628 results on '"Stankiewicz, Pawel"'
Search Results
202. Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome [del(17)(p11.2p11.2)]
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Potocki, Lorraine, primary, Shaw, Christine J., additional, Stankiewicz, Pawel, additional, and Lupski, James R., additional
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- 2003
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203. A girl with duplication 17p10‐p12 associated with a dicentric chromosome
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Shaw, Christine J., primary, Stankiewicz, Pawel, additional, Christodoulou, John, additional, Smith, Ellie, additional, Jones, Kristi, additional, and Lupski, James R., additional
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- 2003
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204. Molecular-evolutionary mechanisms for genomic disorders
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Stankiewicz, Pawel, primary and Lupski, James R, additional
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- 2002
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205. Primate Chromosome Evolution.
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Lupski, James R., Stankiewicz, Pawel, and Müller, Stefan
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During the last two decades, comparative cytogenetics and genomics has evolved from a specialized discipline to a highly dynamic field of research. This development was driven by major technological advancements as well as emergence of the deeper insight that many aspects of human genome function can be better understood when information about its evolutionary changes is taken into account. Whole-genome sequencing projects of biomedical model species and domesticated animals provided important clues to the molecular mechanisms that shaped the human genome. These strategies were complemented by the launch of the chimpanzee genome project, leading to the recent publication of the first chimpanzee draft sequence and its alignment with the human reference sequence. [ABSTRACT FROM AUTHOR]
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- 2006
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206. Genome Plasticity in Evolution.
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Lupski, James R., Stankiewicz, Pawel, Rocchi, Mariano, and Archidiacono, Nicoletta
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The centromere repositioning phenomenon consists in the move of the centromere along the chromosome during evolution. This phenomenon is relatively frequent, and has been documented in primates, nonprimate mammals, and birds. It implies the inactivation of the old centromere and the rapid progression of the newly seeded centromere toward the complex organization that probably stabilizes its activity. Both events have a huge impact on chromosomal architecture. The segmental duplicon clusters at 6p22.1 and 15q24-26 are clear examples of remains of inactivated ancestral centromeres. These duplicons are dispersed in a relatively large area (approx 10 Mb), and contribute to the bulk of nonpericentromeric segmental duplications that constitute approx 5% of the human genome. [ABSTRACT FROM AUTHOR]
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- 2006
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207. Array-CGH for the Analysis of Constitutional Genomic Rearrangements.
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Lupski, James R., Stankiewicz, Pawel, Carter, Nigel P., Fiegler, Heike, Gribble, Susan, and Redon, Richard
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Rapid, high-resolution analysis of genomic rearrangements has become possible using array-comparative genomic hybridization (aCGH), a combination of CGH with DNA microarray technology. Using aCGH, genome copy number changes and rearrangement breakpoints can now be mapped and analyzed at resolutions down to a few kilobases or even less in a single hybridization. This technology is enabling us to identify previously hidden rearrangements in patients with suspected genomic disorders for which no karyotype aberrations could be identified using conventional cytogenetic analysis. Furthermore, the development of array painting has revealed a surprising level of rearrangement complexity in patients with apparently balanced translocations. [ABSTRACT FROM AUTHOR]
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- 2006
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208. Chromosome-Engineered Mouse Models.
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Lupski, James R., Stankiewicz, Pawel, and Liu, Pentao
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Chromosome rearrangements cause genomic disorders and cancer in human. Region-specific low-copy repeats (LCRs) can mediate nonallelic homologous recombination (NAHR) that results in chromosome rearrangements. Using the Cre-loxP site-specific recombination system, chromosome rearrangements that cause genomic disorders and cancer can be recapitulated in the mouse. Technology advancements in mouse genetics, such as recombineering, will undoubtedly facilitate modeling genetic changes associated with genomic disorders in the mouse. [ABSTRACT FROM AUTHOR]
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- 2006
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209. Position Effects.
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Lupski, James R. and Stankiewicz, Pawel
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Position effects describe the observed alteration in protein-coding gene expression that may accompany a change in genomic position of a given gene. A position effect may result from chromosomal translocation or other genomic rearrangements. Recent advances in chromatin studies in several different species including yeast, Drosophila, and mouse have contributed significantly to better understanding of human diseases resulting from abnormal epigenetic effects. Molecular models attempting to explain position effects in humans have been proposed; however, none of them adequately addresses a variety of mechanisms. According to the noncontact models, the cis- or trans-regulatory elements, or locus control regions, are physically separated from the target gene and act either at the RNA level, by protein interactions, or by mediation of boundary elements, termed insulators. On the contrary, the contact models invoke spatial-temporal modifications of chromatin structure (e.g., active chromatin hub). In both models, the conserved nongenic sequences (CNGs) may play an important role in genomic regulation of gene expression. The recent introduction of new techniques including tagging and recovery of associated proteins (RNA-TRAP) and capturing chromatin conformation (CCC or 3C), has provided powerful tools to investigate position effects in humans. [ABSTRACT FROM AUTHOR]
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- 2006
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210. Recombination Hotspots in Nonallelic Homologous Recombination.
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Stankiewicz, Pawel, Hurles, Matthew E., and Lupski, James R.
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Rearrangement breakpoints resulting from nonallelic homologous recombination (NAHR) are typically clustered within small, well-defined portions of the segmental duplications that promote the rearrangement. These NAHR "hotspots" have been identified in every NAHR-promoted rearrangement in which breakpoint junctions have been sequenced in sufficient numbers. Enhancement of recombinatorial activity in NAHR hotspots varies from 3 to 237 times more than in the surrounding "cold" duplicated sequence. NAHR hotspots share many features in common with allelic homologous recombination (AHR) hotspots. Both AHR and NAHR hotspots appear to be relatively small (<2 kb) and are initiated by double-strand breaks. Gene conversion events as well as crossovers are enhanced at NAHR hotspots. Recent work has improved our understanding of the origins of NAHR and AHR hotspots, with both appearing to be relatively short-lived phenomena. Our present understanding of NAHR hotspots comes from a limited number of locus-specific studies. In the future, we can expect genome-wide analyses to provide many further insights. [ABSTRACT FROM AUTHOR]
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- 2006
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211. Mechanisms Underlying Neoplasia-Associated Genomic Rearrangements.
