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      Autism and intellectual disability in a patient with two microdeletions in 6q16: a contiguous gene deletion syndrome?

      case-report

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          Abstract

          Background

          Copy number variations play a significant role in the aetiology of developmental disabilities including non-syndromic intellectual disability and autism.

          Case presentation

          We describe a 19-year old patient with intellectual disability and autism for whom chromosomal microarray (CMA) analysis showed the unusual finding of two de novo microdeletions in cis position on chromosome 6q16.1q16.2 and 6q16.3. The two deletions span 10 genes, including FBXL4, POU3F2, PRDM13, CCNC, COQ3 and GRIK2. We compared phenotypes of patients with similar deletions and looked at the involvement of the genes in neuronal networks in order to determine the pathogenicity of our patient’s deletions.

          Conclusions

          We suggest that both deletions on 6q are causing his disease phenotype since they harbour several genes which are implicated in pathways of neuronal development and function. Further studies regarding the interaction between PRDM13 and GRIK2 specifically may be interesting.

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          Most cited references32

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          The POU proteins Brn-2 and Oct-6 share important functions in Schwann cell development.

          The genetic hierarchy that controls myelination of peripheral nerves by Schwann cells includes the POU domain Oct-6/Scip/Tst-1and the zinc-finger Krox-20/Egr2 transcription factors. These pivotal transcription factors act to control the onset of myelination during development and tissue regeneration in adults following damage. In this report we demonstrate the involvement of a third transcription factor, the POU domain factor Brn-2. We show that Schwann cells express Brn-2 in a developmental profile similar to that of Oct-6 and that Brn-2 gene activation does not depend on Oct-6. Overexpression of Brn-2 in Oct-6-deficient Schwann cells, under control of the Oct-6 Schwann cell enhancer (SCE), results in partial rescue of the developmental delay phenotype, whereas compound disruption of both Brn-2 and Oct-6 results in a much more severe phenotype. Together these data strongly indicate that Brn-2 function largely overlaps with that of Oct-6 in driving the transition from promyelinating to myelinating Schwann cells.
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            Diagnostic genome profiling in mental retardation.

            Mental retardation (MR) occurs in 2%-3% of the general population. Conventional karyotyping has a resolution of 5-10 million bases and detects chromosomal alterations in approximately 5% of individuals with unexplained MR. The frequency of smaller submicroscopic chromosomal alterations in these patients is unknown. Novel molecular karyotyping methods, such as array-based comparative genomic hybridization (array CGH), can detect submicroscopic chromosome alterations at a resolution of 100 kb. In this study, 100 patients with unexplained MR were analyzed using array CGH for DNA copy-number changes by use of a novel tiling-resolution genomewide microarray containing 32,447 bacterial artificial clones. Alterations were validated by fluorescence in situ hybridization and/or multiplex ligation-dependent probe amplification, and parents were tested to determine de novo occurrence. Reproducible DNA copy-number changes were present in 97% of patients. The majority of these alterations were inherited from phenotypically normal parents, which reflects normal large-scale copy-number variation. In 10% of the patients, de novo alterations considered to be clinically relevant were found: seven deletions and three duplications. These alterations varied in size from 540 kb to 12 Mb and were scattered throughout the genome. Our results indicate that the diagnostic yield of this approach in the general population of patients with MR is at least twice as high as that of standard GTG-banded karyotyping.
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              Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features.

              The underlying causes of learning disability and dysmorphic features in many patients remain unidentified despite extensive investigation. Routine karyotype analysis is not sensitive enough to detect subtle chromosome rearrangements (less than 5 Mb). The presence of subtle DNA copy number changes was investigated by array-CGH in 50 patients with learning disability and dysmorphism, employing a DNA microarray constructed from large insert clones spaced at approximately 1 Mb intervals across the genome. Twelve copy number abnormalities were identified in 12 patients (24% of the total): seven deletions (six apparently de novo and one inherited from a phenotypically normal parent) and five duplications (one de novo and four inherited from phenotypically normal parents). Altered segments ranged in size from those involving a single clone to regions as large as 14 Mb. No recurrent deletion or duplication was identified within this cohort of patients. On the basis of these results, we anticipate that array-CGH will become a routine method of genome-wide screening for imbalanced rearrangements in children with learning disability.
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                Author and article information

                Contributors
                daniela.strunk@stud.unibas.ch
                peter.weber@ukbb.ch
                Benno.Roethlisberger@ksa.ch
                isabel.filges@usb.ch
                Journal
                Mol Cytogenet
                Mol Cytogenet
                Molecular Cytogenetics
                BioMed Central (London )
                1755-8166
                3 December 2016
                3 December 2016
                2016
                : 9
                : 88
                Affiliations
                [1 ]Medical Genetics, University Hospital Basel, Schönbeinstrasse 40, CH-4031 Basel, Switzerland
                [2 ]Division of Neuropediatrics and Developmental Pediatrics, University Children’s Hospital, Spitalstrasse 33, CH-4056 Basel, Switzerland
                [3 ]Medical Genetics, Department of Laboratory Medicine, Cantonal Hospital Aarau, Tellstrasse, CH-5001 Aarau, Switzerland
                [4 ]Medical Genetics, University Hospital Basel and University of Basel, Schönbeinstrasse 40, CH-4031 Basel, Switzerland
                Author information
                http://orcid.org/0000-0002-4813-7140
                Article
                299
                10.1186/s13039-016-0299-8
                5135825
                8ed12c6a-82b2-45f6-9dc2-0011c0831e5a
                © The Author(s). 2016

                Open AccessThis 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.

                History
                : 21 July 2016
                : 21 November 2016
                Categories
                Case Report
                Custom metadata
                © The Author(s) 2016

                Genetics
                autism,intellectual disability,6q16 deletion,grik2,prdm13
                Genetics
                autism, intellectual disability, 6q16 deletion, grik2, prdm13

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