Constitutional Chromosome Aberrations Research Articles

Germline MYOF1::WNK4 and VPS25::MYOF1 Chimeras Generated by the Constitutional Translocation t(17;19)(q21;p13) in Two Siblings With Myelodysplastic Syndrome.

Constitutional chromosomal aberrations are rare in hematologic malignancies and their pathogenetic role is mostly poorly understood. We present a comprehensive molecular characterization of a novel constitutional chromosomal translocation found in two siblings - sisters - diagnosed with myelodysplastic syndrome (MDS). Bone marrow and blood cells from the two patients were examined using G-banding, RNA sequencing, PCR, and Sanger sequencing. We identified a balanced t(17;19)(q21;p13) translocation in both siblings' bone marrow, blood cells, and phytohemagglutinin-stimulated lymphocytes. The translocation generated a MYO1F::WNK4 chimera on the der(19)t(17;19), encoding a chimeric serine/threonine kinase, and a VPS25::MYO1F on the der(17), potentially resulting in an aberrant VPS25 protein. The t(17;19)(q21;p13) translocation found in the two sisters probably predisposed them to myelodysplasia. How the MYO1F::WNK4 and/or VPS25::MYO1F chimeras, perhaps especially MYO1F::WNK4 that encodes a chimeric serine/threonine kinase, played a role in MDS pathogenesis, remains incompletely understood.

Constitutional chromosomal anomalies in children, fetal alcohol syndrome, and maternal toxicant exposures: A longitudinal cohort study

DNA alterations in gametes, which may occur either spontaneously or as a result of exposure to genotoxicants, can lead to constitutional chromosomal anomalies in the offspring. Alcohol is an established genotoxicant. The goal of this hypothesis-testing longitudinal cohort study was to evaluate the effect of significant/sustained maternal alcohol exposure on clinically diagnosed constitutional chromosomal anomalies among children diagnosed with fetal alcohol syndrome (FAS). De-identified eligibility and claim healthcare records, prospectively generated from the 1990–2012 Florida Medicaid system within the Independent Healthcare Research Database (IHRD), were analyzed. Children examined were continuously eligible with ≥ 8 outpatient office visits during the 96-month period following birth. Among these children, 377 were diagnosed with FAS and 137,135 were not. The incidence rate of chromosomal anomalies involving segregation (trisomy 13, 18, or 21, n = 625), microdeletions (microdeletion syndromes, n = 39), and point mutations (sickle-cell anemia/cystic fibrosis, n = 2570) were examined using frequency risk ratio (RR) and logistic regression (adjusted odds ratio (aOR) for sex, race, residence, socioeconomic/environmental exposure status, and birth date) models. The incidence rates of chromosomal anomalies involving segregation (RR=5.92, aOR=5.85) and microdeletions (RR=41.6, aOR=34.1) were significantly increased in the FAS cohort as compared to the non-diagnosed cohort, but there was no difference in the incidence rate of point mutations (RR=1.14, aOR=1.29). Maternal toxicant exposure should be considered in the etiology of constitutional chromosomal anomaly in offspring.

The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21

AbstractIntrachromosomal amplification of chromosome 21 defines a subtype of high-risk childhood acute lymphoblastic leukemia (iAMP21-ALL) characterized by copy number changes and complex rearrangements of chromosome 21. The genomic basis of iAMP21-ALL and the pathogenic role of the region of amplification of chromosome 21 to leukemogenesis remains incompletely understood. In this study, using integrated whole genome and transcriptome sequencing of 124 patients with iAMP21-ALL, including rare cases arising in the context of constitutional chromosomal aberrations, we identified subgroups of iAMP21-ALL based on the patterns of copy number alteration and structural variation. This large data set enabled formal delineation of a 7.8 Mb common region of amplification harboring 71 genes, 43 of which were differentially expressed compared with non-iAMP21–ALL ones, including multiple genes implicated in the pathogenesis of acute leukemia (CHAF1B, DYRK1A, ERG, HMGN1, and RUNX1). Using multimodal single-cell genomic profiling, including single-cell whole genome sequencing of 2 cases, we documented clonal heterogeneity and genomic evolution, demonstrating that the acquisition of the iAMP21 chromosome is an early event that may undergo progressive amplification during disease ontogeny. We show that UV-mutational signatures and high mutation load are characteristic secondary genetic features. Although the genomic alterations of chromosome 21 are variable, these integrated genomic analyses and demonstration of an extended common minimal region of amplification broaden the definition of iAMP21-ALL for more precise diagnosis using cytogenetic or genomic methods to inform clinical management.

