| 1. |
- Barbaro, Michela, et al.
(författare)
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Isolated 46,XY gonadal dysgenesis in two sisters caused by a Xp21.2 interstitial duplication containing the DAX1 gene.
- 2007
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 92:8, s. 3305-3313
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Tidskriftsartikel (refereegranskat)abstract
- Context: Testis development is a tightly regulated process that requires an efficient and coordinated spatiotemporal action of many factors, and it has been shown that several genes involved in gonadal development exert a dosage effect. Chromosomal imbalances have been reported in several patients presenting with gonadal dysgenesis as part of severe dysmorphic phenotypes. Results: We screened for submicroscopic DNA copy number variations in two sisters with an apparent normal 46, XY karyotype and female external genitalia due to gonadal dysgenesis, and in which mutations in known candidate genes had been excluded. By high-resolution tiling bacterial artificial chromosome array comparative genome hybridization, a submicroscopic duplication at Xp21.2 containing DAX1 ( NR0B1) was identified. Using fluorescence in situ hybridization, multiple ligation probe amplification, and PCR, the rearrangement was further characterized. This revealed a 637-kb tandem duplication that in addition to DAX1 includes the four MA-GEB genes, the hypothetical gene CXorf21, GK, and part of the MAP3K7IP3 gene. Sequencing and analysis of the breakpoint boundaries and duplication junction suggest that the duplication originated through a coupled homologous and nonhomologous recombination process. Conclusions: This represents the first duplication on Xp21.2 identified in patients with isolated gonadal dysgenesis because all previously described XY subjects with Xp21 duplications presented with gonadal dysgenesis as part of a more complex phenotype, including mental retardation and/or malformations. Thus, our data support DAX1 as a dosage sensitive gene responsible for gonadal dysgenesis and highlight the importance of considering DAX1 locus duplications in the evaluation of all cases of 46, XY gonadal dysgenesis.
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| 2. |
- Bena, Frederique, et al.
(författare)
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Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature
- 2013
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Ingår i: American Journal of Medical Genetics Part B. - : Wiley. - 1552-4841 .- 1552-485X. ; 162B:4, s. 388-403
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed to elucidate the observed variable phenotypic expressivity associated with NRXN1 (Neurexin 1) haploinsufficiency by analyses of the largest cohort of patients with NRXN1 exonic deletions described to date and by comprehensively reviewing all comparable copy number variants in all disease cohorts that have been published in the peer reviewed literature (30 separate papers in all). Assessment of the clinical details in 25 previously undescribed individuals with NRXN1 exonic deletions demonstrated recurrent phenotypic features consisting of moderate to severe intellectual disability (91%), severe language delay (81%), autism spectrum disorder (65%), seizures (43%), and hypotonia (38%). These showed considerable overlap with previously reported NRXN1-deletion associated phenotypes in terms of both spectrum and frequency. However, we did not find evidence for an association between deletions involving the -isoform of neurexin-1 and increased head size, as was recently published in four cases with a deletion involving the C-terminus of NRXN1. We identified additional rare copy number variants in 20% of cases. This study supports a pathogenic role for heterozygous exonic deletions of NRXN1 in neurodevelopmental disorders. The additional rare copy number variants identified may act as possible phenotypic modifiers as suggested in a recent digenic model of neurodevelopmental disorders.
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| 3. |
- Bremer, Anna, et al.
(författare)
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Copy number variation characteristics in subpopulations of patients with autism spectrum disorders.
