新发8p 重复伴缺失综合征患儿细胞分子遗传学研究

目的探讨8号染色体短臂倒位重复伴末端缺失[inv dup del(8p)]综合征的临床特征及细胞分子遗传学特点。方法回顾分析1例inv dup del(8p)综合征患儿的临床资料以及细胞分子遗传学分析资料。结果 6月龄女性患儿,具有发育迟缓、特殊面容、先天性心脏病及喉软化症等临床表现。外周血淋巴细胞染色体核型分析显示,患儿为46,XX,der(8)inv dup(8)(p21),del(8)(p23),父母均无异常;高通量测序染色体组拷贝数分析(CNV)精确定位拷贝数异常改变的染色体片段区域,检出患儿在8p23.3-p23.1(160 001-7 120 000)区域缺失6.96 Mb片段,在8p23.1-p21.1(12 560 001-27 940 000)区域,重复15.38 Mb片段;荧光定量PCR验证CNV显示在重复和缺失片段之间有一个5.4 Mb的拷贝数正常片段。结合临床表现及各检测结果确诊患儿为inv dup del(8p)综合征。结论结合临床特征、外周血染色体核型分析、CNV及荧光定量PCR技术可有效确诊inv dup del(8p)综合征。     

18号染色体短臂缺失综合征1例

18号染色体短臂缺失综合征是由18号染色体短臂部分或全部遗传物质缺失导致的一组临床综合征,其发病罕见,新生儿中的发病率约为1∶50000[1]。本文报道发育迟缓伴腹股沟疝反复发作1例患儿,经染色体核型分析为18号染色体短臂缺失综合征。     

12p三体新生儿1例临床及细胞分子遗传学分析

目的探讨12p三体新生儿的临床及细胞分子遗传学特点。方法回顾1例经外周血行淋巴细胞常规G显带染色体核型分析,高通量测序染色体组拷贝数分析(CNV)并经淋巴细胞间期荧光原位杂交(FISH)技术确认的12p三体新生儿的临床资料。结果患儿外周血染色体核型为47,XX,+mar,父母染色体核型均正常;CNV检出患儿12p13.33-p11.1(160 001～34 860 000)区域重复,片段大小为34.7 Mb;外周血淋巴细胞间期FISH显示患儿所有间期细胞核12号染色体短臂均存在3个信号,无嵌合体存在。确诊为12p三体。结论结合临床特征、外周血染色体核型分析、CNV及FISH技术可有效确诊12p三体。     

2号染色体短臂缺失1例及文献复习

<正>2号染色体短臂缺失很罕见,目前国外报道仅有10例患者涉及2p23-pter的缺失,国内对2号染色体短臂缺失则尚无报道。笔者科室收治1例2号染色体短臂缺失患儿,主要表现为全面性发育落后,肌张力低下,特殊面容。现报告如下。     

一例13号环状染色体综合征患儿的临床及遗传学分析

患儿,女,5个月,因生长发育迟缓就诊,体格检查发现体格发育落后,特殊面容（小头畸形、眼距宽、耳位偏低、鼻梁扁平、短人中）以及一侧小阴唇缺失。外周血染色体核型为46,XX,r（13）（p11q33）[82]/45,XX,-13[10]/46,XX,r（13;13）（p11q33;p11q33）[8];微阵列比较基因组杂交（aCGH）检测显示13q11q33.2区域和13q33.2q34区域分别有87.5 Mb的重复和8.2 Mb的缺失;荧光原位杂交（FISH）显示13号环状染色体长臂末端缺失。诊断为13号环状染色体综合征。该综合征临床表型多变,主要与染色体区带中遗传物质丢失的数量、部位以及不同核型嵌合比例不同等密切相关。     