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Lupski, James R., Stankiewicz, Pawel, and Fioretos, Thoas
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Neoplastic disorders are characterized by recurrent somatically acquired chromosomal aberrations that alter the structure and/or expression of a large number of genes. Most "cancer genes" discovered to date in human neoplasms have been identified through isolation of genes at the breakpoints of balanced chromosomal translocations. Although functional studies of such cancer-causing genes have demonstrated their causal role in tumorigenesis, the mechanisms underlying the formation of recurrent chromosomal changes in cancer remain enigmatic. Low-copy repeats (LCRs) are important mediators of erroneous meiotic recombination, resulting in constitutional chromosomal rearrangements. Recently, LCRs have been implicated in the formation of the frequent and characteristic neoplasia-associated chromosomal aberrations t(9;22)(q34;q1 1) and i(17q), suggesting that similar genome architecture features may play an important role in generating also other somatic chromosomal rearrangements. [ABSTRACT FROM AUTHOR]
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- 2006
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212. inv dup(15) and inv dup(22).
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Lupski, James R., Stankiewicz, Pawel, McDermid, Heather E., and Wevrick, Rachel
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The presence of a small supernumerary marker chromosome (SMC) in a karyotype creates a diagnostic dilemma, because the resulting duplications/triplications may cause abnormal development, depending on the location and size of the extra material. The most common SMC is the inv dup(15), the effect of which varies with size of triplication as well as the parent of origin. inv dup(22) is associated with the highly variable cat eye syndrome. Both are thought to be caused by U-type recombination between neighboring low-copy repeats (LCRs), resulting in both symmetric and asymmetric bisatellited dicentric supernumerary chromosomes. Studies are underway to associate the abnormal features of each syndrome with specific genes in the duplicated regions. [ABSTRACT FROM AUTHOR]
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- 2006
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213. Monosomy 1p36 As a Model for the Molecular Basis of Terminal Deletions.
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Lupski, James R., Stankiewicz, Pawel, Ballif, Blake C., and Shaffer, Lisa G.
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Deletion of the most distal, telomeric band of human chromosomes can result in a variety of mental retardation and multiple congenital anomaly syndromes. These terminal deletions are some of the most commonly observed structural chromosome abnormalities detected by routine cytogenetic analysis. Terminal deletions of 1p36 occur in approx 1 in 5000 live births, making it the most frequently observed terminal deletion and one of the most commonly observed mental retardation syndromes in humans. Molecular characterization of subjects with monosomy 1p36 indicates that, like other terminal deletions, 1p36 deletions have breakpoints occurring in multiple locations over several megabases and are comprised of terminal truncations, interstitial deletions, complex rearrangements, and derivative chromosomes. In addition, cryptic interrupted inverted duplications have been observed at the end of terminally deleted chromosomes, suggesting premeiotic breakage-fusion-bridge (BFB) cycles can be intermediate steps in the process of generating and stabilizing terminal deletions of 1p36. Overall, these observations are identical to those made in yeast and other model systems in which a double-strand break (DSB) near a telomere can be repaired by a variety of mechanisms to stabilize the end of a broken chromosome. Furthermore, sequence analysis and fluorescent in situ hybridization (FISH) mapping of the terminal 10.5 Mb of 1p36 including a variety of terminal deletion breakpoint junctions indicate that segmental duplications, low-copy repeats (LCRs), and short repetitive DNA sequence elements may mediate the generation and stabilization of terminal deletions of 1p36. We hypothesize that nonallelic homologous recombination (NAHR) between palindromic or inverted LCRs in the subtelomeric region of 1p36 could generate a dicentric chromosome that is broken at a random location during the subsequent anaphase as the centromeres move to opposite poles. This model suggests that the molecular basis of terminal deletions may be directly linked to genomic architectural features in the subtelomeric regions that generate the initial, variable-sized terminally deleted chromo-some, and that stabilization of the broken chromosome occurs by one of a variety of competing DSB repair pathways. [ABSTRACT FROM AUTHOR]
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- 2006
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214. Inversion Chromosomes.
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Lupski, James R., Stankiewicz, Pawel, Zuffardi, Orsetta, Ciccone, Roberto, Giglio, Sabrina, and Pramparo, Tiziano
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A number of findings revealed that chromosome inversions are more frequent than deduced from classical cytogenetic studies. Indeed, some paracentric cryptic inversions have been found to be flanked by segmental duplications, either causing a Mendelian disease owing to the interruption of specific genes at inversion breakpoints or being present in the normal population as a polymorphism. In the latter case, in the heterozygous state they predispose to further unbalanced rearrangements such as inv dup rearrangements or simple deletions and duplications. The importance of this susceptibility factor has been well clarified with respect to some genomic disorders involving chromosome 8p and it is now emerging as a possible model that may explain the genetic basis of other recurrent chromosome rearrangements. [ABSTRACT FROM AUTHOR]
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- 2006
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215. Y-Chromosomal Rearrangements and Azoospermia.
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Lupski, James R., Stankiewicz, Pawel, Hurles, Matthew E., and Tyler-Smith, Chris
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Approximately 0.03% of men carry a Y-chromosomal defect that leads to azoospermia, the absence of sperm cells from semen. Deletion mapping of the Y chromosomes of azoospermic or oligozoospermic men suggested that loss of three nonoverlapping regions, AZFa, AZFb, and AZFc, could be responsible. When the finished Y-chromosomal reference sequence became available, the recurrent deletion of each of these intervals could be explained largely by non-allelic homologous recombination between direct repeats. However, in contrast to the conclusion from deletion mapping, AZFb deletions were found to overlap with AZFc deletions. In addition, a background level of nonhomologous recombination was found to generate a minority of deletions of these intervals. USP9Y appears to be the critical gene underlying the AZFa phenotype, but the critical genes lost in the AZFb and AZFc deletions have not yet been identified. Inspection of the sequence allowed additional duplications, inversions, and partial deletions of the AZF intervals to be anticipated, and many of the predicted structures have subsequently been identified in the population. The phenotypic consequences of these additional rearrangements of the AZFc region are unclear. High levels of gene conversion homogenize duplicated sequences in both direct and inverted orientations on the Y, which could potentiate subsequent rearrangements. The Y chromosome provides an excellent model for understanding genomic disorders; however, more finished sequences and new methodologies are needed. [ABSTRACT FROM AUTHOR]
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- 2006
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216. Pelizaeus-Merzbacher Disease and Spastic Paraplegia Type 2.
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Lupski, James R., Stankiewicz, Pawel, and Inoue, Ken
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Pelizaeus-Merzbacher disease (PMD) is a genomic disorder that is caused by altered dosage of a single gene, proteolipid protein 1 (itPLP1). Either duplication or deletion of itPLP1-containing genomic regions on chromosome Xq22.2 results in a severe leukodystrophy characterized by deficits of myelination in the central nervous system (itCNS). In this chapter, the molecular and genomic mechanisms for rearrangements causing PMD are reviewed, emphasizing differences in comparison to Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) [ABSTRACT FROM AUTHOR]
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- 2006
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217. X Chromosome Rearrangements.
