一例8P倒位重复伴末端缺失综合征的细胞和分子遗传学研究

目的 明确1例智力低下患儿8号染色体短臂异常的片段来源和位置,探讨该异常核型的发生机制、临床表型特征和家庭再发风险.方法 高分辨显带分析患者及其父母外周血染色体核型,比较基因组杂交芯片(array comparative genomic hybridization,array CGH)精细定位拷贝数异常改变的染色体片段区域,荧光定量PCR验证芯片分析结果.结果 患儿异常染色体为8p11.2-p23.1倒位重复和8p23.2-pter缺失;在重复和缺失之间间隔有1个长为5.70 Mb的拷贝数正常片段,嗅觉受体(olfactory receptor,OR)基因簇位于该片段的两端.结论 这是1例典型的inv dup del(8p)综合征,临床上以重度智力低下、大脑发育不良和特殊面容为主要特征,由8p23.1上OR基因簇的重复序列发生非等位同源重组所致.再生育时,不仅要预防inv dup del(8p)的再发风险,还要注意由同一重组机制造成的另外3种不良结局的妊娠风险.就目前所知,这是国内第1例明确诊断的inv dup del(8p)综合征.     

8p23.1 duplication detected by array‐CGH with complete atrioventricular septal defect and unilateral hand preaxial hexadactyly

8p23.1 duplication syndrome is a genomic condition with variable phenotype. Isolated 8p23.1 duplication is rare. Here, we report on additional isolated 8p23.1 duplication in a fetus with complete atrioventricular septal defect and right hand preaxial hexadactyly diagnosed by array comparative genomic hybridization (array‐CGH). Array‐CGH indicated an ～1.43 Mb duplication between 8p23.1 olfactory receptor/defensin repeats (ORDRs) in this case, which contains 27 genes of which 21 are known and 6 are novel, including GATA4 and SOX7 and one micro‐RNA gene. In order to better understanding the genotype–phenotype association of 8p23.1 duplications, we summarized the present case and 10 previously reported patients with isolated 8p23.1 duplications between ORDRs and found that minor anomalies (6/11), congenital heart defect (6/11), developmental delay (5/11), and neurodevelopmental problems (5/11) are recurrent manifestations in 8p23.1 duplication patients. Thus, we suggest that 8p23.1 duplications between ORDRs generally result in clinical phenotypes and the phenotypes vary between patients. Because true duplications and euchromatic variants (EVs) of 8p23.1 are cytogenetically indistinguishable and usually lead to different clinical results, it is necessary to differentiate 8p23.1 duplications from EVs using molecular cytogenetic techniques. © 2013 Wiley Periodicals, Inc.     

Language characterization in 16p11.2 deletion and duplication syndromes

Expressive language impairment is one of the most frequently associated clinical features of 16p11.2 copy number variations (CNV). However, our understanding of the language profiles of individuals with 16p11.2 CNVs is still limited. This study builds upon previous work in the Simons Variation in Individuals Project (VIP, now known as Simons Searchlight), to characterize language abilities in 16p11.2 deletion and duplication carriers using comprehensive assessments. Participants included 110 clinically ascertained children and family members (i.e., siblings and cousins) with 16p11.2 BP4‐BP5 deletion and 58 with 16p11.2 BP4‐BP5 duplication between the ages of 2–23 years, most of whom were verbal. Regression analyses were performed to quantify variation in language abilities in the presence of the 16p11.2 deletion and duplication, both with and without autism spectrum disorder (ASD) and cognitive deficit. Difficulties in pragmatic skills were equally prevalent in verbal individuals in both deletion and duplication groups. NVIQ had moderate quantifiable effects on language scores in syntax and semantics/pragmatics (a decrease of less than 1 SD) for both groups. Overall, language impairments persisted even after controlling for ASD diagnosis and cognitive deficit. Language impairment is one of the core clinical features of individuals with 16p11.2 CNVs even in the absence of ASD and cognitive deficit. Results highlight the need for more comprehensive and rigorous assessment of language impairments to maximize outcomes in carriers of 16p11.2 CNVs.     

Direct duplication of 9p22→p24 in a child with duplication 9p syndrome

A de novo direct duplication of 9p22→p24 was shown in a child with a duplication 9p phenotype by GTG banding and fluorescence in situ hybridization (FISH) using a chromosome-9 specific painting probe as well as 6 YAC DNA probes localized to the 9p13–9p23 region. The breakpoints in this patient and previously reported patients suggest that 9p22 may be the critical region for duplication 9p syndrome. Am. J. Med. Genet. 77:268–271, 1998. © 1998 Wiley-Liss, Inc.     

