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Contains fulltext : 229254.pdf (publisher's version ) (Open Access)

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1 september 2010, Contains fulltext : 89736.pdf (publisher's version ) (Closed access), Supernumerary marker chromosomes (SMC) originating from chromosome 15 are the most common SMCs. They encompass clinically irrelevant SMC(15)s containing only heterochromatin and 15p material, and clinically relevant SMC(15)s that consist of both eu- and heterochromatic 15q material. On the basis of size, the clinically relevant SMC(15)s can be subdivided into type A, "large" asymmetric and type B, "small" symmetric SMC(15)s. Type B SMC(15)s contain the triplicated 15pter to BP3 (located at 26.5 Mb) region, while type A SMC(15)s consist of 15pter --> BP4(28.5 Mb)::BP5(30.5 Mb) --> 15pter. In this study, the clinical and molecular features of 18 patients with A and B SMC(15)s and two patients with a partial trisomy 15q were reviewed. Questionnaires (including Child Behavior Check Lists) were used to assess behavior and developmental features in more detail. The marker size and parental origin were determined by multiplex ligation-dependent probe amplification (MLPA). Based on the MLPA results, the majority of patients (14/18) had type A SMC(15)s. The phenotype observed did not show significant differences between types A and B SMC(15)s. A high prevalence of autistic-like behavior, attention problems, aggressive behavior, anxiety, and sleeping problems was reported. Motor and speech development varied extensively among the patients. An association was found between positive seizure history and degree of intellectual disability.

Background. Several cases have been reported of patients with a ring chromosome 18 replacing one of the normal chromosomes 18. Less common are patients with a supernumerary ring chromosomes 18. High resolution whole genome examination in patients with multiple congenital abnormalities might reveal cytogenetic abnormalities of an unexpected complexity. Results. We report a 24 years old male patient with lower spinal anomalies, hypospadia, bifid scrotum, cryptorchism, anal atresia, kidney stones, urethra anomalies, radial dysplasia, and a hypoplastic thumb. Some of the anomalies overlap with the VACTERL association. Chromosome analysis of cultured peripheral blood lymphocytes revealed an additional ring chromosome in 13% of the metaphases. Both parents had a normal karyotype, demonstrating the de novo origin of this ring chromosome. FISH analysis using whole chromosome paints showed that the additional chromosomal material was derived from chromosome 18. Chromosome analysis of cultured fibroblasts revealed only one cell with the supernumerary ring chromosome in the 400 analyzed. To characterize the ring chromosome in more detail peripheral blood derived DNA was analyzed using SNP-arrays. The array results indicated a 5 Mb gain of the pericentromeric region of chromosome 18q10-q11.2. FISH analysis using BAC-probes located in the region indicated the presence of 6 signals on the r(18) chromosome. In addition, microsatellite analysis demonstrated that the unique supernumerary ring chromosome was paternally derived and both normal copies showed biparental disomy. Conclusions. We report on an adult patient with multiple congenital abnormalities who had in 13% of his cells a unique supernumerary ring chromosome 18 that was composed of 6 copies of the 5 Mb gene rich region of 18q11.

Item does not contain fulltext, Anomalies of chromosome number and structure are considered to be the most frequent cause of unexplained, non-syndromic developmental delay and mental retardation (DD/MR). High-resolution, genome-wide, array-based segmental aneusomy profiling has emerged as a highly sensitive technique for detecting pathogenic genomic imbalances. A review of 29 array-based studies of DD/MR patients showed that a yield of at least approximately 19% pathogenic aberrations is attainable in unselected, consecutive DD/MR referrals if array platforms with 30-70 kb median probe spacing are used as an initial genetic testing method. This corresponds to roughly twice the rate of classical cytogenetics. This raises the question whether chromosome banding studies, combined with targeted approaches, such as fluorescence in situ hybridisation for the detection of microdeletions, still hold substantial relevance for the clinical investigation of these patients. To address this question, we reviewed the outcome of cytogenetic studies in all 36,325 DD/MR referrals in the Netherlands during the period 1996-2005, a period before the advent of array-based genome investigation. We estimate that in a minimum of 0.78% of all referrals a balanced chromosomal rearrangement would have remained undetected by array-based investigation. These include familial rearrangements (0.48% of all referrals), de novo reciprocal translocations and inversions (0.23% of all referrals), de novo Robertsonian translocations (0.04% of all referrals), and 69,XXX triploidy (0.03% of all referrals). We conclude that karyotyping, following an initial array-based investigation, would give only a limited increase in the number of pathogenic abnormalities, i.e. 0.23% of all referrals with a de novo, apparently balanced, reciprocal translocation or inversion (assuming that all of these are pathogenic), and 0.03% of all referrals with 69,XXX triploidy. We propose that, because of its high diagnostic yield, high-resolution array-based g

Contains fulltext : 144546.pdf (publisher's version ) (Closed access), The aims of this study were to assess the relationships between numerical aberrations of chromosome 1 and the presence of high-risk human papillomavirus (HPV). Five normal samples, 11 CIN1, 13 CIN2, 18 CIN3, and nine carcinomas were studied by in situ hybridization (ISH), using a DNA probe for the centromere of chromosome 1 (cen#1) and a DNA probe cocktail for HPV types 16 and 18. A short fragment polymerase chain reaction hybridization line probe assay (SPF-PCR-LiPA) technique was used to detect 25 HPV types. The mean number of cen#1 per nucleus (chromosome index, CI) was measured, and the fractional areas of dysplastic epithelium with HPV16/18 infection and with cen#1 aneusomy were estimated. Disomy was found in all normal epithelium and in 36% of CIN1. Tetrasomy was observed in 64% of CIN1, 15% of CIN2, and 17% of CIN3. Hyper-tetrasomy was observed in 77% of CIN2, 83% of CIN3, and 100% of invasive carcinomas. High-risk HPVs were present in 20%, 75%, and 94% of disomic, tetrasomic, and hyper-tetrasomic lesions, respectively. The mean CI value was significantly higher in the lesions infected with high-risk HPV than in the lesions not infected by high-risk HPV (p < 0.001), due to the significantly higher prevalence of hyper-tetrasomy. The ISH study disclosed that HPV16/18 was exclusively found within dysplastically altered epithelium. The area with aneusomy is mostly enclosed within the area infected with HPV. In 83% of the HPV16/18-positive CIN lesions, the fractional area of HPV-infected epithelium was equal to, or larger than, the fractional area with aneusomy. In conclusion, aneusomy for chromosome 1 is strongly associated with high-grade CIN lesions and infection with high-risk HPV; it is likely that the occurrence of numerical aberrations of chromosome 1 is preceded by infection with high-risk HPV.

Contains fulltext : 144772.pdf (Publisher’s version ) (Open Access)

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Contains fulltext : 22010___.PDF (publisher's version ) (Open Access)