Partial 1q Research Articles

When Feeding Difficulties Are due to Genetics: The Case of Familial Partial 9q Duplication.

Chromosomal abnormalities may cause growth failure before or since birth. 9q duplication is reported as a cause of intrauterine growth restriction, mild dysmporphism, and intellectual disabilities. We report a case of a maternally inherited 9q21.31q21.33 duplication causing prenatal and postnatal growth restriction with feeding refusal and mild facial dysmorphisms, prenatally diagnosed by single-nucleotide polymorphism array analysis. Hypothesis of the possible pathogenic mechanisms are discussed.

Cytogenetic and molecular genetic diagnosis of a neonate with partial 13q trisomy and partial 5p monosomy

To diagnose a neonate presenting with multiple dysmorphic features, Cri-du-chat signs and hypoglycemia and to correlate the phenotype with the genotype. The patient was diagnosed with conventional cytogenetics and real-time fluorescence quantitative PCR (QF-PCR). The phenotype was then correlated with the genotype through a review of literature. The neonate was diagnosed with a partial 13q trisomy (q12 → qter) and partial 5p monosomy (p15 →pter). A rare diagnosis has been established with combined cytogenetic and molecular genetic techniques. QF-PCR has a broad application in genetic diagnosis.

Chromosomal‐array analysis reveals partial 11q duplication and partial 12p deletion in a mildly affected case

Partial trisomy 11q is a rare syndrome and may be observed due to an intra-chromosomal duplication or an inter-chromosomal insertion. The deletions of the short arm of chromosome 12 are also uncommon structural aberrations. Only a small fraction of structural chromosome anomalies are related to the unbalanced progeny of balanced translocation carrier parents. We here report on a 10-month-old baby boy who shows a very mild phenotype related to unique chromosomal abnormality, partial trisomy of 11q, and partial monosomy of 12p, due to the maternal balanced reciprocal translocation (11;12). The proband showed a 49.64 Mb duplication of 11q14.1-q25 and 0.44 Mb deletion of 12p13.33 in chromosomal array analysis. Since it is known that the duplications may cause a milder phenotype than deletions. Dysmorphic facial features, minor cardiac anomalies, respiratory distress, central nervous system anomalies, and psychomotor delay observed in the patient was similar to the reported pure 11q duplication cases, while behavioral problems observed in pure monosomy 12p cases could not be evaluated due to the young age of the patient. Phenotype-genotype correlation will be discussed in view of all the reported pure partial 11q trisomies and pure partial 12p deletion cases.

Differential diagnosis of small cell glioblastoma and anaplastic oligodendroglioma: a case report of an elderly man

Small cell glioblastoma is a histological subtype of glioblastoma with characteristic features of highly proliferative, monotonous small glial cells with high nuclear cytoplasm ratio. Morphologically, malignant lymphoma or small cell metastatic carcinoma should be carefully discriminated. Some cases are difficult to differentiate from anaplastic oligodendroglioma. In this report, we present a case of small cell glioblastoma of an elderly man. The lack of IDH1/2 mutation was confirmed by immunohistochemistry and direct sequencing. Fluorescence in situ hybridization revealed the lower rates of chromosome 1p and 19q deletion. Microsatellite analysis disclosed partial 10q alteration near the PTEN locus. Not only morphological and immunohistochemical examinations, but also cytogenetical investigations for IDH1/2 mutation, 1p/19q loss, and PTEN alteration, are strongly supportive methods for the differential diagnosis of small cell glioblastoma and anaplastic oligodendroglioma.

<i>De novo</i> duplication 3q in an infant with a vascular ring and features overlapping Cornelia de Lange phenotype

Partial duplication of chromosome 3q is a recognizable syndrome with characteristic facial features, microcephaly, digital anomalies, genitourinary and cardiac defects as well as growth retardation and developmental delays. While there is clinical overlap with the unrelated Cornelia de Lange syndrome (CDLS), there are distinguishing features and molecular etiologies. Most cases of 3q duplication appear to be the result of an unbalanced translocation or inversion and therefore accompanied by additional cytogenetic anomalies. Consequently, pure duplications of 3q are very rare; we are aware of only 12 such cases that have been reported previously. Here, we present a new case of pure, partial 3q duplication in a 3-month-old female who displayed a number of clinical signs consistent with previously reported phenotypes and the additional novel finding of a vascular ring.