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Lupski, James R., Stankiewicz, Pawel, and Yen, Pauline H.
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X chromosome rearrangements usually convey clinical manifestations in the hemizygous males and are, thus, readily ascertained. They are found in all parts of the X chromosome and are associated with more than 20 disorders. Some of the rearrangements are the results of homologous recombination between low-copy repeats (LCRs) on the X chromosome or between large homologous regions on the X and Y chromosome, whereas others are caused by nonhomologous end-joining (NHEJ). For most large deletions associated with contiguous gene syndromes, the deletion breakpoints remain uncharacterized. The deletions, as well as inversions and duplications on the X chromosome, occur mainly in male germ cells, indicating intrachromatid or sister chromatid exchange as the underlying mechanism. [ABSTRACT FROM AUTHOR]
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- 2006
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218. Sotos Syndrome.
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Lupski, James R., Stankiewicz, Pawel, Kurotaki, Naohiro, and Matsumoto, Naomichi
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Sotos syndrome (SoS) is a well-known overgrowth syndrome with mental retardation, specific craniofacial features, and advanced bone age. Since NSD1 haploinsufficiency was proven to be the major cause of SoS in 2002, many intragenic mutations and chromosomal microdeletions (MDs) involving the entire NSD1 gene have been described. The sizes of most SoS MDs are identical and a specific genomic architecture around these MDs was found. Recently, precise analyses of the low-copy repeats (LCRs) flanking the SoS common deletion showed that the deletion arises through nonhomologous recombination (NAHR) utilizing the LCRs, and proved that SoS is a genomic disorder. [ABSTRACT FROM AUTHOR]
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- 2006
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219. Williams-Beuren Syndrome.
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Lupski, James R., Stankiewicz, Pawel, Scherer, Stephen W., and Osborne, Lucy R.
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Williams-Beuren syndrome (WBS; also called Williams syndrome) is a multisystem developmental disorder that is almost always associated with an approx 1.5-Mb deletion of chromosome 7q11.23 (OMIM no. 194050). The deletion was identified in 1993 based on the observation of phenotypic overlap with supravalvular aortic stenosis (SVAS), a distinct autosomal dominant disorder affecting the cardiovascular system (1). It has since been shown that SVAS arises because of the disruption of one copy of the elastin gene, through either deletion, translocation or point mutation (2-4), but the genes contributing to the remaining aspects of WBS have not yet been definitively determined. [ABSTRACT FROM AUTHOR]
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- 2006
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220. Neurofibromatosis 1.
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Lupski, James R., Stankiewicz, Pawel, and Stephens, Karen
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Among genomic disorders, submicroscopic deletions underlying neurofibromatosis 1 (NF1) are unusual because they involve the deletion of a tumor suppressor gene (NF1), they show a different preference for low-copy repeats (LCR) as substrates for meiotic vs mitotic recombination events, and they account for only a small fraction of mutations that cause the disorder. The NF1 gene at chromosome 17q1 1.2 is flanked by two sets of LCRs in direct orientation that undergo paralogous recombination. A pair of NF1-REPs mediate the recurrent constitutional 1.4-Mb microdeletion that occurs preferentially during maternal meiosis, whereas a pair of JJAZ1 pseudogene and functional gene mediate the recurrent 1.2-Mb microdeletion that occurs preferentially during postzygotic mitosis in females. Breakpoints have been mapped at the nucleotide level for both deletions and sequence features that may contribute to the choice of discrete sites for strand exchange have been identified. NF1 -REP-mediated NF1 microdeletions involve 13 additional genes, whereas JJAZ1 -mediated microdeletions involve the same genes but one. NF1 microdeletions are of great interest because they predispose to a heavy tumor burden, malignancy, and possibly other severe manifestations. [ABSTRACT FROM AUTHOR]
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- 2006
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221. Chromosome 22q11.2 Rearrangement Disorders.
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Lupski, James R., Stankiewicz, Pawel, and Morrow, Bernice E.
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Meiotic unequal crossover events between blocks of low-copy repeats (LCRs) may lead to gene dosage imbalance resulting in genomic disorders. Genomic disorders are frequently associated with mental retardation or learning disabilities and mild to severe congenital anomalies. Chromosome 22q11.2 is particularly susceptible to chromosome rearrangements leading to several genomic disorders including velocardiofacial syndrome/DiGeorge syndrome (VCFS/DGS), der(22) syndrome, and cat-eye syndrome (CES), associated with a monosomy, trisomy, and tetrasomy of 22q11.2, respectively. Most VCFS/DGS patients have a similar hemizygous 3-Mb deletion mediated by meiotic interchromosomal homologous recombination events between LCRs termed LCR22s. The reciprocal duplication of the same interval, predicted on expected products of unequal crossover events, results in a more mild condition termed dup(22)(q11.2; q11.2) syndrome. In contrast to VCFS/DGS, dup(22)(q11.2; q11.2) and CES, der(22) syndrome is caused by a different molecular mechanism. Der(22) disorder arises in offspring of normal carriers of the constitutional t(1 1 ;22) (q23.3; q1 1.2) translocation by recombination between AT-rich (high AT sequence composition) palindromic sequences on 1 1q23.3 and 22q1 1.2. The palindromic sequence on 22q1 1.2 is within one of the LCR22s. Interestingly, both recurrent and novel breakpoints occur most often in LCR22s, making them an important architectural feature associated with susceptibility to genome rearrangements. To gain further insight into the mechanisms of how the LCR22s are involved in chromosome rearrangements, efforts are underway to determine the molecular evolution, structure, size, orientation, and their level of variability in humans. [ABSTRACT FROM AUTHOR]
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- 2006
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222. The CMT1A Duplication and HNPP Deletion.
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Stankiewicz, Pawel, Timmerman, Vincent, and Lupski, James R.
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The Charcot-Marie-Toothtype 1A (CMT1 A) duplication was the first recurrent, large (>1 Mb), submicroscopic DNA duplication rearrangement found to be associated with a common auto-somal dominant trait. Mechanistic studies of the CMT1A duplication have set the paradigm for genomic disorders. The CMT1A-REP low-copy repeats (LCRs) were among the first identified nongenic genomic architectural features that could act as substrates for nonallelic homologous recombination (NAHR). Identification of the predicted reciprocal recombination product, the hereditary neuropathy with liability to pressure palsies (HNPP) deletion, resulted in a model for reciprocal duplication/deletion genomic disorders. [ABSTRACT FROM AUTHOR]
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- 2006
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223. The Impact of LINE-1 Retro transposition on the Human Genome.