- 2011
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Ingår i: American Journal of Medical Genetics, Part B, Neuropsychiatric Genetics. - : Wiley. - 1552-4841. ; 156B156:2, s. 115-124
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Tidskriftsartikel (refereegranskat)abstract
- Autism spectrum disorders (ASDs) are a heterogeneous group of disorders with a complex genetic etiology. We used high-resolution whole genome array-based comparative genomic hybridization (array-CGH) to screen 223 ASD patients for gene dose alterations associated with susceptibility for autism. Clinically significant copy number variations (CNVs) were identified in 18 individuals (8%), of which 9 cases (4%) had de novo aberrations. In addition, 20 individuals (9%) were shown to have CNVs of unclear clinical relevance. Among these, 13 cases carried rare but inherited CNVs that may increase the risk for developing ASDs, while parental samples were unavailable in the remaining seven cases. Classification of all patients into different phenotypic and inheritance pattern groups indicated the presence of different CNV patterns in different patient groups. Clinically relevant CNVs were more common in syndromic cases compared to non-syndromic cases. Rare inherited CNVs were present in a higher proportion of ASD cases having first- or second-degree relatives with an ASD-related neuropsychiatric phenotype in comparison with cases without reported heredity (P=0.0096). We conclude that rare CNVs, encompassing potential candidate regions for ASDs, increase the susceptibility for the development of ASDs and related neuropsychiatric disorders giving us further insight into the complex genetics underlying ASDs
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| 4. |
- Bremer, Anna, et al.
(författare)
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Screening for Copy Number Alterations in Loci Associated With Autism Spectrum Disorders by Two-Color Multiplex Ligation-Dependent Probe Amplification
- 2010
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Ingår i: American journal of medical genetics. Part B, Neuropsychiatric genetics. - : Wiley. - 1552-4841 .- 1552-485X. ; 153B:1, s. 280-285
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Tidskriftsartikel (refereegranskat)abstract
- The autism spectrum disorder (ASD) is a heterogenous condition characterized by impaired socialization and communication in association with stereotypic behaviors. ASD is highly heritable and heterogeneous with a complex genetic etiology. Recurrent submicroscopic deletions or duplications have been identified in a subgroup of individuals with ASD using array technology. Adequate genetic testing for these genomic imbalances have not yet been widely implemented in the diagnostic setting due to lack of feasible and cost-effective methods as well as difficulties to interpret the clinical significance of these small copy number variants (CNVs). We developed a multiplex ligation-dependent probe amplification (MLPA) assay to investigate its usefulness for detection of copy number alterations (CNAs) in autistic patients. This test proved to be easy to perform, fast, cost-effective, and suitable for reliable detection of multiple loci in a single reaction. We screened 148 autistic patients for 15 different loci covering 26 genes and found a 15q11-13 interstitial duplication that had escaped detection by conventional karyotyping in 1.3% of the patients. Synthetic probe MLPA allows for a flexible analysis of a continuously increasing number of CNAs associated with autism. Our result show that MLPA assay is an easy and cost-effective method for the identification of selected CNAs in diagnostic laboratories. (C) 2009 Wiley-Liss, Inc.
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| 5. |
- Forestier, Erik, et al.
(författare)
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Clinical and cytogenetic features of pediatric dic(9;20)(p13.2;q11.2)-positive B-cell precursor acute lymphoblastic leukemias : A nordic series of 24 cases and review of the literature
- 2008
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 47:2, s. 149-158
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Forskningsöversikt (refereegranskat)abstract
- Although dic(9;20)(p13.2;q11.2) is a characteristic abnormality in childhood B-cell precursor acute lymphoblastic leukemias (BCP ALL), little is known about its clinical impact or the type and frequency of additional aberrations it may occur together with. We here review the clinical and cytogenetic features of a Nordic pediatric series of 24 patients with dic(9;20)-positive BCP ALL diagnosed 1996-2006, constituting 1.3% of the BCP ALL, as well as 47 childhood cases from the literature. Consistent immunophenotypic features of the Nordic cases included positivity for HLA-DR, CD10, CD19, CD20, and CD22 and negativity for T-cell and myeloid markers; no detailed immunophenotypes were reported for the previously published cases. In the entire cohort of 71 cases, the modal chromosome distribution was 45 (62%), 46 (21%), 47 (7%), 48 (4%), 49 (3%), 44 (1%), and 50 (1%). Additional changes were present in 63%, the most frequent of which were homozygous loss of CDKN2A (33%) and gains of chromosomes 21 (28%) and X (10%). The median patient age was 3 years, the female/male ratio was 2.0, the median white blood cell count was 24 x 10(9)/l, 11% had central nervous system involvement, and 5% had a mediastinal mass at diagnosis. Risk group stratification was nonstandard risk in 79%. The event-free survival and overall survival at 5 years for the 24 Nordic cases was 0.62 and 0.82, respectively. Thus, although relapses are quite common, postrelapse treatment of many patients is successful.
