Elisa Tassano

MicroRNA-125b-1 and BLID upregulation resulting from a novel IGH translocation in childhood B-Cell precursor acute lymphoblastic leukemia.

Chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus are common abnormalities in mature B‐cell neoplasms. Recent findings have also revealed their significant role in B‐cell precursor acute lymphoblastic leukemia. As a rule, IGH translocations generate transcriptional activation of the oncogene localized in the proximity of the breakpoint. In this study, we describe a pediatric case of B‐cell precursor acute lymphoblastic leukemia showing microRNA‐125b‐1 (MIR125B1) and BLID gene overexpression, resulting from a novel t(11;14)(q24.1;q32) translocation involving IGH. This is the first report describing the upregulation of a microRNA due to its juxtaposition to protein‐coding gene regulatory elements and the overexpression of two neighboring genes as a consequence of transcriptional enhancers localized in the vicinity of the IGH gene.

Identification of a rare 17p13.3 duplication including the BHLHA9 and YWHAE genes in a family with developmental delay and behavioural problems.

BackgroundDeletions and duplications of the PAFAH1B1 and YWHAE genes in 17p13.3 are associated with different clinical phenotypes. In particular, deletion of PAFAH1B1 causes isolated lissencephaly while deletions involving both PAFAH1B1 and YWHAE cause Miller-Dieker syndrome. Isolated duplications of PAFAH1B1 have been associated with mild developmental delay and hypotonia, while isolated duplications of YWHAE have been associated with autism. In particular, different dysmorphic features associated with PAFAH1B1 or YWHAE duplication have suggested the need to classify the patient clinical features in two groups according to which gene is involved in the chromosomal duplication.MethodsWe analyze the proband and his family by classical cytogenetic and array-CGH analyses. The putative rearrangement was confirmed by fluorescence in situ hybridization.ResultsWe have identified a family segregating a 17p13.3 duplication extending 329.5 kilobases by FISH and array-CGH involving the YWHAE gene, but not PAFAH1B1, affected by a mild dysmorphic phenotype with associated autism and mental retardation. We propose that BHLHA9, YWHAE, and CRK genes contribute to the phenotype of our patient. The small chromosomal duplication was inherited from his mother who was affected by a bipolar and borderline disorder and was alcohol addicted.ConclusionsWe report an additional familial case of small 17p13.3 chromosomal duplication including only BHLHA9, YWHAE, and CRK genes. Our observation and further cases with similar microduplications are expected to be diagnosed, and will help better characterise the clinical spectrum of phenotypes associated with 17p13.3 microduplications.

Interstitial 7q31.1 copy number variations disrupting IMMP2L gene are associated with a wide spectrum of neurodevelopmental disorders

BackgroundSince the introduction of the array-CGH technique in the diagnostic workup of mental retardation, new recurrent copy number variations and novel microdeletion/microduplication syndromes were identified. These findings suggest that some genomic disorders have high penetrance but a wide range of phenotypic severity.ResultsWe present the clinical and molecular description of four unrelated patients affected by neurodevelopmental disorders and overlapping 7q31.1 microdeletion/microduplication, identified by array-CGH and involving only part of the IMMP2L gene.ConclusionIMMP2L encodes an inner mitochondrial membrane protease-like protein, which is required for processing of cytochromes inside mitochondria. Numerous studies reported that this gene is implicated in behavioural disorders such as autistic spectrum disorders, attention-deficit hyperactivity disorders, and Gilles de la Tourette syndrome. We discuss the functions of the gene suggesting that IMMP2L may act as risk factor for neurological disease.