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Lupski, James R., Stankiewicz, Pawel, Hulme, Amy E., Kulpa, Deanna A., Perez, José Luis Garcia, and Moran, John V.
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Long interspersed element-1 (LINE-1 or L1) is an abundant retrotransposon that comprises approx 17% of human DNA. L1 retrotransposition events can lead to genome diversification and individual genetic variation by serving as insertional mutagens and by providing recombination substrates either during or long after their insertion. L1 retrotransposition also generates genomic variation by mobilizing DNA derived from its flanks, non-autonomous retrotransposons (e.g., Alu elements), and cellular mRNAs to new genomic locations. Together, these sequences comprise approx 15% of human genomic DNA. Thus, L1-mediated retrotransposition events are responsible for at least one-third of our genome. In this chapter, we discuss how innovative assays developed in recent years have increased our understanding of L1 biology and the impact of L1 on the human genome. [ABSTRACT FROM AUTHOR]
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- 2006
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224. Genomic Organization and Function of Human Centromeres.
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Lupski, James R., Stankiewicz, Pawel, Willard, Huntington E, and Rudd, M. Katharine
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Centromeres are required for normal chromosome segregation in mitosis and meiosis, and a substantial proportion of human pathology stems from abnormalities of chromosome segregation, the underlying genomic basis and mechanism(s) of which are largely unknown. Human centromeres consist of megabases ofα-satelliteDNA, atandemlyrepeatedDNA family whose genomic organization, evolution, and function is increasingly well understood. The study of normal, abnormal, and engineered human chromosomes is providing insights into the nature of human centromeres and their mechanism of action, as well as enabling comparison with centromeres of other eukaryotic organisms and the identification of genomic elements required for normal centromere function. [ABSTRACT FROM AUTHOR]
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- 2006
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225. Genetic Basis of Olfactory Deficits.
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Lupski, James R., Stankiewicz, Pawel, Menashe, Idan, Feldmesser, Ester, and Lancet, Doron
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The completion of the human genome sequencing has opened new opportunities to better understand complex biological systems. In this realm, the human sense of smell is an excellent example of how genome analysis provides new information on genome organization and on deficits. Before the advent of genomic tools, the understanding of this highly sophisticated sensory neuronal pathway has been rather sketchy. In this chapter we summarize the relevant progress made in the last decade, and highlight the initial elucidation of two classes of olfactory deficits and their possible underlying genetic mechanisms. [ABSTRACT FROM AUTHOR]
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- 2006
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226. Non-B DNA and Chromosomal Rearrangements.
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Lupski, James R., Stankiewicz, Pawel, Bacolla, Albino, and Wells, Robert D.
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Certain DNA sequences in the genome may exist either in the canonical right-handed B-duplex or in alternative non-B conformations, depending on conditions such as transcription, supercoil stress, protein binding, and so on. Analyses of breakpoint junctions at deletions, translocations, and inversions, where the sites of DNA breakage could be determined at the nucleotide level, revealed that most, if not all, of the breaks occurred within, or adjacent to, the predicted non-B conformations. These findings support a model whereby rearrangements are caused by recombination/repair processes between two distinct non-B conformations, which may reside either on the same chromosome or on two distinct chromosomes. This model was applicable to both Escherichia coli and humans, suggesting that the mechanisms involved are highly conserved. [ABSTRACT FROM AUTHOR]
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- 2006
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227. Segmental Duplications.
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Lupski, James R., Stankiewicz, Pawel, Sharp, Andrew J., and Eichler, Evan E.
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Until recent times, the identification and characterization of segmental duplications has often been based purely on anecdotal reports. However, the completion of the Human Genome Project has now made possible the systematic analysis of the extent and distribution of duplicated sequences in humans. Both in situ hybridization and in silico approaches have shown that approx 5% of our genome is composed of highly homologous duplicated sequence (1,2), with enrichments of six- to sevenfold in pericentromeric (3), and two- to threefold in subtelomeric regions (4), respectively. Not only does the presence of these paralogous segments represent a significant challenge to the correct assembly of the human genome, but there is also an increasing awareness of their role in human evolution, variation, and disease. We present a review of segmental duplications in the mammalian genome. We describe their basic characteristics, distribution, and dynamic nature during recent evolutionary history. Based on these features, we discuss models to account for the proliferation of these sequences in the mammalian lineage, and also their contribution towards karyotypic evolution and phe-notypic differences between primates. Finally, we highlight the role of segmental duplications as mediators of human variation at the genomic level. [ABSTRACT FROM AUTHOR]
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- 2006
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228. Ancient Transposable Elements, Processed Pseudogenes, and Endogenous Retroviruses.
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Lupski, James R., Stankiewicz, Pawel, Pavlicek, Adam, and Jurka, Jerzy
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The human genome contains a large number of repetitive elements derived from transposable elements (TEs). In addition to active Alu and long interspersed element (LINE or L1) interspersed repeats, the human genome comprises a large number of ancient TEs. These include fossil germ-line insertions of DNA transposons, fossil short interspersed elements (SINEs), L2, and L3 LINEs. Processed pseudogenes and human endogenous retroviruses (HERVs) have amplified more recently in evolutionary history and some of them are still well preserved. Copies of some of the recently extinct TEs continue to contribute to genomic rearrangements by homologous recombination. In this chapter, we review ancient SINE and LINE repeats, processed pseudogenes, HERVs, and DNA transposons. We briefly introduce the genomic structure and replication strategy of these elements, their expression competence, and focus on the contribution of these repeats to human diseases. We also discuss some of the TE-derived genes and regulatory elements. [ABSTRACT FROM AUTHOR]
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- 2006
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229. Alu Elements.
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Lupski, James R., Stankiewicz, Pawel, and Deininger, Prescott
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Alu elements represent one of the most successful mobile elements found in any genome. They have reached a copy number in excess of one million copies, making up more than 10% of the human genome. The level of amplification required to reach this high copy number has created an enormous number of insertion mutations resulting in human disease and genome evolution. They also add extensive diversity to the genome by introducing alternative splicing and editing to a wide range of RNA transcripts. In addition, after insertion Alu elements contribute to a high level of genetic instability through recombination. This instability contributes to a significant number of germ-line mutations and may be an even bigger factor in cancer and/or aging. [ABSTRACT FROM AUTHOR]
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- 2006
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230. The CMT1A Duplication.
