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Clinical and Molecular Characterization of a De Novo 19P13

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Clinical and Molecular Characterization of a De Novo 19P13 Palumbo et al. Molecular Cytogenetics (2016) 9:40 DOI 10.1186/s13039-016-0252-x CASEREPORT Open Access Clinical and molecular characterization of a de novo 19p13.3 microdeletion Pietro Palumbo1, Orazio Palumbo1, Maria Pia Leone1,2, Raffaella Stallone1, Teresa Palladino1, Leopoldo Zelante1 and Massimo Carella1* Abstract Background: Structural rearrangements of chromosome 19p13.3 are a rare condition, and their phenotypic consequences remain not well defined, because of the variability of clinical manifestations. Increasing knowledge of new 19p13.3 microdeletion is useful to clarify the phenotypic variability observed in some patients. In a small number of recent papers, patients with intellectual disabilities, multiple congenital anomalies and microdeletion of the chromosome band 19p13.3 have been described. However, little is known about genes responsible for clinical features in patients carriers of 19p13.3 microdeletion; thus, increasing number of reported cases will be helpful to investigate the contribution of candidate genes, providing bases for future investigations. Case Presentation: Here, we report on a 10-years-old girl referred to our genetics clinic due to intellectual disability, attention deficit, behavioral and speech delay, hypotonia, facial dysmorphisms, eye anomalies and congenital malformations. Using an high resolution SNP array, we identified a de novo microdeletion of chromosome 19p13.3, resulting in the heterozygous loss of 27 RefSeq genes and a miRNA, partially overlapping with three others deletions already reported in literature, but extending downstream (centromeric) for additional 386 Kb. This chromosomal region includes 13 genes amongst of which we suggest for the first time the APC2, PLK5 and MBD3 genes as potential functional candidates for neurodevelopmental and behavioral phenotypes observed. Conclusions: Here we describe a patient with a 19p13.3 microdeletion that spans to the downstream chromosomal region with respect to the overlapping deletions previously reported in several other cases. The neurobehavioral features observed in our case has extended the phenotypic spectrum associated with the 19p13.3 microdeletion. New candidate genes are proposed for the neurobehavioral phenotype observed in our case. Keywords: 19p13.3 microdeletion, SNP-Array analysis, Intellectual disabilities Background its importance in several biological function [1] and, Copy number variations (CNVs) are recognized as therefore, even small aberrations on this chromosome consisting genetic causes or susceptibility factors for are likely to have clinical consequences. To date, with neurodevelopmental disorders (NDDs), dysmorphic syn- the widespread use of genome wide microarray technol- dromes and multiple congenital anomalies (MCAs). ogy, several cases of interstitial 19p13.3 microdeletion CNVs can arise on all chromosomes, and their clinical have been reported, and the increasing resolution of ana- manifestations depends on gene content, on the involve- lysis methods allowed the improvement of genotype- ment of imprinted regions and on the nature of the re- phenotype correlations. These observations highlighted arrangement; furthermore, the variety of phenotypes both common clinical features and phenotype variations may be due to several factors such as incomplete pene- among described patients, probably due to different size trance, variable expressivity and environmental factors. of the deletions and their gene content. Chromosome 19 has the highest gene density, indicating Moreover, some papers started to describe patients with intellectual disabilities (IDs) and MCAs associated * Correspondence: [email protected] with 19p13.3 microdeletions [2, 3], highlighting the 1Laboratorio di Genetica Medica, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy evidence that 19p13.3 microdeletion may cause these Full list of author information is available at the end of the article clinical conditions. In order to deeply investigate the © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Palumbo et al. Molecular Cytogenetics (2016) 9:40 Page 2 of 7 phenotype associated with 19p13.3 microdeletion, we I.Q. of 89 (Stanfod Binet scale) and a mental age of describe the clinical and molecular data of a patient car- 3 years and 10 months. At last clinical evaluation, per- rier of a 0.71 Mb de novo interstitial microdeletion of formed when she