CYTOGENETIC ANALYSIS OF 2,205 CASES OF HEMATOLOGICAL NEOPLASIA AND GENETIC DISEASES: A SINGLE CENTER EXPERIENCE

Cytogenetics is defined as the study of chromosome morphology, pathology function, and behavior. Cytogenetics is important to define clonality for bone marrow disorders and for diagnosing a lot of constitutional disorders. We analyzed a ten-year experience of bone marrow and peripheral blood cytogenetics for defining clonal and not clonal disorders at the Cancer Cytogenomics Laboratory of the Federal University of Ceará. All bone marrow and peripheral blood samples were submitted to cell culture (for 24 hours and 72 hours, respectively), after which all were processed, and G-banding performed using trypsin and Wright-Giemsa staining. The karyotype results of 2,205 patients were analyzed including additional information such as age, sex, requesting unit and suspected diagnosis. Among these, 1744 (79.1%) were bone marrow samples and 461 (20.9%) were peripheral blood samples used to investigate constitutional changes. The female gender (54.4%) stood out in the Bone Marrow samples, aged between 71 and 80 years (20.2%). Among the bone marrow results, 726 of 1744 (42%) were normal and 431 of them (24.7%) were abnormal karyotypes. The main etiological suspicion was Myelodysplastic Syndrome (54.2% of cases), and 42.1% were normal. Among the chromosomal abnormalities, the main alterations found were: 26% cases with isolated del(5q) and/or other alterations, 10% of cases were complex, 10% were isolated del(11q) and/or with other alterations, 9% of cases with del (7q) isolated and/or with other alterations and 7% cases with +8 isolated and/or with other alterations, 2% cases had del(17q) isolated and/or with other alterations, 1% of cases had del(17p) and one case with i(17q). A total of 127 cases were suspected as AML, with 34.6% altered karyotypes, 34.4% normal karyotypes. Among the abnormal karyotypes: 20,5% cases with t(15;17) and 13,6% were complex karyotypes, 6,8% were del(11q23), 4,5% cases with t(8;21), 1 case with del(17p) and another with i(17q). A total of 161 cases were suspected as CML, among which: 49,7% abnormal karyotype, 24.2% were normal. Among the chromosomal abnormalities, 65% were t(9;22) and 2,2% were t(9;22) and other alterations and/or variants of t(9;22). In this way, this study shows that cytogenetic was important for diagnostic purposes of patients principally for diseases such as Myelodysplastic Syndrome, Acute Myeloid Leukemia and Chronic Myeloid Leukemia. Cytogenetic analysis is also fundamental for analysis of constitutional and somatic genetic disorders. Regarding the constitutional results, 176/461 (38%) showed chromosomal abnormalities with 66 (37.5%) showing trisomy 21 followed by trisomy 18 (14.7%) and androgen insensitivity syndrome (11.3%). Identification of constitutional or malignance chromosomal anomalies can provide important information for genetic medical counseling. Cytogenetic analysis of hematological neoplasms and for constitutional disorders is helpful for diagnosis and monitoring the effects of treatment, being still very important in the new molecular era.

