Fine mapping of a de novo interstitial 10q22-q23 duplication in a patient with congenital heart disease and microcephaly

In this study we report a female patient with an interstitial duplication of a region (10q22-q23) which is rarely reported in the literature. We fine mapped the aberration with array CGH, which revealed an 18.6-Mb duplication, covering 89 annotated genes, at 10q22.2-q23.33. There were no other deletions or duplications elsewhere in the genome. The main clinical features of the patient are microcephaly and congenital heart disease, which are likely to be caused by dosage effect of one or several genes in the duplicated region. Similar phenotypes have been found in other patients with 10q11-q22 duplications and in two out of three patients with 10q22-q25 duplications. However, most of the duplication cases were investigated only by conventional chromosome analyses, and fine mapping of these and other duplications of 10q22-q23 are warranted for genotype-phenotype comparisons.     

Toriello-Carey syndrome with a 6Mb interstitial deletion at 22q12 detected by array CGH

Toriello-Carey syndrome is a rare multiple congenital anomaly syndrome comprising agenesis of the corpus callosum, telecanthus, short palpebral fissures, abnormal ears, Pierre Robin sequence, and cardiac anomaly. Autosomal recessive inheritance has been hypothesized and chromosome abnormalities have been reported. The present case is a girl with agenesis of the corpus callosum, a large cleft palate, telecanthus, hypertelorism, atrial septal defect, ventricular septal defect, and patent ductus arteriosus. A routine karyotype and fluorescence in situ hybridization subtelomeric analysis were normal. Array comparative genomic hybridization (CGH) identified a de novo 6 Mb interstitial deletion at 22q12.1→22q12.2. These findings support recent findings of chromosomal abnormalities in patients with the Toriello-Carey phenotype. We suggest that the clinical features described in some cases with Toriello-Carey syndrome might be due to cryptic chromosomal rearrangements and that array CGH should be considered in any case presenting with clinical features of Toriello-Carey.     

单纯17q25.3拷贝数重复导致全面性发育迟缓和多发性先天异常一例

目的探讨单纯17q25.3拷贝数重复的临床特征、遗传方式及基因型与表型的关系。方法应用全外显子测序、染色体微阵列、染色体核型分析、荧光原位杂交技术联合对先证者及其家系成员进行分析。结果先证者为一例4岁的多发性先天异常男性患儿,表现为全面性发育迟缓、矮小、智力障碍、脑发育不良、小头、特殊面容、肌张力低下、注意力缺陷多动障碍、共济失调、骨骼和心血管异常等。全外显子测序和染色体微阵列分析鉴定其在染色体17q25.3→qter发生5.7 Mb拷贝数重复,可能为患儿致病的原因。荧光原位杂交证实先证者该拷贝数重复是遗传自携带该片段平衡易位的母亲,其外祖母和舅舅也为该片段平衡易位携带者,而小姨未见异常。结论本研究结果丰富了单纯17q25.3拷贝数重复的临床表型谱,为遗传咨询提供了依据,并初步提示了P4HB、ACTG1、BAIAP2及TBCD基因为17q25.3拷贝数重复候选基因。     

Duplication 6q21q23 in two unrelated patients

We report on two patients with rare 6q duplications. The karyotype of patient 1 is 46,XY,dup(6)(q21q23.3). The karyotype of patient 2 is 46,XX,dup(6)(q21.15q23.3). These two patients have some nonspecific physical findings in common including a depressed nasal bridge, epicanthal folds, mild heart defects, and developmental delay, but each had other congenital anomalies. Am. J. Med. Genet. 80:112–114, 1998. © 1998 Wiley-Liss, Inc.     

Familial 5q11.2→q13.3 segmental duplication cosegregating with multiple anomalies,including schizophrenia

We report on 2 relatives with a segmental duplication of 5q11.2→13.3. The phenotype is surprisingly limited for the degree of chromosome imbalance, the propositus presenting with schizophrenia. Using RFLP markers, we have shown that the gene for HEXB lies within the duplicated region. We suggest this region as a candidate region for the location of a single major gene which predisposes to schizophrenia and which may be assessed by linkage analysis.     