45，X/46，X，+mar男性患儿临床及遗传学分析

目的分析45,X/46,X,+mar男性患儿的临床及遗传学特征。方法回顾分析2例确诊45,X/46,X,+mar男性患儿的临床资料,并复习相关文献。结果2例男性患儿,年龄分别为10岁7个月和3岁1个月,均有矮小表现,且伴有性腺发育落后。例1合并精索静脉曲张,头颅磁共振成像示部分空蝶鞍,外周血染色体核型分析为45,X[31]/46,X,+mar[69],二代测序检测提示Y染色体短臂SRY基因拷贝数重复,长臂USP9Y基因整体缺失。例2外周血染色体核型分析也为45,X[5]/46,X,+mar[75],全基因组CNV检测提示染色体核型为46,XY,Y染色体AZFb+AZFc区域完全缺失。结论矮小症患儿应密切关注其外生殖器的形态及功能,必要时进行遗传学分析。     

染色体1q21.3q44重复及Xp22.33p11.3缺失1例

1例1岁2月龄女性患儿出现反复呼吸道感染1年1个月余, 并存在喂养困难、体重增长缓慢、发育明显落后等表现, 检查发现包括外貌、心脏及肺部等多发畸形, 染色体核型为46, X, der(X), 全外显子高通量测序检测到1q21.3q44重复区域约93.94 Mb及Xp22.33p11.3缺失区域约44.37 Mb, 患儿父母均无出现上述基因缺失及重复。     

6号环状染色体致隐匿性阴茎1例报告及文献复习

目的探讨6号环状染色体片段缺失与临床表型的关系。方法报道1例因隐匿性阴茎就诊男性患儿,通过常规染色体核型和全基因组染色体微阵列芯片技术,分析缺失片段位置及包含基因与临床表型的关系;同时进行文献复习。结果患儿染色体核型分析结果为6号环状染色体,全基因组染色体微阵列芯片检测发现,6号染色体短臂和长臂末端均存在缺失,del6p25.3p25.1.seq[GRCh37/hg39](204909-4210858)×1,del6q27.seq[GRCh37/hg39](170438227-170898549)×1,短臂p25区域缺失4.01 Mb,包含DUSP22、IRF4、EXOC2、HUS1B、LOC285768、FOXQ1、FOXF2、FOXC1等30个基因,而长臂6q27区域发生0.46 Mb缺失,包含LOC154449、DLL1、FAM120B、PSMB1、TBP、PDCD2等7个基因。分析比较本例患儿和文献报道的6号环状染色体病例,发现所有患儿均存在神经或生长发育障碍,但仅本例和另1例患儿有生殖道畸形。结论 6号环状染色体患者的临床表型与染色体缺失部位、缺失片段大小以及环状染色体稳定性密切相关。     

3p25.3p25.2 染色体杂合缺失伴矮小及多发畸形1 例遗传学特征与临床表型分析

目的分析3号染色体p25.3p25.2(3p25.3p25.2)片段缺失的临床表型及分子遗传学特点。方法回顾分析1例3p25.3p25.2染色体片段缺失患儿的临床资料,分析其临床表型及分子遗传学特征。结果患儿,男,1岁4个月。宫内发育迟缓,重度矮小、全面生长发育落后、语言发育迟缓、特殊面容伴多发畸形(小头畸形、小下颌、长人中、低耳位、双侧耳前瘘管等)、先天性十二指肠闭锁、肠旋转不良,先天性心脏病、隐睾、龟头裸露、肌张力低下、婴儿期喂养困难、睡眠障碍、甲状腺功能减低。患儿染色体核型分析46,XY。基因芯片分析示3p25.3p25.2区域存在一段3 327 kb的杂合缺失,共39个基因缺失。结论 3p25.3p25.2区域3 327 kb杂合缺失,致SETD5、VHL、FANCD2基因缺失导致该患儿临床表型。     

WoIf-Hirschhorn综合征11例临床分析

目的探讨Wolf-Hirschhorn综合征(WHS)的临床表现、遗传学特征、治疗及预后等。方法回顾分析2009年6月-2018年6月诊治的11例WHS患儿的临床资料。结果符合WHS染色体改变诊断标准者15例,其中男6例、女9例,就诊年龄中位数为4月龄。15例患儿的染色体检测均有4p结构畸变,主要为单纯4p缺失(46.6%),其他还存在臂间倒位、重复或插入、衍生染色体、环状染色体。其中3例进一步行基因检测确认缺失片段大小。15例中11例资料完整,临床表现明确。首诊原因包括癫痫5例,生后反应差、低体质量5例,肺炎1例。主要核心临床表现为生长/精神发育迟缓、癫痫、希腊武士头盔面容,还可能存在多系统异常。3例在1岁内因肺炎/惊厥死亡,存活者均存在严重智力运动发育落后。结论WHS为4号染色体的结构畸变,4p16.3上的关键基因缺失,导致生长/精神发育迟缓、癫痫、特殊面容、多系统异常,预后较差。     