Direct tandem duplication in chromosome 19q characterized by array CGH

Partial trisomy of the long arm of chromosome 19 is a rare aneusomy. Only six cases of pure duplications have been previously reported, two of which were prenatally detected. Here we describe the clinical manifestations in a 15-month-old girl with a de novo dup(19)(q12q13.2) and the application of array-based comparative genomic hybridization with a resolution of approximately 1 Mb to characterize the duplicated segment. Seven clones were found duplicated, and the size of the fragment was determined to be 10.8 Mb.

The scarce number of patients reported and the difficulty of accurately defining the duplicated segment when conventional cytogenetic methods are applied hamper the delineation of a clinical phenotype for duplication of chromosome 19q.

To our knowledge this is the fifth live born reported with a pure dup(19), and the first report in which the duplicated segment has been accurately characterized by means of array CGH.     

Normal adaptive function with learning disability in duplication 8p including band p22

Duplication 8p usually results in a syndrome characterized by profound mental retardation, mild facial anomalies, and malformations of hand, heart, and brain. We report on a large kindred segregating a Y;8 translocation in whom several individuals have duplication 8p22→8pter. These individuals have normal adaptive function despite their unbalanced karyotype. The family was studied with G-banding and fluorescent in situ hybridization (FISH) using probes to chromosomes 8 and Y. Comparison of this family with other reported cases defines a mild clinical outcome for trisomy 8p22→8pter in contrast to the severe findings when the duplication involves a longer, more proximal segment. Am. J. Med. Genet. 78:114–117, 1998. © 1998 Wiley-Liss, Inc.     

20‐Mb duplication of chromosome 9p in a girl with minimal physical findings and normal IQ: Narrowing of the 9p duplication critical region to 6 Mb

We studied the case of a girl with a partial 9p duplication, dup(9)(p22.1 → p13.1). Molecular cytogenetics studies defined the chromosome 9 rearrangement as a direct duplication of 20 Mb from D9S1213 to D9S52. Microsatellite analysis demonstrated the presence of a double dosage of the paternal alleles and demonstrated that the duplication occurred between sister chromatids. The patient's phenotype was almost normal, with a few minor anomalies (dolichocephaly, crowded teeth, high arched palate) and normal IQ. The breakpoint's location in this patient and previously reported cases suggest that the critical region for the 9p duplication syndrome lies within a 6‐Mb portion of chromosome 9p22 between markers D9S267 and D9S1213. © 2002 Wiley‐Liss, Inc.     

Trisomy of chromosome 16p13.3 due to an unbalanced insertional translocation into chromosome 22p13

A dysmorphic boy with severe mental retardation was found on array CGH to have an insertional translocation of chromosome 16p13.3 into the short arm of chromosome 22, karyotype 46,XY,.ish der(22),ins(22;16)(p13;p13.3p13.3) de novo. His clinical features overlap with the reported cases of 'duplication 16p' syndrome, namely a round face, hypertelorism, a long philtrum, micrognathia, a thin upper lip, a posterior cleft palate and low set, simple ears, clubbed feet, severe developmental delay, psychomotor retardation and seizures. This 4-year boy with trisomy 16p13.3 has the smallest duplication reported of this critical region, which could not be detected without array CGH. The maximal duplicated region is gene rich and contains about 80 genes and/or candidate genes. Assignment of the genes that contribute to the observed phenotype awaits the characterisation of other patients with small duplications in this region.     

De novo trisomy 16p

We report on a patient with psychomotor retardation and a pattern of malformations comprising single umbilical artery, cranio-facial anomalies, severe truncal hypotonia, and lower-limb hyporreflexia. G-banding cytogenetics demonstrated a 16p+ chromosome. Parental chromosomes were normal. The use of fluorescent in situ hybridization (FISH) showed that this extra material derived from chromosome 16. High-resolution G-banding demonstrated a duplicated segment on the 16p arm, confirming our suspicion of a de novo tandem duplication; hence, the cytogenetic diagnosis was given as 46,XY,dir dup(16)(p11.2→p12). Am. J. Med. Genet. 68:219–221, 1997 © 1997 Wiley-Liss, Inc.     