Optical genome mapping enables constitutional chromosomal aberration detection

Chromosomal aberrations including structural variations (SVs) are a major cause of human genetic diseases. Their detection in clinical routine still relies on standard cytogenetics. Drawbacks of these tests are a very low resolution (karyotyping) and the inability to detect balanced SVs or indicate the genomic localization and orientation of duplicated segments or insertions (copy number variant [CNV] microarrays). Here, we investigated the ability of optical genome mapping (OGM) to detect known constitutional chromosomal aberrations. Ultra-high-molecular-weight DNA was isolated from 85 blood or cultured cells and processed via OGM. A de novo genome assembly was performed followed by structural variant and CNV calling and annotation, and results were compared to known aberrations from standard-of-care tests (karyotype, FISH, and/or CNV microarray). In total, we analyzed 99 chromosomal aberrations, including seven aneuploidies, 19 deletions, 20 duplications, 34 translocations, six inversions, two insertions, six isochromosomes, one ring chromosome, and four complex rearrangements. Several of these variants encompass complex regions of the human genome involved in repeat-mediated microdeletion/microduplication syndromes. High-resolution OGM reached 100% concordance compared to standard assays for all aberrations with non-centromeric breakpoints. This proof-of-principle study demonstrates the ability of OGM to detect nearly all types of chromosomal aberrations. We also suggest suited filtering strategies to prioritize clinically relevant aberrations and discuss future improvements. These results highlight the potential for OGM to provide a cost-effective and easy-to-use alternative that would allow comprehensive detection of chromosomal aberrations and structural variants, which could give rise to an era of "next-generation cytogenetics."

Telomere aberrations, including telomere loss, doublets, and extreme shortening, are increased in patients with infertility

To test the hypothesis that telomere shortening and/or loss are risk factors for infertility. Retrospective analysis of the telomere status in patients with infertility using conventional cytogenetic data collected prospectively. Academic centers. Cytogenetic slides with cultured peripheral lymphocytes from 50 patients undergoing fertility treatment and 150 healthy donors, including 100 donors matched for age. Cytogenetic slides were used to detect chromosomal and telomere aberrations. Telomere length and telomere aberrations were analyzed after telomere and centromere staining. The mean telomere length of patients consulting for infertility was significantly less than that of healthy donors of similar age. Moreover, patients with infertility showed significantly more extreme telomere loss and telomere doublet formation than healthy controls. Telomere shortening and/or telomere aberrations were more pronounced in patients with structural chromosomal aberrations. Dicentric chromosomes were identified in 6/13 patients, with constitutional chromosomal aberrations leading to chromosomal instability that correlated with chromosomal end-to-end fusions. Our findings demonstrate the feasibility of analyzing telomere aberrations in addition to chromosomal aberrations, using cytogenetic slides. Telomere attrition and/or dysfunction represent the main common cytogenetic characteristic of patients with infertility, leading to potential implications for fertility assessment. Pending further studies, these techniques that correlate the outcome of assisted reproduction and telomere integrity status may represent a novel and useful diagnostic and/or prognostic tool for medical care in this field.

Overview of Clinical Cytogenetics.

Chromosome analysis is one of the first approaches to genetic testing and remains a key component of genetic analysis of constitutional and somatic genetic disorders. Numerical or unbalanced structural chromosome abnormalities usually lead to multiple congenital anomalies. Sometimes these are compatible with live birth, usually resulting in severe cognitive and physical handicaps; other times they result in miscarriage or stillbirth. Chromosome rearrangements also occur as somatic changes in malignancies. Identification of constitutional chromosomal anomalies (anomalies present in most or all cells of the body and/or the germline) can provide important information for genetic counseling. In this unit, we introduce chromosomal microarray analysis (CMA), which is a relatively recent addition to cytogenetic technologies, and has become the recommended first-tier testing method for patients with developmental delay, intellectual disability, autism, and/or multiple congenital anomalies. We also discuss non-invasive prenatal testing/screening (NIPTS), which uses circulating cell-free fetal DNA (cfDNA) from maternal plasma to rapidly screen for autosomal and sex-chromosome aneuploidies. Cytogenetic analysis of tumors is helpful in diagnosis and in monitoring the effects of treatment. The protocols in this chapter cover the clinical study of chromosomes in nonmalignant tissues.