伴皮层下囊肿的巨脑性白质脑病一家系MLC1基因突变分析

收集伴皮层下囊肿的巨脑性白质脑病(MLC)先证者及其父母的临床资料,采用聚合酶链反应和DNA 直接测序法进行MLC1 基因突变检测。患儿临床表现为运动发育迟缓、巨颅,头颅MRI 扫描显示弥漫性脑白质肿胀,伴双侧额顶部皮层下囊肿。基因测序结果发现患儿携带MLC1 基因2 个杂合突变:第3 外显子的错义突变c.217G>A(p.Gly73Arg)和第9 内含子的剪接位点突变c.772-1G>C in IVS9-1。患儿的父母均为c.772-1G>C in IVS9-1 杂合突变携带者,无临床症状。可推测患儿c.772-1G>C in IVS9-1 突变来源于父母;c.217G>A(p.Gly73Arg)为新生突变,为国内外首次报道。     

Autoimmune polyendocrinopathy associated with ring chromosome 18

Phenotypic and clinical features of individuals with ring chromosome 18 [r(18)] vary with the extent of deletion of the short (18p-) or long arm (18q-). Most patients with r(18), therefore, demonstrate a clinical spectrum of both 18p- and 18q- deletions. Short stature, microcephaly, mental and motor retardation, craniofacial dysmorphism and extremity abnormalities are the most commonly reported features in patients with r(18). Abnormalities of chromosome 18, especially 18p- syndrome, are often reported with autoimmune thyroid disease and growth hormone deficiency, but reports of endocrine abnormalities associated with r(18) are rare. Here, we report a case of an African-American female with hyperthyroidism, type 1 diabetes mellitus, vitiligo and IgA deficiency associated with a r(18) chromosome complement. This patient additionally had mild intellectual disability and dysmorphic features. Karyotype analysis showed a de novo ring chromosome 18 (deletion 18q23-18qter and deletion 18p11.3-18pter). Although this unique association of autoimmune polyglandular endocrinopathy with ring chromosome 18 could be coincidental, we speculate that a gene or genes on chromosome 18 might play a role in the autoimmune process.     

一例15号额外标记染色体致智力障碍、难治性癫癎伴中枢性性早熟患者的临床及遗传学分析

15号额外标记染色体是一种罕见的染色体异常,本文报道1例15号额外标记染色体患儿,就其临床诊治经过及遗传缺陷进行研究。患儿,女,9岁半,自幼智力、运动发育落后,7岁出现乳房发育,8岁半出现癫癎发作：发作形式多样,多种抗癫癎药物控制欠佳,头颅磁共振未见异常,脑电图提示癎样放电频繁。采用G显带核型分析、荧光原位杂交（FISH）、甲基化多重连接依赖性探针扩增技术（甲基化MLPA）和微阵列比较基因组杂交（array-CGH）等多种遗传学检测手段,明确患儿存在新生的15q重复：15q11-13区域母源性拷贝数复制增加,基因组重排的形式为47,XX,+inv dup （15）（pter→q13：q13→pter）。15q11-13区域拷贝数复制增加与智力障碍、难治性癫癎伴中枢性性早熟临床表现密切相关。建议对于不明原因智力障碍伴癫癎患儿进行高分辨染色体核型分析。     