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| 6. |
- Fossum, Magdalena, et al.
(författare)
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Long-term culture of human urothelial cells : a qualitative analysis
- 2005
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Ingår i: Cells Tissues Organs. - : S. Karger AG. - 1422-6405 .- 1422-6421. ; 181:1, s. 11-22
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Tidskriftsartikel (refereegranskat)abstract
- Today, in vitro culturing of autologous cells is an established method in the field of tissue reconstruction. It can be applied to urothelial cells and could have many clinical implications in urological reconstructive surgery. This development calls for quality controls concerning cells used for clinical treatment when cells are autotransplanted back to the patient. We have studied cultured cells in order to detect whether genetic or morphologic changes occur. Urothelial cells isolated from bladder lavage were cultured according to different protocols based on the presence or absence of feeder cells. Genetic studies were performed by means of karyotyping with standard G-banding and interphase fluorescent in situ hybridization (FISH) analyses. The morphology of these epithelial cells was judged as well as immunostaining for epithelial cell markers. In addition, to minimize the risk of feeder cell contamination, proliferation studies were performed on cultures including feeder cells that had been pretreated with different doses of mitomycin or radiation. In initial studies, when using feeder cells in each passage according to standard protocols, urothelial cells proliferated unfavourably after the fourth passage with increasing numbers of mouse cells as well as urothelial tetraploid cells. We could also show that urothelial cells from bladder lavage need feeder cells in order to establish primary cultures. Further propagation up to 14 passages was performed without feeder cells and the urothelial cells retained normal karyotypes. We also found that mitomycin treatment had its main effect on feeder cells during the first 2 h. When feeder cells were irradiated, 20 Gy was effective and no feeder cell contamination was seen. In conclusion, we found that a high standard of quality in urothelial cell culturing can be achieved with a careful culturing technique.
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| 7. |
- Grigelioniene, Giedre, et al.
(författare)
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Analysis of short stature homeobox-containing gene ( SHOX) and auxological phenotype in dyschondrosteosis and isolated Madelung deformity
- 2001
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 1432-1203 .- 0340-6717. ; 109:5, s. 551-558
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Tidskriftsartikel (refereegranskat)abstract
- Dyschondrosteosis (DCO; also called Leri-Weill syndrome) is a skeletal dysplasia characterised by disproportionate short stature because of mesomelic shortening of the limbs. Madelung deformity is a feature of DCO that is distinctive, variable in expressivity and frequently observed. Mutations of the SHOX (short stature homeobox-containing) gene have been previously described as causative in DCO. Isolated Madelung deformity (IMD) without the clinical characteristics of DCO has also been described in sporadic and a few familial cases but the genetic defect underlying IMD is unknown. In this study, we have examined 28 probands with DCO and seven probands with IMD for mutations in the SHOX gene by using polymorphic CA-repeat analysis, fluorescence in situ hybridisation (FISH), Southern blotting, direct sequencing and fibre-FISH analyses. This was combined with auxological examination of the probands and their family members. Evaluation of the auxological data showed a wide intra- and interfamilial phenotype variability in DCO. Out of 28 DCO probands, 22 (79%) were shown to have mutations in the SHOX gene. Sixteen unrelated DCO families had SHOX gene deletions. Four novel DCO-associated mutations were found in different families. In two additional DCO families, the previously described nonsense mutation (Arg195Stop) was detected. We conclude that mutations in the SHOX gene are the major factor in the pathogenesis of DCO. In a female proband with severe IMD and her unaffected sister, we detected an intrachromosomal duplication of the SHOX gene.
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| 8. |
- Gustavsson, Peter, et al.