Cytogenetic and single nucleotide polymorphism array findings in soft tissue tumors in infants

Soft tissue tumors in children under one year of age (infants) are rare. The etiology is usually unknown, with external factors or congenital birth defects and hereditary syndromes being recognized in only a small proportion of the cases. We ascertained the cytogenetic findings in 16 infants from whom tumor tissue had been obtained during a 25-year period. In eight of them, single nucleotide polymorphism (SNP) array analyses could also be performed. No constitutional chromosome aberrations were detected, and assessment of clinical files did not reveal any congenital or later anatomical defects. Three tumors--one infantile fibrosarcoma, one embryonal rhabdomyosarcoma, and one angiomatoid fibrous histiocytoma (AFH)--had abnormal karyotypes. As the AFH had an exchange between chromosome arms 12p and 15q, additional fluorescence in situ hybridization and reverse transcription-polymerase chain reaction analyses were performed, unexpectedly revealing an ETV6/NTRK3 fusion. Three of the eight tumors, including the AFH with an abnormal karyotype, analyzed by SNP array showed aberrations (loss of heterozygosity or imbalances). The present series suggests that the addition of array-based technologies is valuable for detecting underlying pathogenetic mechanisms.

Chromosomal aberrations in 2000 couples of Indian ethnicity with reproductive failure

Constitutional chromosomal aberrations contribute to infertility and repeated miscarriage leading to reproductive failure in couples. These aberrations may show no obvious clinical manifestations and remain undetected across multiple generations. However, infertility or recurrent spontaneous pregnancy loss, and/or genotypic/phenotypic aberrations may be manifested in the progeny during gametogenesis. The current study was a retrospective analysis to examine the chromosomal aberrations and prevalence in 2000 couples of Indian ethnicity with reproductive failure. Cytogenetic analysis via conventional G-band karyotyping analysis was carried out on phytohaemagglutinin stimulated peripheral blood lymphocytes, cultured in RPMI1640 medium. The chromosomes were enumerated as per International System for Human Cytogenetic Nomenclature at 500–550 band resolution, and recorded in the screening sheets. Chromosomal aberrations were detected in a total of 110 (2.78%) couples, with structural chromosomal aberrations in 88 cases including reciprocal translocations in 56 cases, Robertsonian translocations in 16 cases, inversions in eight cases, deletions in three cases, derivative chromosomes in five cases and numerical chromosome aberrations in 23 cases. The study emphasizes the importance of cytogenetic work up in both the partners associated with a history of reproductive failure. Genetic counselling with an option of prenatal diagnosis should be offered to couples with chromosomal aberrations.Alteration in the number or structure of chromosomes is associated with adverse obstetric outcome in the form of infertility or recurrent miscarriages. Most of these aberrations are balanced and hence, the person does not manifest any obvious clinical signs and symptoms. However, because of the formation of abnormal gametes (i.e. the eggs and sperm), these chromosomal aberrations result in infertility and recurrent spontaneous pregnancy losses. In the present study, we studied 2000 couples of Indian ethnicity with reproductive failure. Karyotyping was done on the blood sample of these couples using standard protocols. Chromosomal aberrations were detected in a total of 110 (2.78%) couples with structural chromosomal aberrations in 88 cases including reciprocal translocations in 56 cases, Robertsonian translocations in 16 cases, inversions in eight cases, deletions in three cases, derivative chromosomes in five cases and numerical chromosome aberrations in 23 cases. Thus, our study emphasizes the importance of cytogenetic work up in both the associated partners with history of reproductive failure which would help in better patient counselling and management.