Comprehensive Workup of Myelodysplastic Syndromes: Comparing Targeted DNA Sequencing, Oligo/SNP Microarray and Higher Dimensional Flow Cytometry.

Abstract 2519The myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic diseases characterized by ineffective hematopoiesis, cytopenias, and dysplasia in the erythroid, myeloid or megakaryocytic lineages. However, MDS can be difficult to recognize when blasts are not increased. Subtle phenotypic shifts in early MDS can be detected using higher-dimensional flow cytometry, by DNA mutation profiling, or by detection of a range of large and small genomic abnormalities by genome-wide SNP microarray. We compared the diagnostic potential of these 3 modalities in a group of 33 patients >50 years old referred for workup of cytopenia (17 blood, 16 bone marrow aspirate samples). Platforms compared were an oligo/SNP 2.6 million-probe microarray (Cytoscan HD, Affymetrix), a 161-amplicon targeted exome sequencing assay that includes TET2, ASXL1, EZH2, IDH1, IDH2, JAK2, KRAS, and NRAS (Ion Torrent protocol with PCR/product harvesting using Fluidigm Access Array), and flow cytometry using a 6-color, 22-marker panel and an 8-color, 26-marker panel (BD FACS Canto II). Nine patients had increased myeloblasts consistent with MDS (up to 20% in blood or 5%–20% in bone marrow)(Group 1), 23 had cytopenia(s) without increase in blasts (Group 2); an additional patient had a B-cell lymphoma. Group 1 patients all had aberrations detected by at least 1 of the 3 modalities (Table). In Group 2, 1 patient had unequivocal alterations by all 3 methods, 8 by 2 assays, and 6 by 1 assay; the other 9 patients had no unequivocal aberrations (Table). Copy-neutral loss of homozygosity (CN-LOH) of >10 Mb was the sole genomic aberration observed in 3 cases of cytopenia without an increase in blasts (affecting 5q, 7q and 20q), whereas others had losses/gains at chromosomal sites characteristic of MDS [i.e., partial 1q trisomy, del(5q), del(7q), +8, del(13q) and del(20q)].Genes with mutations detected by sequencingSubmicroscopic gene deletions or CN-LOH detected by arrayFlow cytometry abnormalityGroup 1: Cytopenia(s) with increased blasts (n=9)ASXL1 (2) TET2 (1) KRAS (1) EZH2 (1) JAK2 (1)BRAF (3)EZH2 (3)FLT3 (2) TP53 (2) RPS14 (2) EPO (2) ASXL1 (1) ETV6 (1)Myeloid maturation (9/9) CD56 expression (5/9)Group 2: Cytopenia(s) without increased blasts (n=24)TET2 (4) ASXL1 (2) KRAS (2) IDH2 (1)BRAF (2) EZH2 (2) TET2 (2) ASXL1 (1) ETV6 (1) RPS14 (1) EPO (1) TP53 (1)Myeloid maturation (9/24) CD56 expression (1/24)Among older MDS patients with cytopenias(s) but no increase in blasts, phenotypic and genomic profiling can frequently identify aberrations similar to those seen in higher-grade MDS. Locations of some submicroscopic deletions included loci commonly implicated in MDS pathogenesis. Detection of these aberrations in peripheral blood should facilitate the diagnosis of early MDS. Disclosures:No relevant conflicts of interest to declare.