Low-level complex mosaic with multiple cell lines affecting the 18q21.31q21.32 region in a patient with de novo 18q terminal deletion

We describe a 5-year-old girl who was diagnosed at birth with 18q de novo homogeneous deletion at G-banding karyotype. Her clinical condition, characterized by hypotonia, psychomotor retardation, short stature, deafness secondary to bilateral atresia of the external auditory canals, was in agreement with the 18q deletion syndrome though presence of coloboma of a single eye only suggested a mosaic condition as an unusual sign. By combining multiple technologies including array-CGH, FISH, and WGS, we found that the terminal deletion 18q21.32q23 (21 Mb) was in segmental mosaicism of the proximal region 18q21.31q21.32 (2.7 Mb), which showed a variable number of copies: one, two, or three, in 7, 41 and 55% of the cells respectively. Breakpoint junction analysis demonstrated the presence of an inv-dup del (18q) with a disomic segment of 4.7 kb between the inverted and non-inverted copies of the duplicated region 18q21.31q21.32. From these results, we propose that all three types of abnormal chr18 (the inv-dup del and the two 18q terminal deletions of different sizes) arisen from breaks in a dicentric mirror chromosome 18q, either in more than one embryo cell or from subsequent breaking-fusion-bridge cycles. The duplication region was with identical polymorphisms as in all non-recurrent inv-dup del rearrangements though, in contrast with most of them, the 18q abnormality was of maternal origin. Taking into account that distal 18q deletions are not rarely associated with inv-dup del(18q) cell lines, and that the non-disjunction of chromosome 18 takes place especially at maternal meiosis II rather than meiosis I, multiple rescue events starting from trisomic zygotes could be considered alternative to the postmitotic ones. From the clinical point of view, our case, as well as those of del(18q) in mosaic with the dic(18q), shows that the final phenotype is the sum of the different cell lines that acted on embryonic development with signs typical of both the 18q deletion syndrome and trisomy 18. Asymmetrical malformations, such as coloboma of the iris only in the right eye, confirm the underlying mosaicism regardless of whether it is still detectable in the blood.     

一例嵌合型13q倒位重复胎儿的遗传学分析

目的:分析1例产前诊断的嵌合型13q倒位重复的形成机制,探讨其基因型与表型的对应关系。方法:分别于孕23周和孕32周抽取胎儿羊水和脐带血样,联合应用G显带染色体核型分析、单核苷酸多态性微阵列和荧光原位杂交技术对其进行检测,并复习相关文献。结果:胎儿的核型最终被确定为47,XY,+inv dup(13)(q14.3q34...     

Precise mapping of a de novo duplication 18(q21→q22) utilizing cytogenetic,biochemical, and molecular techniques

We describe the first de novo inverted duplication of 18q. Due to the difficulty of identifying de novo chromosome abnormalities based solely on cytologic studies, precise definition of the 18q duplication was attempted by integrating cytogenetic and clinical findings with biochemical and molecular dosage studies. The combined results demonstrated that the proposita had a duplication of 18q21→q22 with a karyotype of 46,XX,–18,+inv dup(18) (pter→q12.1::q22→q21::q12.1→qter). The duplication of this specific chromosome region does not result in the typical 18 phenotype, supporting the hypothesis that various loci on chromosome 18 may interact to produce the manifestations of this syndrome. © 1993 Wiley-Liss, Inc.     

Cardiac anomalies in individuals with the 18q deletion syndrome; report of a child with Ebstein anomaly and review of the literature

Individuals with the 18q deletion syndrome are presented with various clinical characteristics, including cardiac anomalies in 24–36% of the reported cases. Nonetheless, genotype–phenotype correlations for cardiac anomalies in the 18q deletion syndrome have rarely been reported. We report on two girls with a terminal 18q deletion, one in whom an Ebstein anomaly and Wolff–Parkinson–White syndrome were detected and the other with multiple valve stenosis and a ventricular septal defect. The genotype and cardiac abnormalities of these girls and 17 other individuals with a de novo 18qter deletion reported in the literature are reviewed. All 19 individuals shared a small overlapping deletion region between 18q22.3q23. The most common cardiac defects detected were pulmonary valve anomalies and atrial septal defects. Ebstein anomaly, a rare cardiac malformation, was diagnosed in two individuals. Additional molecularly based genotype–phenotype studies are needed in order to pinpoint candidate genes within this region that contribute to normal cardiac development. A careful cardiac evaluation consisting of physical examination, ECG and ultrasound examination should be performed in all individuals diagnosed with the 18q deletion syndrome.     

Duplication 3q: Severe manifestations in an infant with duplication of a short segment of 3q

A patient with duplication of a short segment of 3q (3q21→26) without apparent deletion of 3 or of other chromosomes provided a further opportunity to study manifestations of this abnormality. The proposita had a broad nasal bridge, anteverted nostrils, webbed neck, and clinodactyly V in addition to congenital heart disease, limb abnormalities, cleft palate, and severe developmental delay. The infant did not have the hirsutism and synophrys present in other cases.     