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Stankiewicz, Pawel, Lupski, James R., and Timmerman, Vincent
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I came to Houston, Texas in 1986 with one goal being to identify "the gene" for Charcot-Marie-Tooth (CMT) disease. I was peripherally aware of the paper by Botstein and colleagues (1) proposing the genetic mapping of human "disease genes" using linked restriction fragment length polymorphisms (RFLPs) to position the gene within the human genome and indeed became very excited as a graduate student when Gusella' s paper (2) appeared in Nature linking the Huntington disease locus to markers on chromosome 4. It was a natural extension to think this "positional cloning" approach might be applied to a host of other human traits. There was apersonal, one might say egocentric, reason to choose CMT because I have the disease (3) and, in fact, the first blood samples collected for DNA linkage studies were from my own family wherein CMT segregated as an apparent autosomal recessive trait. [ABSTRACT FROM AUTHOR]
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- 2006
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231. Genome architecture, rearrangements and genomic disorders
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Stankiewicz, Pawel, primary and Lupski, James R., additional
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- 2002
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232. Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia
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Boerkoel, Cornelius F., primary, Takashima, Hiroshi, additional, John, Joy, additional, Yan, Jiong, additional, Stankiewicz, Pawel, additional, Rosenbarker, Lisa, additional, André, Jean-Luc, additional, Bogdanovic, Radovan, additional, Burguet, Antoine, additional, Cockfield, Sandra, additional, Cordeiro, Isabel, additional, Fründ, Stefan, additional, Illies, Friederike, additional, Joseph, Mark, additional, Kaitila, Ilkka, additional, Lama, Giuliana, additional, Loirat, Chantal, additional, McLeod, D. Ross, additional, Milford, David V., additional, Petty, Elizabeth M., additional, Rodrigo, Francisco, additional, Saraiva, Jorge M., additional, Schmidt, Beate, additional, Smith, Graham C., additional, Spranger, Jürgen, additional, Stein, Anja, additional, Thiele, Hannelore, additional, Tizard, Jane, additional, Weksberg, Rosanna, additional, Lupski, James R., additional, and Stockton, David W., additional
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- 2002
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233. The Evolutionary Chromosome Translocation 4;19 in Gorilla gorilla is Associated with Microduplication of the Chromosome Fragment Syntenic to Sequences Surrounding the Human Proximal CMT1A-REP
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Stankiewicz, Pawel, primary, Park, Sung-Sup, additional, Inoue, Ken, additional, and Lupski, James R., additional
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- 2001
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234. Comparative Analyses of Lung Transcriptomes in Patients with Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins and in Foxf1 Heterozygous Knockout Mice.
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Sen, Partha, Dharmadhikari, Avinash V., Majewski, Tadeusz, Mohammad, Mahmoud A., Kalin, Tanya V., Zabielska, Joanna, Ren, Xiaomeng, Bray, Molly, Brown, Hannah M., Welty, Stephen, Thevananther, Sundararajah, Langston, Claire, Szafranski, Przemyslaw, Justice, Monica J., Kalinichenko, Vladimir V., Gambin, Anna, Belmont, John, and Stankiewicz, Pawel
- Subjects
COMPARATIVE studies ,DYSPLASIA ,PULMONARY vein abnormalities ,KNOCKOUT mice ,DEVELOPMENTAL disabilities ,LUNG diseases ,PATIENTS - Abstract
Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV) is a developmental disorder of the lungs, primarily affecting their vasculature. FOXF1 haploinsufficiency due to heterozygous genomic deletions and point mutations have been reported in most patients with ACDMPV. The majority of mice with heterozygous loss-of-function of Foxf1 exhibit neonatal lethality with evidence of pulmonary hemorrhage in some of them. By comparing transcriptomes of human ACDMPV lungs with control lungs using expression arrays, we found that several genes and pathways involved in lung development, angiogenesis, and in pulmonary hypertension development, were deregulated. Similar transcriptional changes were found in lungs of the postnatal day 0.5 Foxf1
+/− mice when compared to their wildtype littermate controls; 14 genes, COL15A1, COL18A1, COL6A2, ESM1, FSCN1, GRINA, IGFBP3, IL1B, MALL, NOS3, RASL11B, MATN2, PRKCDBP, and SIRPA, were found common to both ACDMPV and Foxf1 heterozygous lungs. Our results advance knowledge toward understanding of the molecular mechanism of ACDMPV, lung development, and its vasculature pathology. These data may also be useful for understanding etiologies of other lung disorders, e.g. pulmonary hypertension, bronchopulmonary dysplasia, or cancer. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
- View/download PDF
235. Combined array CGH plus SNP genome analyses in a single assay for optimized clinical testing.
- Author
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Wiszniewska, Joanna, Bi, Weimin, Shaw, Chad, Stankiewicz, Pawel, Kang, Sung-Hae L, Pursley, Amber N, Lalani, Seema, Hixson, Patricia, Gambin, Tomasz, Tsai, Chun-hui, Bock, Hans-Georg, Descartes, Maria, Probst, Frank J, Scaglia, Fernando, Beaudet, Arthur L, Lupski, James R, Eng, Christine, Wai Cheung, Sau, Bacino, Carlos, and Patel, Ankita
- Subjects
DNA microarrays ,SINGLE nucleotide polymorphisms ,COMPARATIVE genomic hybridization ,HETEROZYGOSITY ,GENETIC testing - Abstract
In clinical diagnostics, both array comparative genomic hybridization (array CGH) and single nucleotide polymorphism (SNP) genotyping have proven to be powerful genomic technologies utilized for the evaluation of developmental delay, multiple congenital anomalies, and neuropsychiatric disorders. Differences in the ability to resolve genomic changes between these arrays may constitute an implementation challenge for clinicians: which platform (SNP vs array CGH) might best detect the underlying genetic cause for the disease in the patient? While only SNP arrays enable the detection of copy number neutral regions of absence of heterozygosity (AOH), they have limited ability to detect single-exon copy number variants (CNVs) due to the distribution of SNPs across the genome. To provide comprehensive clinical testing for both CNVs and copy-neutral AOH, we enhanced our custom-designed high-resolution oligonucleotide array that has exon-targeted coverage of 1860 genes with 60 000 SNP probes, referred to as Chromosomal Microarray Analysis - Comprehensive (CMA-COMP). Of the 3240 cases evaluated by this array, clinically significant CNVs were detected in 445 cases including 21 cases with exonic events. In addition, 162 cases (5.0%) showed at least one AOH region >10 Mb. We demonstrate that even though this array has a lower density of SNP probes than other commercially available SNP arrays, it reliably detected AOH events >10 Mb as well as exonic CNVs beyond the detection limitations of SNP genotyping. Thus, combining SNP probes and exon-targeted array CGH into one platform provides clinically useful genetic screening in an efficient manner. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
236. Genomic and Epigenetic Complexity of the FOXF1 Locus in 16q24.1: Implications for Development and Disease
- Author
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V. Dharmadhikari, Avinash, Szafranski, Przemyslaw, V. Kalinichenko, Vladimir, and Stankiewicz, Pawel
- Abstract
The FOXF1 (Forkhead box F1) gene, located on chromosome 16q24.1 encodes a member of the FOX family of transcription factors characterized by a distinct forkhead DNA binding domain. FOXF1 plays an important role in epithelium-mesenchyme signaling, as a downstream target of Sonic hedgehog pathway. Heterozygous point mutations and genomic deletions involving FOXF1 have been reported in newborns with a lethal lung developmental disorder, Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV). In addition, genomic deletions upstream to FOXF1 identified in ACDMPV patients have revealed that FOXF1 expression is tightly regulated by distal tissue-specific enhancers. Interestingly, FOXF1 has been found to be incompletely paternally imprinted in human lungs; characterized genomic deletions arose de novo exclusively on maternal chromosome 16, with most of them being Alu-Alu mediated. Regulation of FOXF1 expression likely utilizes a combination of chromosomal looping, differential methylation of an upstream CpG island overlapping GLI transcription factor binding sites, and the function of lung-specific long non-coding RNAs (lncRNAs). Foxf1 knock-out mouse models demonstrated its critical role in mesoderm differentiation and in the development of pulmonary vasculature. Additionally, epigenetic inactivation of FOXF1 has been reported in breast and colorectal cancers, whereas overexpression of FOXF1 has been associated with a number of other human cancers, e.g. medulloblastoma and rhabdomyosarcoma. Constitutional duplications of FOXF1 have recently been reported in congenital intestinal malformations. Thus, understanding the genomic and epigenetic complexity at the FOXF1 locus will improve diagnosis, prognosis, and treatment of ACDMPV and other human disorders associated with FOXF1 alterations.