Partial trisomy of the long arm of chromosome 1: Prenatal diagnosis, clinical evaluation and cytogenetic findings. Case report and review of the literature

Partial trisomy of the long arm of chromosome 1 is a relatively rare cytogenetic anomaly. Its phenotype has still not been completely defined, because of the cytogenetic heterogeneity of the cases so far described. We report a prenatal case of partial 1q trisomy associated with partial monosomy 4q, secondary to balanced maternal translocation t(1;4). The trisomic segment extended from 1q31.1 to qter and the monosomy 4q was from 4q35.2 to qter. The phenotypic anomalies found by post-mortem and autopsy examinations were compared with those of similar cases reported in the literature. We performed standard cytogenetics and fluorescence in situ hybridization. Cerebral ventriculomegaly, present in our case, seemed to be a constant feature in partial 1q trisomies, so this cerebral malformation could be considered as the main echographic marker for this chromosomal imbalance and trisomy 1q should be added to the list of chromosomal abnormalities associated with ventriculomegaly.

Familial distal monosomy 3p26.3‐pter with trisomy 4q32.2‐qter, presenting with progressive ataxia, intellectual disability, and dysmorphic features

We present a boy diagnosed with partial 3p monosomy and partial 4q trisomy. The patient was 9 years of age with intellectual disability, dysmorphic features, and ataxia. A family history and medical evaluation showed that the father manifested similar facial dysmorphic features, intellectual disability, quadriparesis, and progressive cerebrospinal ataxia. The chromosomal aberration found in the proband was inherited from his father who was found to have a balanced reciprocal translocation of chromosomes 3p and 4q, which was in turn inherited from the paternal grandfather. The final cytogenetic diagnosis according to microarray was 46,XY,der(3)t(3;4)(p26.1;q32.2)arr 3p26.1(39,066-5,363,502)x1,4q32.2q35.2(162,555,236-191,173,881)x3. We describe the cytogenetic investigations that led to the identification of the breakpoints. In addition, we present an overview of the clinical features found in patients with partial 3p monosomies and partial 4q trisomies as reported in the literature.

Partial 9P Monosomy and Partial 8Q Trisomy by Adjacent 1 Segregation of Balanced Paternal Translocation Revealed by Molecular Karyotyping

ABSTRACTWe present here the details of a six-month male infant with multiple congenital anomalies and developmental delay with an apparently balanced karyotype - 46, XY, inv(9)(p11q13) - and revealed by oligo array CGH del(9)(p24.3p22.2) and dup(8) (q24.13q24.3). We used BlueGnome CytoChip oligo 2X105K microarray, v1.1, with 35kbp backbone resolution. Fluorescence in situ hybridization (FISH) with BAC clones was performed to confirm the array CGH results in the patient and his family. The proband's father and sister carried the same inversion in 9th chromosome. It was initially assumed that the patient's imbalances are de novo, but the subsequent fine analysis of the FISH results and the karyotype reexamination revealed that it comes to familial reciprocal translocation between the 8th chromosome and the inverted 9th chromosome. The patient's phenotype was a result of adjacent 1 segregation during the 1st meiotic division. The duplicated segment from 8th chromosome harbors 84 OMIM genes and the deleted region in 9th chromosome contains 40 OMIM genes. We discuss the role of the gene dosage change to find some genotype-phenotype correlations.

Frequent Chromosome 1q Aberrations in HIV Associated B-Cell Lymphoma Unclassifiable with Intermediate Features Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma,