Cryptic duplication of 21q in an individual with a clinical diagnosis of Down syndrome

We describe an adult male who was diagnosed with Down syndrome (DS) at 9 months of age, but had repeatedly normal karyotypes until recent mid‐resolution chromosome studies showed a possible duplication of 21q22.13 to 21q22.3. The abnormality was investigated using fluorescent in situ hybridization (FISH) studies. These showed hybridization of a whole chromosome paint probe (wcp21, Oncor Coatasome 21) to the entire length of both chromosome 21 homologues and one very large hybridization signal of a cosmid contig probe localized within bands 21q22.13‐21q22.2(LSI‐21, Vysis) on the ?dup(21q) homologue. CGH analysis identified a ratio of 1.5 for the segment of chromosome 21 involving band 21q22, indicating a gain of part, or all, of the terminal band of chromosome 21. The karyotype was thus defined as 46,XY,?dup(21) (q22.13q22.2).ish dup(21)(LSI‐21++,wcp21+). Common DS characteristics in our case and 12 previously reported cases with duplications involving chromosome 21 included mental retardation, fifth finger clinodactyly, open mouth and oblique eye fissures. Transverse palmar creases and congenital heart defects, seen in DS less than 40% of the time, were infrequent. Presence of these features did not appear to depend on the specific portion of chromosome 21 that was duplicated. A review of 18 additional clinical features showed no consistent phenotype–genotype correlations.     

Tandem duplication (1) (q11 → q22) in a male infant with multiple congenital malformations

An inverted tandem duplication of 1q11-q22 was found in a male infant with severely retarded psychomotor development, growth retardation, and multiple congenital malformations. Trisomy for this segment of chromosome 1 has not been previously reported.     

A boy with partial trisomy of chromosome 3q24–q28 from paternal balanced insertion and multiple congenital anomalies

Although many patients with duplication 3q syndrome have been described reports on duplication derivatives from an insertion are rare in the previous literature. Here we describe the genotype and phenotype of a 32‐month‐old boy with a partial trisomy of 3q24–q28. We carefully mapped the aberration with SNP‐array analysis, and found a duplication region of 44 Mb. By conventional cytogenetic techniques including fluorescence in situ hybridization (FISH) and spectral karyotyping (SKY) analysis, the patient was found to have inherited a derivative chromosome 6 from his father, which was contained a direct insertion from 3q24–28. The main clinical features of the patient included severe mental retardation, postnatal developmental delay, ventricular septal defect (VSD), and craniofacial anomalies including cleft palate, frontal bossing, hypertelorism, and a broad nasal bridge. The symptoms partially overlap with previously reported patients with duplication in the same region. Prenatal diagnosis for the fetus of this family was performed based on the results of genetic tests and ultrasonic evaluation. © 2013 Wiley Periodicals, Inc.     

Prader-Willi–like syndrome in a patient with an Xq23q25 duplication

We report on a 24-year old woman with an Xq duplication and findings suggestive of Prader-Willi syndrome (PWS). Her birth weight was at the 3rd centile and her birth length was less than the 3rd centile. She was hypotonic and had a weak cry as an infant. There were no feeding difficulties, although her mother reports that as an infant, she was “small for her age.” Excessive weight gain began between 3 and 4 years. The patient's development was delayed and she received special education. She has a history of hiding food. She has a sleep disturbance disorder and inappropriate social behavior. At the age of 24 years her height was below the 5th centile and weight >>95th centile. She has physical findings typical of PWS, skin picking, and speech articulation defects. Cytogenetic analysis showed a 46,X,dup(X)(q23q25) karyotype. Fluorescent in situ hybridization (FISH) studies using a chromosome X painting probe demonstrated that the rearrangement was intrachromosomal. The X-chromosome fold scoring technique was used to determine the X inactivation pattern and indicated that some cells expressed the abnormal X chromosome. Results of FISH studies using the SNRPN probe localized to 15q11q13 and DNA studies using the PW71B and SNRPN probes were normal. The duplicated X chromosome, random X inactivation pattern, and the negative molecular studies for PWS indicate that the abnormal X chromosome is the basis of this patient's phenotype. This patient emphasizes the importance of obtaining a karyotype even when a syndrome diagnosable by molecular methods is strongly suspected. Am. J. Med. Genet. 80:227–231, 1998. © 1998 Wiley-Liss, Inc.