- Published
- 2015
237. A familial case of alveolar capillary dysplasia with misalignment of pulmonary veins supports paternal imprinting of FOXF1 in human.
- Author
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Sen, Partha, Gerychova, Romana, Janku, Petr, Jezova, Marta, Valaskova, Iveta, Navarro, Colby, Silva, Iris, Langston, Claire, Welty, Stephen, Belmont, John, and Stankiewicz, Pawel
- Subjects
DYSPLASIA ,PULMONARY veins ,RARE diseases ,GENETIC mutation ,HUMAN genetic variation ,HAPLOTYPES ,DISEASES - Abstract
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare developmental lung disorder that is uniformly lethal. Affected infants die within the first few weeks of their life despite aggressive treatment, although a few cases of late manifestation and longer survival have been reported. We have shown previously that mutations and deletions in FOXF1 are a cause of this disorder. Although most of the cases of ACD/MPV are sporadic, there have been infrequent reports of familial cases. We present a family with five out of six children affected with ACD/MPV. DNA analysis identified a missense mutation (c.416G>T; p.Arg139Leu) in the FOXF1 gene that segregated in the three affected siblings tested. The same variant is also present as a de novo mutation in the mother and arose on her paternally derived chromosome 16. The two tested affected siblings share the same chromosome 16 haplotype inherited from their maternal grandfather. Their single healthy sibling has a different chromosome 16 haplotype inherited from the maternal grandmother. The results are consistent with paternal imprinting of FOXF1 in human. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
238. Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders.
- Author
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Nagamani, Sandesh C S, Erez, Ayelet, Ben-Zeev, Bruria, Frydman, Moshe, Winter, Susan, Zeller, Robert, El-Khechen, Dima, Escobar, Luis, Stankiewicz, Pawel, Patel, Ankita, and Wai Cheung, Sau
- Subjects
COMPARATIVE genomic hybridization ,AUTISM spectrum disorders ,SPASMS ,EXONS (Genetics) ,HUMAN genome ,DIAGNOSIS - Abstract
Small genomic rearrangements and copy-number variations (CNVs) involving a single gene have been associated recently with many neurocognitive phenotypes, including intellectual disability (ID), behavioral abnormalities, and autistic spectrum disorders (ASDs). Such small CNVs in the Autism susceptibility candidate 2 (AUTS2) gene have been shown to be associated with seizures, ID, and ASDs. We report four patients with small CNVs ranging in size between 133-319 kb that disrupt AUTS2. Two patients have duplications involving single exons, whereas two have deletions that removed multiple exons. All patients had developmental delay, whereas two patients had a diagnosis of ASDs. The CNVs were detected by an exon-targeted array CGH with dense oligonucleotide coverage in exons of genes known or hypothesized to be causative of multiple human phenotypes. Our report further shows that disruption of AUTS2 results in a variety of neurobehavioral phenotypes. More importantly, it demonstrates the utility of targeted exon array as a highly sensitive clinical diagnostic tool for the detection of small genomic rearrangements in the clinically relevant regions of the human genome. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
239. Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities.
- Author
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Lalani, Seema R, Shaw, Chad, Wang, Xueqing, Patel, Ankita, Patterson, Lance W, Kolodziejska, Katarzyna, Szafranski, Przemyslaw, Ou, Zhishuo, Tian, Qi, Kang, Sung-Hae L, Jinnah, Amina, Ali, Sophia, Malik, Aamir, Hixson, Patricia, Potocki, Lorraine, Lupski, James R, Stankiewicz, Pawel, Bacino, Carlos A, Dawson, Brian, and Beaudet, Arthur L
- Subjects
CARDIOVASCULAR diseases ,HUMAN genetic variation ,GENOMICS ,GENETIC research ,PROTEINS - Abstract
Clinically significant cardiovascular malformations (CVMs) occur in 5-8 per 1000 live births. Recurrent copy number variations (CNVs) are among the known causes of syndromic CVMs, accounting for an important fraction of cases. We hypothesized that many additional rare CNVs also cause CVMs and can be detected in patients with CVMs plus extracardiac anomalies (ECAs). Through a genome-wide survey of 203 subjects with CVMs and ECAs, we identified 55 CNVs >50 kb in length that were not present in children without known cardiovascular defects (n=872). Sixteen unique CNVs overlapping these variants were found in an independent CVM plus ECA cohort (n=511), which were not observed in 2011 controls. The study identified 12/16 (75%) novel loci including non-recurrent de novo 16q24.3 loss (4/714) and de novo 2q31.3q32.1 loss encompassing PPP1R1C and PDE1A (2/714). The study also narrowed critical intervals in three well-recognized genomic disorders of CVM, such as the cat-eye syndrome region on 22q11.1, 8p23.1 loss encompassing GATA4 and SOX7 and 17p13.3-p13.2 loss. An analysis of protein-interaction databases shows that the rare inherited and de novo CNVs detected in the combined cohort are enriched for genes encoding proteins that are direct or indirect partners of proteins known to be required for normal cardiac development. Our findings implicate rare variants such as 16q24.3 loss and 2q31.3-q32.1 loss, and delineate regions within previously reported structural variants known to cause CVMs. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
240. Co-occurrence of recurrent duplications of the DiGeorge syndrome region on both chromosome 22 homologues due to inherited and de novo events.