Abstract 3572Human Immunodeficiency Virus (HIV) infection is known to be strongly associated with an increased risk of high grade B-Cell Lymphoma (such as Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma). As South Africa has more than 5 million people living with HIV infection, this region sees a sharp increase in the diagnosis of high-grade lymphomas. HIV infection may associate with a number of atypical morphological features making it difficult to differentiate between classically described DLBCL and BL. As these two diseases have different prognosis and treatment, it is essential to accurately differentiate the type of disease and/or to diagnose the intermediate category of B-Cell Lymphoma, unclassifiable, with features intermediate between DLBCL and BL newly introduced in the 2008 WHO classification.In this study, we report on twelve patients (seven males and five females) who presented with high grade B cell lymphoma and a cell morphology comprising a mixture of medium to large cells that expressed B Cell markers. Patients' age ranged from 29 to 43 years old with a mean age of 34 years. Eight patients had a documented HIV positive status. Complex cytogenetic features associated with atypical morphologic features best fitted the diagnosis of B cell lymphoma unclassifiable, with features intermediate between DLBCL and BL.Conventional cytogenetics analysis revealed the presence of a complex karyotype in all cases. The chromosomes number varied from 46 to 49 with the exception of one case that had near-tetraploid cells (69 to 84 chromosomes). Ten cases had a t(8;14) classical Burkitt translocation involving the Immunoglobulin heavy chain gene as a partner, and one case had a variant Burkitt translocation t(8;22) involving the lambda light chain gene. Double hits were seen in two cases. In both cases, a translocation t(3;22)(q27;q11) rearranged the BCL6 gene in addition to a t(8;14). MYC and BCL6 genes rearrangements were confirmed using fluorescence in situ hybridization with the MYC and BCL6 break-apart probes (Abbott Molecular) and with the IGH/MYC/CEP probes. The most common secondary chromosomal aberration associated with a MYC rearrangement, was a chromosome 1 long arm structural abnormality present in nine cases, (75%) and resulting in a full trisomy 1q (n=3), or in partial duplication/ triplication of chromosome 1q (n=3), with both types of aberrations associated in 3 cases.Genome-Wide Affymetrix SNP6.0 array analysis was used to delineate chromosome 1q regions of gains. In brief, high molecular weight tumor DNA was extracted from tumor cells together with normal controls. DNA was processed and hybridized to the arrays according to the manufacturer's instructions. Data analysis was performed using the dChip software and Circulary Binary Segmentation. Copy number analysis using SNP arrays delineated three minimum regions of gains on the chromosome 1 long arm, 1q21.1q23.3, 1q24.1q24.2 and 1q32.1q32.2. The smallest region of amplification 1q24.11q24.2 included 27 genes of which the RCSD1 gene normally expressed in B-cells and previously found to be involved in acute B cell lymphoid leukemia (De Braekeleer et al 2007). These regions were smaller than 1q gains previously mapped by array comparative genomic hybridization in acute lymphoblastic leukemia and BL (Davidsson, et al 2007). Abnormalities of chromosome 7q were also non-randomly detected in four cases, in the form of trisomy 7q, or partial 7q duplication. Gains of 1q and 7q are known to occur in 20% and 10% of Burkitt lymphomas respectively (Boerma et al 2009; Scholtysik et al 2010).On the basis of these molecular cytogenetic features, we argue that these aggressive immunodeficiency associated, mostly t(8;14) positive lymphomas, represent advanced, clonally evolved forms of BL. These findings support the notion that there are distinguishable subgroups in DLBCL/BL intermediate lymphomas. Disclosures:No relevant conflicts of interest to declare.

Jumping Translocation of Homogeneously Staining Region Hsr(11q) in An Erythroid Leukemia: Identification of Amplified Regions by Fluorescence Hybridization, M-FISH and M-Banding.

Abstract 4890Gene amplification is a mechanism whereby a tumor cell can increase the copy number of specific gene sequences and gain a proliferative advantage. Although amplifications are common in solid tumors, they are relatively rare in hematological neoplasms. We report here on a patient with an acute erythroid leukemia and a jumping translocation of a hsr(11q) in a complex karyotype, without MLL amplification.The patient was 40 years old when he was admitted for asthenia, peripheral blood showing pancytopenia (Hb=111G/L; neutrophils= 0.23 G/L; platelets 92 G/L), without circulating blast cells. Bone marrow was hypercellular with the presence of more than 50% of erythroid precursors and more than 20% of myeloid blast cells in non-erythroid cell population, leading to the diagnosis of erythroblastic acute leukemia. A marked dysgranulopoiesis was also detected.Conventional cytogenetics showed a complex karyotype with a del(5q), a unbalanced t(7;17) leading to partial 7q deletion and homogeneously staining regions (hsr). Fluorescence in situ hybridization confirmed the del(5q), and showed that TP53 was not deleted in the t(7;17). Multi-FISH (M-FISH) pointed out that the hsr consisted of chromosome 11 and was implicated in 3 different translocations with 3 different partner chromosomes in 3 different clones. To further characterize the amplicon and determine which bands were implicated, we used a chromosome 11 m-band probe. It revealed that the bands implicated are the same on the der(3), der(12) and der(20) and are localized between 11q23.3 and 11q25. A series of BAC probes showed that different genes, present in these regions, were amplified: ETS1, FLI1, KCNJ5, NFRKB, SNX19, HNT, OPCM, but not MLL.Amplifications of chromosome 11q usually includes MLL, but more telomeric amplicons have also been reported in AML and myelodysplatic syndromes (MDS). A very close 11q amplification was identified in 3 AML/MDS cases (Crossen et al, 1999; Tyybäkinoja et al, 2006). Also, the ETS1 oncogene was found to be rearranged and 30-fold amplified in a case of acute myelomonocytic leukaemia, in which an hsr occurred on 11q23 (Rovigatti et al, 1986).The role of chromosomal amplifications in leukemia is unclear, but it has been suggested that they are associated with rapid disease progression and short survival. Jumping translocations are an unusual phenomenon and have been rarely reported in hematological malignancies. Whether jumping translocations play a role in tumor genesis or confer a selective growth advantage on tumor cells is unknown. The combination of hsr and jumping translocations as described here are very rare in hematological malignancies. The cases of the literature (Yoshida et al, 1999) and the one presented here suggest that the 11q24-q25 region may harbor new candidate oncogenes, together with unusual chromosomal mechanisms. Disclosures:No relevant conflicts of interest to declare.