De novo deletion of chromosome 11q12.3 in monozygotic twins affected by Poland Syndrome

BackgroundPoland Syndrome (PS) is a rare disorder characterized by hypoplasia/aplasia of the pectoralis major muscle, variably associated with thoracic and upper limb anomalies. Familial recurrence has been reported indicating that PS could have a genetic basis, though the genetic mechanisms underlying PS development are still unknown.Case presentationHere we describe a couple of monozygotic (MZ) twin girls, both presenting with Poland Syndrome. They carry a de novo heterozygous 126 Kbp deletion at chromosome 11q12.3 involving 5 genes, four of which, namely HRASLS5, RARRES3, HRASLS2, and PLA2G16, encode proteins that regulate cellular growth, differentiation, and apoptosis, mainly through Ras-mediated signaling pathways.ConclusionsPhenotype concordance between the monozygotic twin probands provides evidence supporting the genetic control of PS. As genes controlling cell growth and differentiation may be related to morphological defects originating during development, we postulate that the observed chromosome deletion could be causative of the phenotype observed in the twin girls and the deleted genes could play a role in PS development.

Differential diagnosis of lipoma‐like lipoblastoma

Lipoblastomas are rare benign tumors of white fatty tissue that occur primarily in young children. Occasionally, heterogeneity of morphological appearance and histological overlap with other lipogenic tumors are described. In such cases fluorescence in situ hybridization (FISH) analysis of PLAG1, a gene specifically rearranged in lipoblastoma, is necessary to prevent misdiagnosis. We present a case of lipoblastoma arising in an atypical site with histological features characteristic of lipoma. The correct diagnosis was made possible on cytogenetic grounds through the identification of the characteristic PLAG1‐HAS2 fusion gene, thus allowing an appropriate clinical approach. Pediatr Blood Cancer 2009;52:132–134.

Clonal chromosome anomalies and propensity to myeloid malignancies in congenital amegakaryocytic thrombocytopenia (OMIM 604498)

Congenital amegakaryocytic thrombocytopenia (CAMT, OMIM 604498) is an autosomal recessive disorder characterized by absent or reduced number of megakaryocytes in the bone marrow (BM) since birth, elevated serum levels of thrombopoietin (TPO), and very low platelet count. Prognosis of CAMT patients

De novo 13q31.1–q32.1 interstitial deletion encompassing the miR-17-92 cluster in a patient with Feingold syndrome-2†‡

Partial deletions of the long arm of chromosome 13 are relatively rare and they produce a wide phenotypic spectrum related to the length andpositionof thedeleted segment. Several literature studies have reported a correlation between 13q deletion intervals and specific clinical features. Although genotype–phenotype correlations are still awaiting a definition, a pattern of common dysmorphic features, and malformations have emerged [Ballarati et al., 2007; Kirchhoff et al., 2009; Balci et al., 2010]. Brown et al. [1995] proposed division 13q deletions into three groups: interstitial deletions not extending into 13q32; deletions including at least part of 13q32, and distal deletions involving 13q33–q34. Based only on conventional cytogenetic and FISH, they defined 13q32 as the critical band for the most severe phenotype, showing that monosomy of 13q32 is related to the development of severe intellectual disability and growth delay, microcephaly, and major malformations including the brain and digits. A mosaic deletion of 13q31– 32.3, encompassing the critical region, in a boy with hand malformations and partial growth hormone deficiency was reported [Amor et al., 2005]. Recently, the identification of germline hemizygous deletion ofMIR17HG locus, mapping in 13q31.3, has been described in two individuals with microcephaly, short stature, and digital anomalies (Feingold syndrome-2,MIM614326) [dePontual et al., 2011]. Here, we report on the clinical and molecular findings in a 16-month-old with growth and psychomotor retardation, microcephaly, and hand and foot malformations presenting a 16.23Mb interstitial deletion of 13q31.1–q32.1. The patient, a girl, was the second child born to nonconsanguineous healthy parents. There was no history of hereditary disorders in her family. Cesarean was performed at 39.5 weeks of gestation. Birth weight was 2,450 g (<3rd centile), length 43 cm (<3rd centile), head circumference 32 cm. Apgar scores were 8 and 9 at 1 and 5min, respectively. From the first months of life she showed growth failure and developmental delay. She came to our observation at the age of 16 months; on physical examination weight was 7.1 kg ( 5.4 SDS), height 67 cm ( 3.9 SDS), BMI 15.59 ( 1.2 SDS), head circumference 43 cm ( 2.3 SDS), and genetic target 156.5 cm ( 1 SDS). Mild facial dysmorphisms (epicanthus and short palpebral fissures) and digital abnormalities (brachymesophalangy and clinodactyly of fifth finger and third toe, bilaterally) were also present. Neurologic examination showed mild generalized hypotonia. She was able to stand with support but not to walk. Language was also delayed with no spoken word. Laboratory examinations, including routine blood and urine tests, were normal. Conventional chromosome analysis demonstrated an interstitial deletionof chromosome13 in thepatient and anormal karyotype in her parents. A 180K oligoarray CGH performed on DNA from peripheral blood lymphocytes led to the identification of an interstitial deletion encompassing 16.23Mb in 13q31.1–q32.1 (centromeric breakpoint: 80,249,939–80,267,352 bp, telomeric breakpoint: 96,501,445–96,505,542 bp). The aberration can be cytogenetically described as 46,XX,del(13)(q31.1q32.1) (Fig. 1A). Array-CGH analysis of her parents was normal. The deleted region harbors 17 known protein-coding genes according to GRCh 37/ hg19 assembly (http://genome.cse.ucsc.edu/), but we focus our attention primarily on 13q31.3 bandwhich includes a polycistronic miRNA cluster, MIR17HG locus (MIM 609415) (Fig. 1B). The importance of miRNAs in normal cellular development and