- Author
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Weimin Bi, Probst, Frank J., Wiszniewska, Joanna, Plunkett, Katie, Roney, Erin K., Carter, Brian S., Williams, Misti D., Stankiewicz, Pawel, Patel, Ankita, Stevens, Cathy A., Lupski, James R., and Sau Wai Cheun
- Subjects
DIGEORGE syndrome ,CHROMOSOMES ,PHENOTYPES ,HUMAN abnormality genetics ,SINGLE nucleotide polymorphisms ,COMPARATIVE genomic hybridization - Abstract
Background Genomic rearrangements usually involve one of the two chromosome homologues. Homozygous microdeletion/duplication is very rare. The chromosome 22q11.2 region is prone to recurrent rearrangements due to the presence of low-copy repeats. A common 3 Mb microdeletion causes the well-characterised DiGeorge syndrome (DGS). The reciprocal duplication is associated with an extremely variable phenotype, ranging from apparently normal to learning disabilities and multiple congenital anomalies. Methods and results We describe duplications of the DGS region on both homologues in five patients from three families, detected by array CGH and confirmed by both fluorescence in situ hybridisation and single nucleotide polymorphism arrays. The proband in the first family is homozygous for the common duplication; one maternally inherited and the other a de novo duplication that was generated by nonallelic homologous recombination during spermatogenesis. The 22q11.2 duplications in the four individuals from the other two families are recurrent duplications on both homologues, one inherited from the mother and the other from the father. The phenotype in the patients with a 22q11.2 tetrasomy is similar to the features seen in duplication patients, including cognitive deficits and variable congenital defects. Conclusions Our studies that reveal phenotypic variability in patients with four copies of the 22q11.2 genomic segment, demonstrate that both inherited and de novo events can result in the generation of homozygous duplications, and further document how multiple seemingly rare events can occur in a single individual. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
241. Delineation of a deletion region critical for corpus callosal abnormalities in chromosome 1q43-q44.
- Author
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Nagamani, Sandesh C Sreenath, Erez, Ayelet, Bay, Carolyn, Pettigrew, Anjana, Lalani, Seema R, Herman, Kristin, Graham, Brett H, Nowaczyk, Malgorzata JM, Proud, Monica, Craigen, William J, Hopkins, Bobbi, Kozel, Beth, Plunkett, Katie, Hixson, Patricia, Stankiewicz, Pawel, Patel, Ankita, and Cheung, Sau Wai
- Subjects
HUMAN abnormalities ,CHROMOSOMES ,GENES ,PROTEINS ,NEURONS - Abstract
Submicroscopic deletions involving chromosome 1q43-q44 result in cognitive impairment, microcephaly, growth restriction, dysmorphic features, and variable involvement of other organ systems. A consistently observed feature in patients with this deletion are the corpus callosal abnormalities (CCAs), ranging from thinning and hypoplasia to complete agenesis. Previous studies attempting to delineate the critical region for CCAs have yielded inconsistent results. We conducted a detailed clinical and molecular characterization of seven patients with deletions of chromosome 1q43-q44. Using array comparative genomic hybridization, we mapped the size, extent, and genomic content of these deletions. Four patients had CCAs, and shared the smallest region of overlap that contains only three protein coding genes, CEP170, SDCCAG8, and ZNF238. One patient with a small deletion involving SDCCAG8 and AKT3, and another patient with an intragenic deletion of AKT3 did not have any CCA, implying that the loss of these two genes is unlikely to be the cause of CCA. CEP170 is expressed extensively in the brain, and encodes for a protein that is a component of the centrosomal complex. ZNF238 is involved in control of neuronal progenitor cells and survival of cortical neurons. Our results rule out the involvement of AKT3, and implicate CEP170 and/or ZNF238 as novel genes causative for CCA in patients with a terminal 1q deletion. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
242. Detection of ≥1Mb microdeletions and microduplications in a single cell using custom oligonucleotide arrays.
- Author
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Bi W, Breman A, Shaw CA, Stankiewicz P, Gambin T, Lu X, Cheung SW, Jackson LG, Lupski JR, Van den Veyver IB, Beaudet AL, Bi, Weimin, Breman, Amy, Shaw, Chad A, Stankiewicz, Pawel, Gambin, Tomasz, Lu, Xinyan, Cheung, Sau Wai, Jackson, Laird G, and Lupski, James R
- Abstract
Objective: High resolution detection of genomic copy number abnormalities in a single cell is relevant to preimplantation genetic diagnosis and potentially to noninvasive prenatal diagnosis. Our objective is to develop a reliable array comparative genomic hybridization (CGH) platform to detect genomic imbalances as small as ~1Mb ina single cell.Methods: We empirically optimized the conditions for oligonucleotide-based array CGH using single cells from multiple lymphoblastoid cell lines with known copy number abnormalities. To improve resolution, we designed custom arrays with high density probes covering clinically relevant genomic regions.Results: The detection of megabase-sized copy number variations (CNVs) in a single cell was influenced by the number of probes clustered in the interrogated region. Using our custom array, we reproducibly detected multiple chromosome abnormalities including trisomy 21, a 1.2Mb Williams syndrome deletion, and a 1.3Mb CMT1A duplication. Replicate analyses yielded consistent results.Conclusion: Aneuploidy and genomic imbalances with CNVs as small as 1.2Mb in a single cell are detectable by array CGH using arrays with high-density coverage in the targeted regions. This approach has the potential to be applied for preimplantation genetic diagnosis to detect aneuploidy and common microdeletion/duplication syndromes and for noninvasive prenatal diagnosis if single fetal cells can be isolated. [ABSTRACT FROM AUTHOR]- Published
- 2012
243. Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE.
- Author
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Celestino-Soper, Patricia B.S., Shaw, Chad A., Sanders, Stephan J., Li, Jian, Murtha, Michael T., Ercan-Sencicek, A. Gulhan, Davis, Lea, Thomson, Susanne, Gambin, Tomasz, Chinault, A. Craig, Ou, Zhishuo, German, Jennifer R., Milosavljevic, Aleksandar, Sutcliffe, James S., Cook, Edwin H., Stankiewicz, Pawel, State, Matthew W., and Beaudet, Arthur L.
- Published
- 2011
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244. Complex genomic rearrangement of chromosome 16p13.3 detected by array comparative genomic hybridization in a patient with multiple congenital anomalies, dysmorphic craniofacial features, and developmental delay.
