一例2q37微缺失综合征患儿的遗传学分析

目的:对1例2q37微缺失综合征患儿进行诊断和精细定位。方法:对患儿进行染色体G显带、多重连接探针扩增(multiplex ligation-dependent probe amplification,MLPA)、单核苷酸多态性微阵列(single nucleotide polymorphism array,SNP-a...     

人类Y染色体微缺失与精子生成障碍的研究进展

本文就人类Y染色体的结构及其与精子生成相关的主要功能基因的研究进展作了综述,重点对AZF区的USP9Y.RBM. DAZ. CDY等基因的缺失与精子生成障碍的关系进行了探讨。为临床实施辅助生育技术治疗前对精子质量的筛查.无精症患者的诊断及遗传咨询提供理论依据。     

无创产前检测筛查胎儿染色体拷贝数变异临床价值

目的 探讨无创产前检测(NIPT)筛查胎儿染色体拷贝数变异(CNV)(主要为染色体微缺失/微重复)的临床价值。方法 选择2019年1月至2021年10月,于山西医科大学第一医院接受NIPT,结果提示胎儿染色体缺失或重复,并接受介入性产前诊断的67例孕妇为研究对象。回顾性分析其临床病例资料。对孕妇羊水细胞进行胎儿染色体核型分析及染色体微阵列分析(CMA),并分析NIPT发现的胎儿染色体CNV与上述介入性产前诊断结果的一致性。本研究遵循的程序符合2013年修订的《世界医学协会赫尔辛基宣言》要求。所有孕妇对其上述检测均知情同意,并签署临床研究知情同意书。结果 (1)于上述选择的时间段内,接受NIPT筛查的29 479例孕妇中,胎儿染色体缺失或重复为87例,筛查结果胎儿染色体CNV发生率为0.30%(87/29 479)。(2)介入性产前诊断的67例孕妇中,确诊胎儿染色体CNV为35例,NIPT筛查胎儿染色体CNV的阳性预测值为52.2%(35/67);29例胎儿的CMA与NIPT筛查结果显示的胎儿染色体CNV基本一致,二者检测胎儿染色体CNV符合率为43.2%(29/67)。结论 NIPT筛...     

微阵列比较基因组杂交技术检测不明原因智力低下/发育迟缓患儿的基因组拷贝数变异

目的应用高分辨微阵列比较基因组杂交技术(Array-CGH),对中国人群不明原因的智力低下/发育迟缓(MR/DD)患儿进行全基因组拷贝数变异(CNVs)筛查,获得在这些不明原因MR/DD患儿中CNVs的检出率,并分析其中的罕见CNVs与MR/DD的相关性,以此评估Array-CGH对不明原因MR/DD可能的遗传病因诊断作用。方法根据特定筛选条件收集在首都儿科研究所临床诊断为不明原因MR/DD患儿,用Oligo244KDNA芯片筛查全基因组CNVs。针对所发现的CNVs,首先将其与国际基因组CNVs多态性数据库(databaseofgenomicvariants)进行比对,剔除常见多态性CNVs,将获得的罕见CNVs应用美国波士顿儿童医院遗传诊断实验室的临床分子诊断平台,结合基因组异常拷贝数数据库(DECIPHER)进行核查并与既往相关文献比对,以发现罕见CNVs在不明原因MR/DD患儿中的检出率。结果2004年7月至2008年7月共收集111例不明原因MR/DD患儿,平均年龄为6岁,男女比例为1.775。28例患儿发现36个罕见CNVs,CNVs平均长度为1326kb(29～8760kb),这些CNVs均无法被常规染色体G带检查所识别。通过评估,19例患儿携带可能与MR/DD相关的CNVs,另1例患儿的CNVs临床意义不明确,Array-CGH在不明原因MR/DD患儿中发现携带与疾病相关的罕见CNVs的诊断率为17.1%(19/111例)。22/36个(66.1%)罕见CNVs曾被美国波士顿儿童医院Array-CGH数据库、DECIPHER数据库、既往MR/DD微阵列研究文献所报道。1例患儿在15q11.2-13.1存在2098kb的基因组缺失,覆盖Prader-Willi综合征/Angelman综合征关键区的多个候选基因,包括SNRPN、NECDIN、SnRNAs和UBE3A,结合该患儿面部表型、临床检查以及Array-CGH结果,诊断为非典型性Prader-Willi综合征。结论基因组CNVs相关的微缺失/重复是中国人群中不明原因MR/DD患儿的原因之一,高分辨Array-CGH技术可在不明原因MR/DD患儿中发现更多的遗传病因,帮助和提高不明原因MR/DD的分子诊断水平。     

Array-CGH in unclear syndromic nephropathies identifies a microdeletion in Xq22.3-q23