An experimental loop design for the detection of constitutional chromosomal aberrations by array CGH

BackgroundComparative genomic hybridization microarrays for the detection of constitutional chromosomal aberrations is the application of microarray technology coming fastest into routine clinical application. Through genotype-phenotype association, it is also an important technique towards the discovery of disease causing genes and genomewide functional annotation in human. When using a two-channel microarray of genomic DNA probes for array CGH, the basic setup consists in hybridizing a patient against a normal reference sample. Two major disadvantages of this setup are (1) the use of half of the resources to measure a (little informative) reference sample and (2) the possibility that deviating signals are caused by benign copy number variation in the "normal" reference instead of a patient aberration. Instead, we apply an experimental loop design that compares three patients in three hybridizations.ResultsWe develop and compare two statistical methods (linear models of log ratios and mixed models of absolute measurements). In an analysis of 27 patients seen at our genetics center, we observed that the linear models of the log ratios are advantageous over the mixed models of the absolute intensities.ConclusionThe loop design and the performance of the statistical analysis contribute to the quick adoption of array CGH as a routine diagnostic tool. They lower the detection limit of mosaicisms and improve the assignment of copy number variation for genetic association studies.

The DNA methylome of pediatric acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, with high hyperdiploidy [51-67 chromosomes] and the t(12;21)(p13;q22) [ETV6/RUNX1 fusion] representing the most frequent abnormalities. Although these arise in utero, there is long latency before overt ALL, showing that additional changes are needed. Gene dysregulation through hypermethylation may be such an event; however, this has not previously been investigated in a detailed fashion. We performed genome-wide methylation profiling using bacterial artificial chromosome arrays and promoter-specific analyses of high hyperdiploid and ETV6/RUNX1-positive ALLs. In addition, global gene expression analyses were performed to identify associated expression patterns. Unsupervised cluster and principal component analyses of the chromosome-wide methylome profiles could successfully subgroup the two genetic ALL types. Analysis of all currently known promoter-specific CpG islands demonstrated that several B-cell- and neoplasia-associated genes were hypermethylated and underexpressed, indicating that aberrant methylation plays a significant leukemogenic role. Interestingly, methylation hotspots were associated with chromosome bands predicted to harbor imprinted genes and the tri-/tetrasomic chromosomes in the high hyperdiploid ALLs were less methylated than their disomic counterparts. Decreased methylation of gained chromosomes is a previously unknown phenomenon that may have ramifications not only for the pathogenesis of high hyperdiploid ALL but also for other disorders with acquired or constitutional numerical chromosome anomalies.

Is there an association with constitutional structural chromosomal abnormalities and hematologic neoplastic process? A short review

The occasional observation of constitutional chromosomal abnormalities in patients with a malignant disease has led to a number of studies on their potential role in cancer development. Investigations of families with hereditary cancers and constitutional chromosomal abnormalities have been key observations leading to the molecular identification of specific genes implicated in tumorigenesis. Large studies have been reported on the incidence of constitutional chromosomal aberrations in patients with hematologic malignancies, but they could not confirm an increased risk for hematologic malignancy among carriers of structural chromosomal changes. However, it is of particular interest that constitutional structural aberrations with breakpoints similar to leukemia-associated specific breakpoints have been reported in patients with hematologic malignancies. Because of insufficient data, it remains still unclear if these aberrations represent random events or are associated with malignancy. There has been a substantial discussion about mechanisms involved in constitutional structural chromosomal changes in the literature. The documentation of more patients with constitutional structural chromosomal changes could be of major importance. Most importantly, the molecular investigation of chromosomal regions involved in rearrangements could give useful information on the genetic events underlying constitutional anomalies, contributing to isolation of genes important in the development of the neoplastic process. Regarding constitutional anomalies in patients with hematologic disorders, a survey of the cytogenetic data of our cytogenetics unit is herein also presented.

Neuroimaging findings in children with rare or novel de novo chromosomal anomalies

De novo constitutional chromosomal anomalies provide important insights into the genetic loci responsible for congenital neurological disorders. However, most phenotypic descriptions of patients with rare chromosomal abnormalities are published as individual case reports or small group studies, making genotype-phenotype correlations unclear. Moreover, many clinical genetic reports do not include neuroimaging. We conducted a retrospective case series study of all children who had genetic testing done at Children's Memorial Hospital in Chicago, Illinois between 1985 and 2006. The case series was selected from a database containing all chromosomal testing results, clinical data, and neuroimaging. Clinical examination results were assigned by board certified geneticists and/or neurologists and neuroimages were reviewed by both a neurologist or neuroradiologist and a blinded neurologist. Of the 28,108 children in the series, we identified 34 children with novel or apparently novel de novo chromosomal abnormalities. Several of the cases represent potentially new genetic loci for neurological malformations and novel syndromic conditions. This study demonstrates the utility of large clinical databases in assessing genotype-phenotype correlations and mapping loci for congenital neurological disorders. We describe a case-series strategy to analyze existing databases to reveal new genotype-phenotype correlations.