Genotype-Phenotype Correlation of 2q37 Deletions Including NPPC Gene Associated with Skeletal Malformations

Coordinated bone growth is controlled by numerous mechanisms which are only partially understood because of the involvement of many hormones and local regulators. The C-type Natriuretic Peptide (CNP), encoded by NPPC gene located on chromosome 2q37.1, is a molecule that regulates endochondral ossification of the cartilaginous growth plate and influences longitudinal bone growth. Two independent studies have described three patients with a Marfan-like phenotype presenting a de novo balanced translocation involving the same chromosomal region 2q37.1 and overexpression of NPPC. We report on two partially overlapping interstitial 2q37 deletions identified by array CGH. The two patients showed opposite phenotypes characterized by short stature and skeletal overgrowth, respectively. The patient with short stature presented a 2q37 deletion causing the loss of one copy of the NPPC gene and the truncation of the DIS3L2 gene with normal CNP plasma concentration. The deletion identified in the patient with a Marfan-like phenotype interrupted the DIS3L2 gene without involving the NPPC gene. In addition, a strongly elevated CNP plasma concentration was found in this patient. A possible role of NPPC as causative of the two opposite phenotypes is discussed in this study.

Clinical and molecular characterization of a patient with interstitial 6q21q22.1 deletion.

BackgroundInterstitial 6q deletions, involving the 6q15q25 chromosomal region, are rare events characterized by variable phenotypes and no clear karyotype/phenotype correlation has been determined yet.ResultsWe present a child with a 6q21q22.1 deletion, characterized by array-CGH, associated with developmental delay, intellectual disability, microcephaly, facial dysmorphisms, skeletal, muscle, and brain anomalies.DiscussionIn our patient, the 6q21q22.1 deleted region contains ten genes (TRAF3IP2, FYN, WISP3, TUBE1, LAMA4, MARCKS, HDAC2, HS3ST5, FRK, COL10A1) and two desert gene regions. We discuss here if these genes had some role in determining the phenotype of our patient in order to establish a possible karyotype/phenotype correlation.

Cytogenetic characterization of a fibrous hamartoma of infancy with complex translocations.

Fibrous hamartoma of infancy is a rare pediatric superficial soft tissue lesion. The diagnosis depends on microscopic examination. Conventional cytogenetic analysis has been reported in only two previous cases, which showed apparently balanced translocations with involvement of different chromosomes. In the present study, we used multicolor fluorescence in situ hybridization to characterize a case of fibrous hamartoma of infancy that had arisen in an unusual location. This molecular analysis revealed complex structural rearrangements involving chromosomes 1, 2, 4, and 17.