(författare)
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Duplication 16q12.1-q22.1 characterized by array CGH in a girl with spina bifida
- 2007
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Ingår i: European Journal of Medical Genetics. - : Elsevier BV. - 1769-7212 .- 1878-0849. ; 50:3, s. 237-241
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Tidskriftsartikel (refereegranskat)abstract
- We report a 7-year-old girl with spina bifida carrying a complex chromosome abnormality resulting in duplication 16q12.1–q22.1. An abnormal karyotype was identified involving the long arm of chromosome 11 and fluorescent in situ hybridization (FISH) to metaphase chromosomes revealed an insertion of part of chromosome 16 on chromosome 11. A detailed mapping of the chromosome abnormality using whole genome array based comparative genomic hybridization (CGH) of the patient DNA revealed a duplication 16q12.1–q22.1 corresponding to gain of 19.8 Mb of DNA without any detectable loss of genetic material on chromosome 11. The karyotype is defined as 46,XX,der(11)ins(11;16)(q13;q12.1q22.1). We present here the clinical findings and a fine mapping of the associated structural chromosome abnormalities. We suggest that a gene dosage imbalance of 16q12.1–q22.1 is associated with spina bifida in the patient.
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| 9. |
- Kuchinskaya, Ekaterina, et al.
(författare)
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Array-CGH reveals hidden gene dose changes in children with acute lymphoblastic leukaemia and a normal or failed karyotype by G-banding
- 2008
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 140:5, s. 572-577
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Tidskriftsartikel (refereegranskat)abstract
- A tiling path 33K BAC array was used to study 28 children with acute lymphoblastic leukaemia (ALL) who had normal or failed G-banded karyotypes. Twenty-two patients (79%) had a total of 135 copy number alterations (CNA) (69 gains and 66 losses); most of these patients showed CNA that were below the resolution of G-banding. Molecular cytogenetic and array comparative genomic hybridization results enabled the division of B-precursor ALL patients into five groups: high hyperdiploidy, intrachromosomal amplification of 21q, ETV6/RUNX1 rearrangement, others and no CNA. Apart from a shared deletion of 9p21.3, T-ALL patients had additional small CNA, with no region in common.
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| 10. |
- Leeksma, Alexander C., et al.
(författare)
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Genomic arrays identify high-risk chronic lymphocytic leukemia with genomic complexity : A multi-center study
- 2020
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Ingår i: Haematologica. - 0390-6078. ; 105:5
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Tidskriftsartikel (refereegranskat)abstract
- Complex karyotype (CK) identified by chromosome-banding analysis (CBA) has shown prognostic value in chronic lymphocytic leukemia (CLL). Genomic arrays offer high-resolution genome-wide detection of copy-number alterations (CNAs) and could therefore be well equipped to detect the presence of a CK. Current knowledge on genomic arrays in CLL is based on outcomes of single center studies, in which different cutoffs for CNA calling were used. To further determine the clinical utility of genomic arrays for CNA assessment in CLL diagnostics, we retrospectively analyzed 2293 arrays from 13 diagnostic laboratories according to established standards. CNAs were found outside regions captured by CLL FISH probes in 34% of patients, and several of them including gains of 8q, deletions of 9p and 18p (p<0.01) were linked to poor outcome after correction for multiple testing. Patients (n=972) could be divided in three distinct prognostic subgroups based on the number of CNAs. Only high genomic complexity (high-GC), defined as 5 CNAs emerged as an independent adverse prognosticator on multivariable analysis for time to first treatment (Hazard ratio: 2.15, 95% CI: 1.36-3.41; p=0.001) and overall survival (Hazard ratio: 2.54, 95% CI: 1.54-4.17; p<0.001; n=528). Lowering the size cutoff to 1 Mb in 647 patients did not significantly improve risk assessment. Genomic arrays detected more chromosomal abnormalities and performed at least as well in terms of risk stratification compared to simultaneous chromosome banding analysis as determined in 122 patients. Our findings highlight genomic array as an accurate tool for CLL risk stratification.
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