Genetic and molecular analysis of a new unbalanced X;18 rearrangement: localization of the diminished ovarian reserve disease locus in the distal Xq POF1 region

Diminished ovarian reserve (DOR) is a heterogeneous disorder causing infertility, characterized by a decreased number of oocytes, the genetic cause of which is still unknown. We describe a family with a new unbalanced X;18 translocation der(X) associated with either fully attenuated or DOR phenotype in the same family. Cytogenetics and array comparative genomic hybridization (aCGH) studies have revealed the same partial Xq monosomy and partial 18q trisomy in both the 32-year-old female with DOR and the unaffected mother. The genetic analysis has defined a subtelomeric deletion spanning 13.3 Mb from Xq27.3 to -Xqter, which covers the premature ovarian failure locus 1 (POF1); and a duplication spanning 13.4 Mb, from 18q22.1 to 18qter. From a parental-origin study, we have inferred that the rearranged X chromosome is maternally derived. The Xq27 and 18q22 breakpoint regions fall in a region extremely rich in long interspersed nuclear element, a class of retrotransposons able to trigger mispairing and unusual crossovers. X-inactivation studies reveal a skewing of der(X) both in the mother and the proband. Therefore, the phenotypic expression of der(X) is fully attenuated in the fertile mother and partially attenuated in the DOR daughter. We report on an unbalanced maternally derived translocation (X;18)(q27;q22) with different intra-familial reproductive performances, ranging from fertility to DOR. Skewed X-inactivation seems to restore the unbalanced genetic make-up, fully silencing the 18q22 trisomy and at least in part the Xq27 monosomy. The chromosomal abnormality observed in this family supports the presence of a DOR susceptibility locus in the distal Xq region and targets the POF1 region for further investigation.

Populacije limfocita periferne krvi u pedijatrijskih pacijenata sa konotrunkalnim anomalijama srca

Objective – To determine the abundance of principal lymphocyte subpopulations in the peripheral blood of patients with conotruncal cardiac anomalies. Conotruncal cardiac anomalies arise from a developmental defect of the conotruncal septum and often occur as part of 22q11.2 deletion syndrome, also characterized by hypoparathyroidism, growth retardation, characteristic facial dysmorphia and an immune system impairment due to thymic hypoplasia. Patients and Methods – Deletion of 22q11.2 is detected by fluorescent in situ hybridization in over 90% of patients showing the characteristic phenotype. In these patients, a broad spectrum of immunological defects has been described. Most typical of these is a mild to moderate decrease of T cell number and function. In this study, we determined the numbers of lymphocyte subpopulations (CD3+, CD19+, CD3-CD16/CD56+, CD3+CD4+, CD3+CD8+, CD3+HLA-DR+) in patients treated for conotruncal anomalies (8 patients with 22q11.2 deletion, 7 without 22q11.2 deletion and 4 in whom deletion was not sought) by immunofluorescence/flow cytometry. Results – The number of patients whose CD3+ cells were decreased in number, as compared to the age-specific reference range, was 4/8, 3/7 and 2/4 in the three groups, respectively (total: 9/19 patients). The remaining lymphocyte subpopulations investigated demonstrated wide variability in all three groups of patients. Conclusion – This finding is in concurrence with published data and, overall, supports the significance of determining the numbers of lymphocyte subpopulations in all patients with conotruncal anomalies, whether carrying 22q11.2 deletion or not.

