR2基因第7和第9外显子,对PCR产物进行双向测序检测基因突变。检索PubMed和中国知网数据库中相关文献进行系统分析。结果在患）LFGFR2基因的第7外显子的937碱基发生杂合突变,由c转变为G,导致FGFR2蛋白第253位密码子由脯氨酸变为精氨酸（P253w）,患儿父母均未检测到该基因突变。文献检索国内外已报道15例Apert综合征患儿,其中6例进行FGFR2基因突变分析,5例为S252W突变,1例为外显子Ⅲb／Ⅲc之间杂合缺失突变。结论该例hpert综合征患儿由FGFR2基因937C-G的杂合突变所致。     

Intronic L1 insertion and F268S, novel mutations in RPS6KA3 (RSK2) causing Coffin-Lowry syndrome

Two novel mutations of the ribosomal S6 kinase 2 gene (also known as RSK2) have been identified in two unrelated patients with Coffin-Lowry syndrome. The first mutation consists of a de novo insertion of a 5'-truncated LINE-1 element at position -8 of intron 3, which leads to a skipping of exon 4, leading to a shift of the reading frame and a premature stop codon. The L1 fragment (2800 bp) showed a rearrangement with a small deletion, a partial inversion of the ORF 2, flanked by short direct repeats which duplicate the acceptor splice site. However, cDNA analysis of the patient shows that both sites are apparently not functional. The second family showed the nucleotide change 803T>C in exon 10, resulting in the F268S mutation. This mutation was detected in two monozygotic twin patients and in their mother, who was mildly affected. The patients fulfill the clinical criteria of the syndrome, and therefore the mutation provides further support for the importance of phenylalanine at position 268, which is highly conserved in the protein kinase domain of many serine-threonine protein kinases.     

Coffin–Lowry syndrome in Chinese

Coffin–Lowry syndrome (CLS) is a well‐described syndrome characterized by intellectual disability, growth retardation, recognizable dysmorphic features, and skeletal changes. It is an X‐linked syndrome where males are more severely affected and females have high variability in clinical presentations. This case series reports nine molecularly confirmed Chinese CLS patients from six unrelated families (three with familial variants and three with de novo variants). There is a wide genotypic spectrum with five novel variants in RPS6KA3 gene. Clinical phenotype and facial features of these Chinese CLS patients are comparable to what has been described in other ethnicities.     

An unusual cause for Coffin–Lowry syndrome: Three brothers with a novel microduplication in RPS6KA3

Coffin–Lowry syndrome (CLS) is a rare X‐linked disorder characterized by moderate to severe intellectual disability, hypotonia, craniofacial features, tapering digits, short stature, and skeletal deformities. Using whole exome sequencing and high‐resolution targeted comparative genomic hybridization array analysis, we identified a novel microduplication encompassing exons five through nine of RPS6KA3 in three full brothers. Each brother presented with intellectual disability and clinical and radiographic features consistent with CLS. qRT‐PCR analyses performed on mRNA from the peripheral blood of the three siblings revealed a marked reduction of RPS6KA3 levels suggesting a loss‐of‐function mechanism. PCR analysis of the patients’ cDNA detected a band greater than expected for an exon 4–10 amplicon, suggesting this was likely a direct duplication that lies between exons 4 through 10, which was later confirmed by Sanger sequencing. This microduplication is only the third intragenic duplication of RPS6KA3, and the second and smallest reported to date thought to cause CLS. Our study further supports the clinical utility of methods such as next‐generation sequencing and high‐resolution genomic arrays to detect small intragenic duplications. These methods, coupled with expression studies and cDNA structural analysis have the capacity to confirm the diagnosis of CLS in these rare cases.     

Coffin-Lowry syndrome in sibs

The authors report the Coffin-Lowry syndrome in two sibs and suggest autosomal recessive inheritance of the condition in this family.     

Cognitive function in Coffin-Lowry syndrome

Coffin-Lowry syndrome (CLS) is an X-linked disorder associated with mental retardation, distinctive facies and hands, hypotonia, and skeletal abnormalities. The syndrome results from mutations in the RSK2 gene located in Xp22.2. Although the syndrome has been elucidated clinically, few, if any, studies have focused on the cognitive deficits of the affected males or carrier females. The subjects of the present study were selected from two African-American families who have the same missense mutation (C340T) in RSK2. The subjects included six affected males, seven carrier females, three normal males and three non-carrier (normal) females. Normal family members served as contrast/comparison cohorts to control for socio-economic, sociocultural and genetic variables which would impinge on intellectual abilities. Analysis of cognitive function, as measured by the Stanford-Binet Intelligence Scale, 4th edn, demonstrated a distinct hierarchy of abilities from normal to carrier to affected patients. The mean composite IQs of the cohorts were 90.8, 65.0 and 43.2 for normal, carrier and affected individuals, respectively. These findings lend support to the clinical concept of negative intellectual effects in carriers of certain X-linked mental retardation conditions. X-inactivation studies showed that carrier females had mild to significant skewing. Normal females in the family did not demonstrate skewing. The correlation coefficient between IQ and X-inactivation status among carriers was not significant.     

Stimulus-induced drop episodes in Coffin-Lowry syndrome

The Coffin-Lowry syndrome (CLS) is a rare but well-defined X-linked semidominant syndrome characterized by psychomotor and growth retardation, and progressive skeletal changes. CLS is caused by loss of function mutations in the Rps6ka3 gene encoding the ribosomal S6 kinase 2 (RSK2) protein. A distinctive paroxysmal disorder has been described in some CLS patients, characterized by episodes of sudden falling, without apparent alteration of consciousness, usually induced by unexpected tactile or auditory stimuli. Duration of episodes is very short, usually lasting a few seconds. The appellation "Stimulus-induced drop episodes" (SIDEs) was proposed for these non-epileptic events in CLS patients. SIDEs are clinically heterogeneous; with some patients exhibiting cataplexy-like events characterized by sudden hypotonia and collapse, and others hyperekplexia-like episodes with a startle response. The pathophysiology of SIDEs is not well understood.