Partial trisomy and monosomy 8p due to inversion duplication

Fluorescent in situ hybridization with probes specific for a chromosomal subregion and chromosome-specific libraries (chromosome painting) are important new methods for assessing chromosome rearrangements. In this paper we present four patients with additional chromosomal material on chromosome 8p who have been studied using G-banding techniques, chromosome painting and FISH with cosmid probes specific for the region 8p23.1 → 8pter. In all cases we found a partial inversion duplication of 8p along with a deletion of the region 8p23.1 → 8pter.     

Trisomy 16p in a liveborn offspring due to maternal translocation t(16;21)(q11;p11) and review of the literature

We report on a case of dup(16p) and review previous cases. The triplicated chromosome region leading to this specific syndrome lies in 16p13.1 p13.3. Most of the cases are inherited and the mode of segregation was found to be 3:1 in half of the cases, but these observations might be due to biases. The other chromosomes involved in the translocations as well as the breakpoints in these chromosomes do not appear to be random. © 1992 Wiley-Liss, Inc.     

M-banding characterization of a 16p11.2p13.1 tandem duplication in a child with autism, neurodevelopmental delay and dysmorphism

We describe a partial duplication of the chromosome 16 short arm [46,XY,dup(16)(p11.2p13.1)] in an Iranian girl with autism, neurodevelopmental delay, mental retardation, very poor memory, and dysmorphism including sparse hair, upslanting palpebral fissures, long philtrum, micrognathia, hypotonia, small feet and hands, syndactyly of the fingers, and hypoplastic thumbs. The patient now four years old, has a normal twin sister, and the parents are unrelated. The abnormal 16p was originally detected by banding cytogenetic techniques, and was characterized by multicolour banding fluorescence in situ hybridization (MCB). The MCB pattern on the derivative chromosome 16 indicated a direct duplication of the region 16p11.2 to 16p13.1.     

Patient with de novo 12p+ syndrome identified as dir dup (12) (p13) using subchromosomal painting libraries from somatic cell hybrids

Several patients with partial 12p duplications are known. An additional patient, who presented with the clinical manifestations of trisomy 12p syndrome, is described. De novo duplication 12p13.1 →pter was diagnosed using subchromosomal painting libraries obtained from somatic cell hybrids.     

Characterization of a duplication in the terminal band of 4p by molecular cytogenetics

An infant with multiple anomalies including small head, Large apparently low-set ears, beaked nose, micrognathia, choanal stenosis, proptosis, atrial-septal defect, and left inguinal hernia was found, on chromosome analysis, to have a longer than normal terminal band 4p16 by G and R-banding. In situ hybridization of biotin-labeled DNA probes C39, BJ14, BJ54, BJ19, BJ7, and BJ11 showed them to be duplicated. Probes I14, A157.1, and the telomeric sequence, (TTAGGG)n, which hybridized to the more distal part of 4p16.3, were not duplicated. These result confirm the impression by G and R-banding of a duplication within band 4p16, a region extending from approximately 2.1 Mb from the telomere, proximally, to the junction of 4p16.1 and 4p15.3. This is the smallest confirmed duplication of distal 4p reported to date, with many of the classical findings of dup(4p) syndrome. © 1993 Wiley-Liss, Inc.     

Partial duplication 16p resulting from a 3:1 segregation of a maternal reciprocal translocation

We report on a male infant with a duplication 9p (pter → _q13) and duplication 16p (p13 → pter) resulting from a 3:1 meiotic disjunction of a maternal reciprocal translocation. In this case, the mode of segregation fits to the Pachytene-Diagram Model of Jalbert el al [1980]. The infant showed clinical features that have been described both in dup(16p) and in dup(9p). To our knowledge, this is the first time that this unbalanced karyotype has been reported.     

Trisomy 16p in a liveborn infant and review of trisomy 16p

We report on an infant boy with duplication of part of 16p and partial deficiency of 9p:46.XY, ?9, + der(9)t(9;16)(p24;p13.1)mat. The child has the typical phenotype of dup(16p) even though the extra piece of 16p is small (16pl3.1→pter). Manifestations include severe developmental delay, rounded face, sparse hair, ear anomalies, hypertelorism, cleft soft palate, a thin vermilion border of the upper lip, and left renal dysgenesis. We review 16p duplications.