Detection of submicroscopic constitutional chromosome aberrations in clinical diagnostics: a validation of the practical performance of different array platforms

For several decades etiological diagnosis of patients with idiopathic mental retardation (MR) and multiple congenital anomalies (MCA) has relied on chromosome analysis by karyotyping. Conventional karyotyping allows a genome-wide detection of chromosomal abnormalities but has a limited resolution. Recently, array-based comparative genomic hybridization (array CGH) technologies have been developed to evaluate DNA copy-number alterations across the whole-genome at a much higher resolution. It has proven to be an effective tool for detection of submicroscopic chromosome abnormalities causing congenital disorders and has recently been adopted for clinical applications. Here, we investigated four high-density array platforms with a theoretical resolution < or =100 kb: 33K tiling path BAC array, 500K Affymetrix SNP array, 385K NimbleGen oligonucleotide array and 244K Agilent oligonucleotide array for their robustness and implementation in our diagnostic setting. We evaluated the practical performance based on the detection of 10 previously characterized abnormalities whose size ranged from 100 kb to 3 Mb. Furthermore, array data analysis was performed using four computer programs developed for each corresponding platform to test their effective ability of reliable copy-number detection and their user-friendliness. All tested platforms provided sensitive performances, but our experience showed that accurate and user-friendly computer programs are of crucial importance for reliable copy-number detection.

Direct fluorescent labelling of clones by DOP PCR.

BackgroundArray Comparative Genomic Hybridisation (array CGH) is a powerful technique for the analysis of constitutional chromosomal anomalies. Chromosomal duplications or deletions detected by array CGH need subsequently to be validated by other methods. One method of validation is Fluorescence in situ Hybridisation (FISH). Traditionally, fluorophores or hapten labelling is performed by nick translation or random prime labelling of purified Bacterial Artificial Chromosome (BAC) products. However, since the array targets have been generated from Degenerate Oligonucleotide Primed (DOP) amplified BAC clones, we aimed to use these DOP amplified BAC clones as the basis of an automated FISH labelling protocol. Unfortunately, labelling of DOP amplified BAC clones by traditional labelling methods resulted in high levels of background.ResultsWe designed an improved labelling method, by means of degenerate oligonucleotides that resulted in optimal FISH probes with low background.ConclusionWe generated an improved labelling method for FISH which enables the rapid generation of FISH probes without the need for isolating BAC DNA. We labelled about 900 clones with this method with a success rate of 97%.

Mapping of constitutional translocation breakpoints in renal cell cancer patients: identification of KCNIP4 as a candidate gene

Our group and others had previously developed a high throughput procedure to map translocation breakpoints using chromosome flow sorting in conjunction with microarray-based comparative genomic hybridization (arrayCGH). Here we applied both conventional positional cloning and integrated arrayCGH procedures to the mapping of constitutional chromosome anomalies in four patients with renal cell cancer (RCC), three with a chromosome 3 translocation, and one with an insertion involving chromosome 3. In one of these patients, who was carrying a t(3;4)(p13;p15), the KCNIP4 gene was found to be disrupted. KCNIP4 belongs to a family of potassium channel–interacting proteins and is highly expressed in normal kidney cells. In addition, KCNIP4 splice variants have specifically been encountered in RCC.