To investigate whether submicroscopic chromosomal deletions or duplications can be causative of unclear syndromic nephropathies, we analyzed ten patients with congenital abnormalities of the kidney and urinary tract or glomerulopathies combined with important extrarenal anomalies by whole-genome array-based comparative genomic hybridization. In a 14-year-old girl presenting with hematuria, proteinuria, mental retardation (MR), sensorineural hearing loss, dysmorphisms, and epilepsy, we detected a microdeletion in chromosome Xq22.3-q23. This deletion was verified and characterized by fluorescence in situ hybridization and multiplex ligation-dependent probe amplification analyses, found to be de novo, uniallelic and 3.3 Mb in size. Electron microscopy of a kidney biopsy showed glomerular basement membrane thinning and segmental splitting of the lamina densa compatible with Alport syndrome. Cranial magnetic resonance and diffusion tensor imaging detected a severe neuronal migration disorder with double cortex formation and pronounced reduction of the fronto-occipital tract system. Thus, in one of ten patients with unclear syndromic nephropathies we identified a previously undescribed contiguous gene syndrome at Xq22.3-q23. The microdeletion contains the X-linked Alport syndrome gene COL4A5, the MR genes FACL4 and PAK3, and parts of the X-chromosomal lissencephaly gene DCX associated with double cortex formation in girls, MR, and epilepsy. The phenotype in our patient combines features of the Alport–MR contiguous gene syndrome with lissencephaly. A. Hoischen and C. Landwehr contributed equally to this study and should both be considered as first authors.     

Analyses of the associations between the genes of 22q11 deletion syndrome and schizophrenia

Schizophrenia is a severe, debilitating mental disorder characterized by profound disturbances of cognition, emotion and social functioning. The lifetime morbid risk is surprisingly uniform at slightly less than 1% across different populations and different cultures. The evidence of genetic risk factors is our strongest clue to the cause of schizophrenia. Linkage and association analyses have identified genes associated with the development of schizophrenia. However, most of the alleles or haplotypes identified thus far have only a weak association or are reported to be population specific. A deletion of 22q11.2 that causes the most common microdeletion syndrome (22q11DS) with an estimated prevalence of 1:2,500–1:4,000 live births may represent one of the greatest known genetic risk factors for schizophrenia. Schizophrenia is a late manifestation in approximately 30% of patients with 22q11.2 deletion, comparable to the risk to offspring of two parents with schizophrenia. Clinical and neuroimaging assessments indicate that 22q11DS-schizophrenia is a neurodevelopmental model of schizophrenia. Recent studies have provided evidence that haploinsufficiency of TBX1 is likely to be responsible for many of the physical features associated with the deletion. Most of the genes in the 22q11 deletion region are conserved together on mouse chromosome 16, enabling the generation of mouse models. Similarities in the cardiovascular and other phenotypes between 22q11DS patients and mouse models can provide important insights into roles of genes in neurobehavioral phenotypes. Because more than one gene in the 22q11DS region is likely to contribute to the marked risk for schizophrenia, further extensive studies are necessary. Analyses of 22q11DS will help clarify the molecular pathogenesis of schizophrenia.     

Cri du chat syndrome determined by the 5p15.3-->pter deletion--diagnostic problems

A cytogenetic analysis was performed on an 8-day-old girl, who was suspected of Cri du chat syndrome (CdCS) on the basis of a cat-like cry, despite her dysmorphic features not being characteristic of this syndrome. The cytogenetic analysis revealed a partial deletion of the short arm of chromosome 5, but did not allow precise specification of the break points. Fluorescence in situ hybridization (FISH) analysis, using the specific probe for CdCS, revealed two signals in all the cells analyzed. However, one of two signals was less intense than the other. Thus, telomere probes were applied for all chromosomes. Two signals from 5q and one signal from 5p were observed. The results allowed us to establish the location of the deleted fragment as 5p15.3-->5pter [46,XX,del(5)(p15.3)]. The analysis of a genotype-phenotype correlation confirmed that the cat-like cry, but not the characteristic dysmorphic features of CdCS are correlated with the deletion of 5p15.3.     

Detection of a deletion of exons 8-16 of the UBE3A gene in familial Angelman syndrome using a semi-quantitative dosage PCR based assay

Angelman syndrome (AS) is a neurodevelopmental disorder caused by failure of expression of the maternal copy of the imprinted UBE3A gene through a variety of mechanisms detected by methylation studies, mutation analysis of UBE3A and FISH. In 10–15% of suspected cases of AS these investigations do not reveal a genetic abnormality. We report here the development of a semi-quantitative dosage PCR technique used to identify sub-microscopic deletions involving UBE3A. Using this method we analysed a panel of 26 patients from 24 families, all fulfilling the clinical criteria for AS. We identified a deletion of UBE3A exons 8–16 in a sibling pair. Analysis of parental samples revealed the same deletion in their phenotypically normal mother. This is an inexpensive and valuable method for detecting UBE3A deletions in a small but important proportion of AS cases of unidentifiable cause.