A 14-Year Follow-Up of a Case Detected Prenatally of Partial Trisomy 13q21.32-qter and Monosomy 18q22.3-qter as a Result of a Maternal Complex Chromosome Rearrangement Involving Chromosomes 6, 13, and 18

A balanced complex chromosome rearrangement (CCR) involving three chromosomes is rare and may lead to different types of aneuploid germ cells. We report here a 14-year follow-up of a boy with a karyotype defined as 46,XY,der(18)t(6;13;18)(q21;q21.32;q22.3).ish der(18)(13qter+,18qter-) characterized by multiple congenital abnormalities, including distinctive minor facial anomalies, short neck, abnormalities of the extremities, anogenital abnormalities, flexion contractures, especially at extremities, and severe mental and growth retardation. Chromosome analysis in the mother showed a CCR involving chromosomes 6, 13, and 18. This CCR was the result of a three-break rearrangement, and the derivative chromosome 13 consisted of parts of chromosomes 18 and 13. The karyotype of the child was not balanced, and resulted in partial trisomy for 13q and partial monosomy for 18q detected prenatally by conventional and molecular cytogenetics. Although such a karyotype and its phenotype have not previously been reported, we have compared the clinical and cytogenetic data from our patient with previously described cases of partial trisomy 13q and monosomy 18q despite different break points. We are presenting a new CCR in a woman with normal phenotype with a history of four early abortions and a long follow-up of her malformed newborn with partial 13q trisomy and 18q monosomy.

Molecular cytogenetic characterisation of a mosaic add(12)(p13.3) with an inv dup(3)(q26.31 --> qter) detected in an autistic boy.

BackgroundInverted duplications (inv dup) of a terminal chromosome region are a particular subset of rearrangements that often results in partial tetrasomy or partial trisomy when accompanied by a deleted chromosome. Associated mosaicism could be the consequence of a post-zygotic event or could result from the correction of a trisomic conception. Tetrasomies of distal segments of the chromosome 3q are rare genetic events and their phenotypic manifestations are diverse. To our knowledge, there are only 12 cases reported with partial 3q tetrasomy. Generally, individuals with this genomic imbalance present mild to severe developmental delay, facial dysmorphisms and skin pigmentary disorders.ResultsWe present the results of the molecular cytogenetic characterization of an unbalanced mosaic karyotype consisting of mos 46,XY,add(12)(p13.3) [56]/46,XY [44] in a previously described 11 years old autistic boy, re-evaluated at adult age. The employment of fluorescence in situ hybridization (FISH) and multicolor banding (MCB) techniques identified the extra material on 12p to be derived from chromosome 3, defining the additional material on 12p as an inv dup(3)(qter → q26.3::q26.3 → qter). Subsequently, array-based comparative genomic hybridization (aCGH) confirmed the breakpoint at 3q26.31, defining the extra material with a length of 24.92 Mb to be between 174.37 and 199.29 Mb.ConclusionThis is the thirteenth reported case of inversion-duplication 3q, being the first one described as an inv dup translocated onto a non-homologous chromosome. The mosaic terminal inv dup(3q) observed could be the result of two proposed alternative mechanisms. The most striking feature of this case is the autistic behavior of the proband, a characteristic not shared by any other patient with tetrasomy for 3q26.31 → 3qter. The present work further illustrates the advantages of the use of an integrative cytogenetic strategy, composed both by conventional and molecular techniques, on providing powerful information for an accurate diagnosis. This report also highlights a chromosome region potentially involved in autistic disorders.