was 10 years old, the patient showed chromosome 19p13.3. Interestingly, the deletion identi- facial dysmorphisms such as prominent mandible and fied in our patient partially overlap with those already enlarged nasal root (Fig. 1), in association with mild reported in literature, and extend towards the proximal hypotonia, a hint of curvature of the trunk; a compre- (centromeric) end for further 386 Kb. This region in- hensive neuropsychiatric evaluation has also been per- cludes 13 genes and a miRNA, some of them seems to formed. The girl showed mild ID, with a greater be functional candidates for the clinical traits observed operating capacity of verbal thought than visual-motor in our patient. thought. If properly stimulated, the patient offers the best overall performance; she showed also graphomotor Case presentation delay, handling and grip difficulties. Regarding the Case report affective and relational behavior, the child was intro- The patient described herein, a 10-year-old girl, is the verted and showed attention deficit. About the commu- first child of healthy non-consanguineous parents, born nication and language area, the child showed speech after an uneventful pregnancy affected by ID, attention delay (dyslexia). Finally, audiological tests showed nor- deficit, behavioral and speech delay, hypotonia, facial mal hearing, and eye exams showed exotropia. dysmorphisms, eye anomalies. She also showed congeni- tal malformations such as cerebral anomaly and forward Results anus. Her birth weight was 3,450 g (50th centile), length SNP-array analysis of the patient revealed a heterozy- was 50,7 cm (50th centile), and head circumference was gous deletion involving chromosome 19p13.3. The de- 34 cm (25-50th centile). The Apgar score was 9/9. Since leted region was 710 Kb in size and covered by 159 SNP the birth, the child has been subjected to a series of array probes. The proximal breakpoint (telomeric) was medical tests that revealed a complex clinical picture, located between the last present probe CN_780351 such as a brain ultrasound that showed the presence of (1,118,914 bp) and the first deleted probe SNP_A- a slightly wider left ventricle. Furthermore, the presence 8630732 (1,120,329 bp), while the distal breakpoint of further forward anus relative to the sphincter floor (centromeric) was located between the last deleted probe was observed, so she was subsequently subjected to elec- CN_782662 (1,829,934 bp) and the first present probe tro stimulation and submitted to surgery for the removal SNP_A-1937744 (1,837,061 bp) (USCS Genome Browser of vegetation skin. At 30 days visit, a cranial ultrasound build February 2009 hg19). Consequently, the maximum showed a slightly dilated left ventricle, while there were size of the deletion is 718 Kb while the minimum size is not cardiologic alterations or skeletal anomalies. A brain 710 Kb. The subsequent microarray analysis of the pa- MRI (Magnetic Resonance Imaging) confirm the pres- tient’s parents, by using the same platform, revealed nor- ence of a wider left ventricle. Standard karyotype was mal chromosomes 19 in both of them, indicating a de normal, as well as X-Fragile test. The neuropsychiatric novo deletion in the child (Fig. 2a). No additional rare evaluation performed at the age of 4.7 years showed an CNVs were detected in her genome. Fig. 1 Facial phenotypes (frontal and lateral view) of the patient described in detail in the text Palumbo et al. Molecular Cytogenetics (2016) 9:40 Page 3 of 7 Fig. 2 a Microarray-based copy number analysis performed with the Affymetrix Genome Wide Human SNP 6.0 array and visualized using the Affy- metrix Genotyping Console Browser. Copy number state of each probe is drawn along chromosome 19 from 0 to 7,000,000 bp. The upper panel represents the copy number state of the proband, the middle panel the father and the lower panel the mother. Values of Y-axis indicate the in- ferred copy number according to probe intensities. Red bar is the deleted region identified in the patient. b Localization of overlapping deletions identified in our patient and in patients already described in literature According to the International System for Human hypotonia and MCAs carriers of a de novo 19p13.3 Cytogenetic Nomenclature (ISCN 2013), the molecular interstitial microdeletion, 0.71 Mb in size, identified by karyotype of the patient was arr[hg19]19p13.3(1,118, SNP-array analysis. To date, only three other cases with 914x2,1,120,328-1,829,934x1,1,837,061x2)dn. This re- overlapping rearrangement, similar in size and chromo- arrangement was
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