Evaluation of a commercially available focused aCGH platform for the detection of constitutional chromosome anomalies

Microarray-based comparative genomic hybridization (aCGH) allows for simultaneous high-resolution analysis of multiple genomic loci. Recently, focused aCGH platforms have emerged allowing for analysis of numerous clinically relevant chromosome loci. The purpose of our study was to evaluate the Spectral Genomics Constitutional Chip 1.0 (CC) for use in the clinical laboratory. The CC consisted of 429 BAC clones for 41 known genetic deletion/duplication syndromes, subtelomeric regions, and chromosomal backbone clones. We conducted a blinded study of 48 samples including 46 patients (one sample was run in triplicate) with previously determined constitutional chromosome anomalies and two negative controls. Patient samples included 31 microdeletions, four duplications, three derivative chromosomes, three trisomies, and five sex chromosome aneuploidies. Our results show that the CC identified the expected gains and/or losses in 46 of 48 samples. The two negative controls were considered to be normal and the three replicates of the same patient sample were concordant. Two samples yielded false-negative results; however, repeat analysis produced acceptable results for one of them. One sample ultimately had an insufficient amount of DNA precluding aCGH analysis. While promising, the results suggest that further studies are needed to reduce protocol variability and to establish standard analysis and interpretation criteria. Further, this study verifies the importance of extensive validation studies prior to clinical implementation of new clinically available methodologies.

Evidence for involvement of TRE-2 (USP6) oncogene, low-copy repeat and acrocentric heterochromatin in two families with chromosomal translocations

We report clinical findings and molecular cytogenetic analyses for two patients with translocations [t(14;17)(p12;p12) and t(15;17)(p12;p13.2)], in which the chromosome 17 breakpoints map at a large low-copy repeat (LCR) and a breakage-prone TRE-2 (USP6) oncogene, respectively. In family 1, a 6-year-old girl and her 5-year-old brother were diagnosed with mental retardation, short stature, dysmorphic features, and Charcot-Marie-Tooth disease type 1A (CMT1A). G-banding chromosome analysis showed a der(14)t(14;17)(p12;p12) in both siblings, inherited from their father, a carrier of the balanced translocation. Chromosome microarray and FISH analyses revealed that the PMP22 gene was duplicated. The chromosome 17 breakpoint was mapped within an approximately 383 kb LCR17pA that is known to also be the site of several breakpoints of different chromosome aberrations including the evolutionary translocation t(4;19) in Gorilla gorilla. In family two, a patient with developmental delay, subtle dysmorphic features, ventricular enlargement with decreased periventricular white matter, mild findings of bilateral perisylvian polymicrogyria and a very small anterior commissure, a cryptic duplication including the Miller-Dieker syndrome region was identified by chromosome microarray analysis. The chromosome 17 breakpoint was mapped by FISH at the TRE-2 oncogene. Both partner chromosome breakpoints were mapped on the short arm acrocentric heterochromatin within or distal to the rRNA cluster, distal to the region commonly rearranged in Robertsonian translocations. We propose that TRE-2 together with LCR17pA, located approximately 10 Mb apart, also generated the evolutionary gorilla translocation t(4;19). Our results support previous observations that the USP6 oncogene, LCRs, and repetitive DNA sequences play a significant role in the origin of constitutional chromosome aberrations and primate genome evolution.

No Evidence For Large-scale Germline Genomic Aberrations in Hereditary Bladder Cancer Patients with High-Resolution Array-Based Comparative Genomic Hybridization

Linkage studies in high-risk families have led to the identification of several important susceptibility genes for hereditary cancer. Unfortunately, such studies offer limited possibilities in the search for high-penetrance bladder cancer genes, as extended bladder cancer families are very rare.

Cytogenetics--in color and digitized.

Cytogenetics is the genetic analysis of cells, a discipline that has flourished since the chromosome-banding techniques introduced in 1969 by Torbjörn Caspersson and Lore Zech first provided a simple and inexpensive way to gauge the number and assess the structural integrity of chromosomes. Chromosome banding (see Figure 1A) is probably the most commonly performed genetic test: it is used about 500,000 times each year in North America (most laboratories use G-banding, named after the German chemist Gustav Giemsa). It is used prenatally and postnatally to screen for the presence of constitutional chromosomal aberrations associated with birth defects, as well as for . . .