High Resolution Array-Based Analysis in Marginal Zone Lymphomas and Lymphoplasmacytic Lymphomas Identified Disease-Specific Patterns of Chromosome Abnormalities

Marginal zone B-cell lymphomas (MZL) represent a sub-group of indolent B-cell lymphomas, normally localized in the “marginal zone” of the secondary lymphoid follicles. Depending on the site of involvement, three distinct sub-types have been identified: extra nodal MZL of MALT type, splenic MZL (SMZL), and nodal MZL (NMZL). MALT lymphoma is the most frequent of the MZL subtypes, representing 70% of MZL and 7% to 8% of non-Hodgkin lymphomas. SMZL and NMZL comprise the remaining 20% and 10% of MZL, respectively, and account for less than 1% of NHL. The relative rarity of these lymphomas and difficulty in distinguishing them from other low-grade B-cell lymphoma subtypes like lymphoplasmacytic lymphomas (LPL), making therapeutic decisions difficult. The aim of this study was to perform a comprehensive high-resolution study to identify distinctive molecular markers in MZL and LPL, which would help to better define these lymphomas at genomic level and distinguish them from other types of low-grade B-cell lymphoma. We analyzed 119 patients, including 22 pulmonary MALT (pMALT), 20 non-pulmonary MALT (npMALT), 34 SMZL, 21 NMZL and 22 LPL (8 Waldenström's Macroglobulinemia and 14 non-WM) cases. Human Agilent 244A platform was used by array-based comparative genomic hybridization (aCGH) analysis. Overall, 93% of patients have an altered genome. LPL had the highest amount of copy number abnormalities (median of 7.5 per patient; average of 11.7; range: 0–44), followed by npMALT (6.5; 7.6; 0–33), NMZL (5; 8.3; 0–31), SMZL (4; 7.1; 0–56) and pMALT (3.5; 4.3; 1–11). When the overall size of the abnormalities was considered, LPL was also the most affected disease with an average size of 245.15Mb included in copy number changes per patient, followed by NMZL (188.6Mb), npMALT (187.2Mb), SMZL (126.4Mb) and pMALT (109Mb). Deletions were more commonly observed than amplifications but the affected area was significantly smaller (average of 55.2Mb and 118.6Mb included in deletions and amplifications per genome, respectively). Partial or total gains of chromosome 3 and 18 were recurrently identified in all the entities, being the most common abnormalities in npMALT (60% and 50%, respectively) and pMALT (27% each). Trisomy 12 was also ubiquitously observed, ranging from 24% of NMZL to 9% of pMALT. Deletions in 6q were commonly identified in LPL (55%), npMALT (35%) and, in a less extent, in SMZL (12%) and NMZL (5%), but not in pMALT. Biallelic and focal monoallelic deletions at 6q23 clearly delineate a minimal deleted region (MDR) that includes TNFAIP3 as being the target gene of the abnormality. Deletions on 7q were found in SMZL and npMALT, thus delineating two MDR. Interstitial 11q deletions were found in LPL, NMZL and SMZL, but not in MALT. Chromosome 13 abnormalities were monosomies in NMZL and interstitial 13q14 deletions in LPL and SMZL, comprising MIRN15A and MIRN16-1 in the MDR. Partial X chromosome gains were common to all the entities but involving different areas: Xq27.3–q28 gains were recurrent events in LPL and NMZL, but not in SMZL and MALT, which were characterized by p arm gains or trisomies. Finally, some recurrent abnormalities were exclusive of specific entities: 1p deletions and 1q gains were only common in NMZL; a focal 2p gain including BCL11A and REL was found in npMALT and partial 8q gains were only identified in LPL. Trisomy 4 was only identified in the subgroup of LPL with WM, but not in the remaining LPL cases or in the remaining diseases. In this study we made a compendium of chromosomal abnormalities present in a group of related diseases, in which the molecular basis remains poorly defined. Using this high-resolution approach we were able to establish recurrent and disease-specific patterns of abnormalities and minimal deleted/amplified regions were redefined. Furthermore, TNFAIP3, a negative regulator of the NF-kB pathway, has been identified as being a commonly affected gene in MALT, LPL and NMZL, highlighting its potential role in pathogenesis.