Microarray analysis of unbalanced translocation in Wolf‐Hirschhorn syndrome

Wolf–Hirschhorn syndrome (WHS) is caused by deletions involving chromosome region 4p16.3, which is characterized by growth delay, mild‐to‐severe mental retardation, hypotonia, facial dysmorphisms and shows extensive phenotypic variability include feeding difficulties, epilepsy and congenital anomalies. Variation in the size of the deletion involving chromosome region 4p16.3 may explain the clinical variation. However, previous studies indicate that duplication for another chromosome region due to an unbalanced translocation elucidate approximately 40–45% WHS patients. Therefore, we used whole genomic cytogenetics array to analyze the entire genome at a significantly higher resolution over conventional cytogenetics to characterize the exact subtelomeric aberration region of one patient with developmental delay and several facial characteristics reminiscent Wolf–Hirschhorn syndrome. Here we report that our patient had 3.7 Mb deletion at the 4p16.2 and 6.8 Mb duplication at 8p23.1 resulted from the unbalanced translocations der(4)t(4;8)(p16.2;p23.1). We confirmed that our patient with monosomy 4p16.2 which is consistent with Wolf–Hirschhorn syndrome and trisomy 8p23.1. The combination of the 4p deletion with 8p partial trisomy explains the complex phenotype presented by our patient.     

Muscular hypotonia, developmental retardation, speech delay and mildly dysmorphic features: 22q13 deletion syndrome (Phelan-McDermid Syndrome) as an important differential diagnosis

BACKGROUND: Clarifying the cause of global developmental and speech delay is of considerable significance in pediatrics. We present the clinical phenotype of the 22q13 deletion syndrome - also known as Phelan-McDermid syndrome - and show the diagnostic options. PATIENT: We report on a female patient with muscular hypotonia, tall stature, minor facial dysmorphism, retarded motor and mental development, and severe speech delay. METHOD: Chromosomal analysis was performed first on peripheral lymphocytes on GTG-banded chromosomes. Fluorescence in situ hybridization (FISH) analysis was carried out using the dual-color LSI DiGeorge/VCFS Region Probe (TUPLE1, N25) (Vysis/Abbott) and the subtelomeric probe tel 22q13.3 (Tel Vysion 22q).Results: The analysis of metaphase chromosomes at 450 band resolution showed a normal female karyotype 46,XX. FISH analysis revealed a 22q13 deletion. CONCLUSION: Muscular hypotonia and developmental delay are non-specific findings observed in many genetic syndromes. In association with severe speech delay and normal or advanced growth pediatricians should consider 22q13 deletion syndrome as a potential cause and initiate a genetic examination.     

11p15 duplication and 13q34 deletion with Beckwith–Wiedemann syndrome and factor VII deficiency

Here we report a patient with 11p15.4p15.5 duplication and 13q34 deletion presenting with Beckwith–Wiedemann syndrome (BWS) and moderate deficiency of factor VII (FVII). The duplication was initially diagnosed on methylation‐sensitive multiplex ligation‐dependent probe amplification. Array comparative genome hybridization confirmed its presence and indicated a 13q34 distal deletion. The patient's clinical symptoms, including developmental delay and facial dysmorphism, were typical of BWS with paternal 11p15 trisomy. Partial 13q monosomy in this patient is associated with moderate deficiency of FVII and may also overlap with a few symptoms of paternal 11p15 trisomy such as developmental delay and some facial features. To our knowledge this is the first report of 11p15.4p15.5 duplication associated with deletion of 13q34 and FVII deficiency. Moreover, this report emphasizes the importance of detailed clinical as well as molecular examinations in patients with BWS features and developmental delay.     

6p subtelomere deletion with congenital glaucoma,severe mental retardation,and growth impairment

Submicroscopic deletion of the 6p subtelomere has recently been recognized as a clinically identifiable syndrome. A distinct phenotype has emerged consisting of developmental delay/mental retardation, language impairment, hearing loss, and ophthalmologic, cardiac, and craniofacial abnormalities, including hypertelorism, midface hypoplasia, small nose, and high arched palate. We describe here a patient with 6p subtelomere deletion associated with congenital glaucoma, severe mental retardation, and growth impairment. Fluorescent in situ hybridization analysis revealed only one 6p25.3 signal. Array comparative genomic hybridization assay showed 2.1 Mb deletion and 4.14 Mb duplication in the 6p25 region. Generally, developmental delay and language impairment are common findings in patients with 6p subtelomere deletion syndrome, but growth impairment is not. Compared to that, the present patient showed atypically severe developmental delay and growth impairment.