- Author
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Gu, Jun, Sreenath Nagamani, Sandesh C., Hopwood, Vicki L., Sanchez, Beatriz, Saeidinejad, Yasaman, Ou, Zhishuo, Peacock, Sandra, Grange, Dorothy K., Stankiewicz, Pawel, and Cheung, Sau Wai
- Published
- 2011
- Full Text
- View/download PDF
245. Alveolar Capillary Dysplasia.
- Author
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Bishop, Naomi B., Stankiewicz, Pawel, and Steinhorn, Robin H.
- Published
- 2011
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- View/download PDF
246. Recurrent partial rhombencephalosynapsis and holoprosencephaly in siblings with a mutation of ZIC2.
- Author
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Ramocki, Melissa B., Scaglia, Fernando, Stankiewicz, Pawel, Belmont, John W., Jones, Jeremy Y., and Clark, Gary D.
- Abstract
Rhombencephalosynapsis (RES) is a rare congenital brain malformation typically identified by magnetic resonance imaging and characterized by fusion of the cerebellar hemispheres and dentate nuclei and vermian agenesis or hypogenesis. Although RES is frequently found in conjunction with other brain malformations and/or congenital anomalies, no specific molecular etiology has been discovered to date and no animal models exist. We identified two half sisters with alobar or semi-lobar holoprosencephaly (HPE) and partial RES, suggesting that genes linked to HPE may also contribute to RES. A deletion of seven base pairs in exon one of the ZIC2 gene (c.392_98del7) was identified in each of the two half sisters with HPE and partial RES. To identify genetic causes of RES and to assess whether genes identified in HPE have a role in RES, we tested 11 additional individuals with RES by high-resolution chromosome analysis, chromosomal microarray analysis, and sequencing of four HPE genes. No mutations in ZIC2 or in other genes that cause HPE were identified, suggesting that mutation of ZIC2 is a rare cause of, or contributor to, RES associated with HPE. In addition, an individual with a complex rearrangement of chromosome 22q13.3 and RES was identified, suggesting the presence of a dosage-sensitive gene that may contribute to RES in this region. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
247. TGFBR2 deletion in a 20-month-old female with developmental delay and microcephaly.
- Author
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Campbell, Ian M., Kolodziejska, Katarzyna E., Quach, Michael M., Wolf, Varina Louise, Cheung, Sau Wai, Lalani, Seema R., Ramocki, Melissa B., and Stankiewicz, Pawel
- Abstract
To date, over 70 mutations in the TGFBR2 gene have been reported in patients with Loeys-Dietz syndrome (LDS), Marfan syndrome type 2 (MFS2), or other hereditary thoracic aortic aneurysms and dissections. Whereas almost all of mutations analyzed thus far are predicted to disrupt the constitutively active C-terminal serine/threonine kinase domain of TGFBR2, mounting evidence suggests that the molecular mechanism underlying these diseases is more complex than simple haploinsufficiency. Using exon-targeted oligonucleotide array comparative genomic hybridization, we identified an ∼896 kb deletion of TGFBR2 in a 20-month-old female with microcephaly and global developmental delay, but no stigmata of LDS. FISH analysis showed no evidence of this deletion in the parental peripheral blood samples; however, somatic mosaicism was detected using PCR in the paternal DNA from peripheral blood lymphocytes and lymphoblasts. Our data suggest that TGFBR2 haploinsufficiency may cause a phenotype, which is distinct from LDS. Moreover, we propose that somatic mosaicism below the detection threshold of FISH analysis in asymptomatic parents of children with genomic disorders may be more common than previously recognized. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
248. Copy number gain at Xp22.31 includes complex duplication rearrangements and recurrent triplications.
- Author
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Liu, Pengfei, Erez, Ayelet, Sreenath Nagamani, Sandesh C., Bi, Weimin, Carvalho, Claudia M. B., Simmons, Alexandra D., Wiszniewska, Joanna, Fang, Ping, Eng, Patricia A., Cooper, M. Lance, Sutton, V. Reid, Roeder, Elizabeth R., Bodensteiner, John B., Delgado, Mauricio R., Prakash, Siddharth K., Belmont, John W., Stankiewicz, Pawel, Berg, Jonathan S., Shinawi, Marwan, and Patel, Ankita
- Published
- 2011
- Full Text
- View/download PDF
249. A de novo deletion of CALN1 in a male with a bilateral diaphragmatic defect does not definitely cause this malformation.
- Author
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Slavotinek, Anne M., Rosenfeld, Jill A., Chao, Ryan, Niyazov, Dimitry, Eswara, Marthand, Bader, Patricia I., Stockton, David W., Stankiewicz, Pawel, and Adam, Margaret P.
- Published
- 2011
- Full Text
- View/download PDF
250. Phenotypic manifestations of copy number variation in chromosome 16p13.11.
- Author
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Nagamani, Sandesh C. Sreenath, Erez, Ayelet, Bader, Patricia, Lalani, Seema R., Scott, Daryl A., Scaglia, Fernando, Plon, Sharon E., Chun-Hui Tsai, Reimschisel, Tyler, Roeder, Elizabeth, Malphrus, Amy D., Eng, Patricia A., Hixson, Patricia M., Kang, Sung-Hae L., Stankiewicz, Pawel, Patel, Ankita, and Sau Wai Cheung
- Subjects
HUMAN behavior ,PHENOTYPES ,COMPARATIVE genomic hybridization ,JOINT hypermobility ,CRANIOSYNOSTOSES ,CHROMOSOMES ,POLYDACTYLY ,GENETICS - Abstract
The widespread clinical utilization of array comparative genome hybridization, has led to the unraveling of many new copy number variations (CNVs). Although some of these CNVs are clearly pathogenic, the phenotypic consequences of others, such as those in 16p13.11 remain unclear. Whereas deletions of 16p13.11 have been associated with multiple congenital anomalies, the relevance of duplications of the region is still being debated. We report detailed clinical and molecular characterization of 10 patients with duplication and 4 patients with deletion of 16p13.11. We found that patients with duplication of the region have varied clinical features including behavioral abnormalities, cognitive impairment, congenital heart defects and skeletal manifestations, such as hypermobility, craniosynostosis and polydactyly. These features were incompletely penetrant. Patients with deletion of the region presented with microcephaly, developmental delay and behavioral abnormalities as previously described. The CNVs were of varying sizes and were likely mediated by non-allelic homologous recombination between low copy repeats. Our findings expand the repertoire of clinical features observed in patients with CNV in 16p13.11 and strengthen the hypothesis that this is a dosage sensitive region with clinical relevance. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
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