Pure duplication 1q41‐qter: Further delineation of trisomy 1q syndromes

Several authors have attempted to characterize the partial 1q trisomy syndrome, reporting clinical features such as mental retardation, macrocephaly, large fontanels, prominent forehead, broad flat nasal bridge, high-arched palate, micro/retrognathia, low-set ears, and cardiac defects. However, defining the partial trisomy 1q syndrome is difficult, because it is a rare chromosomal abnormality and in most instances the trisomy 1q is combined with partial monosomy of another autosomal segment. We report on the clinical and molecular cytogenetic study of a patient who presents pure partial 1q duplication. This is the first case of pure duplication 1q41-qter in the literature.

Concurrent microdeletion and duplication of 22q11.2

Microduplication of 22q11.2 has been reported in fewer than 40 cases, all of them including the DiGeorge critical region (DGCR). We here present the characterization of a new duplication that does not include the DGCR. The duplication was initially found by multiplex ligation-dependent probe amplification analysis of 22q11.2 in a young girl with a concurrent deletion of the DGCR in 70% of her peripheral blood lymphocytes. Her phenotype included many of the features of the velocardiofacial syndrome, with velopharyngeal insufficiency, recurrent infections, learning and concentration problems as well as difficulties in social interactions. However, there were no congenital malformations, and her facial appearance was not typical for the syndrome. Further investigations included array comparative genomic hybridization (CGH) to size map the deletion/duplication and interphase fluorescent in situ hybridization to investigate mosaicism and the structure of the rearrangement. An identical duplication of this part of 22q11.2 has not been reported before, and the duplication itself seems to be associated with very mild or no symptoms. This study contributes to the growing knowledge regarding new deletions and duplications of 22q11.2, most of them mediated by the pre-disposing high number of low-copy repeats in the region.

A Case of Partial 14q- with Facial Features of Holoprosencephaly and Hydranencephaly

We report a rare case of facial features of holoprosencephaly associated with hydranencephaly, with a de novo proximal interstitial deletion of the long arm of chromosome 14, specifically, del(14)(q13q21). She was born at 37 weeks of gestation and transferred to our institution at 3 years of age. The patient had midline facial anomalies consisting of cleft palate, defective nasal septum, and hypotelorism, together with endocrine abnormalities such as diabetes insipidus and hypothyroidism. Cranial computed tomography revealed the near-total loss of all cerebral tissue, with a frontal part of the cerebral falx lacking. None of the few reports of holoprosencephaly with 14q- chromosomal abnormality describe holoprosencephaly in association with hydranencephaly. The partial deletion of chromosome 14, del(14)(q13q21), may underlie the association of facial features of holoprosencephaly and hydranencephaly.

Duplication/deletion mosaicism of the 7q(21.1 → 31.3) region

Mosaicism for structural aberrations is a rare event and the coexistence of a cell line with a duplication and another with a deletion of the same chromosome segment is even more infrequent. We report a boy with a 46,XY,del(7q)/46,XY,dup(7q) mosaicism. High-resolution cytogenetic analysis and fluorescent in situ hybridization (FISH) performed at birth showed a trisomy for region 7q21.1 to 7q31.3 in 90% of metaphases analyzed and monosomy for the same region in 10% of metaphases. At the age of 12 months, karyotype on peripheral blood and exfoliated urinary epithelial cells was 46,XY,dup(7)(q21.1q31.3) in all cells analyzed. The patient presented malformations and psychomotor retardation. His phenotype is compared with other previously case reports describing patients with an interstitial duplication of 7(q21 or q22 --> q31.3). Due to the absence of a normal cell line, we propose a post-zygotic origin of the abnormality during the first mitotic division and a progressive loss of the deleted cells during pre- and post-natal development by selective pressure. The patient described here emphasizes the possible existence of an undetectable cell line in patients previously diagnosed of pure partial 7q trisomy or monosomy to explain the great clinical variability between reported patients. We also describe the culture of urinary epithelial cells in order to perform cytogenetic analysis as a useful non-invasive method.