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Further delineation of the 15q13 microdeletion and duplication syndromes: A clinical spectrum varying from non-pathogenic to a severe outcome
  1. B W M van Bon (b.vanbon{at}antrg.umcn.nl)
  1. Radboud University Nijmegen Medical Centre, Netherlands
    1. H C Mefford (hmefford{at}u.washington.edu)
    1. Department of Genome Sciences, Radboud University Nijmegen Medical Centre, University of Washington, United States
      1. B Menten (bjorn.menten{at}ugent.be)
      1. Centre for Medical Genetics and Centre for Developmental Disorders, Ghent University Hospital, Belgium
        1. D A Koolen (d.koolen{at}antrg.umcn.nl)
        1. Radboud University Nijmegen Medical Centre, Netherlands
          1. A J Sharp (andrew.sharp{at}medecine.unige.ch)
          1. Department of Genetic Medicine and Development, University of Geneva Medical School 1211 Geneva, Switzerland
            1. W M Nillesen (w.nillesen{at}antrg.umcn.nl)
            1. Radboud University Nijmegen Medical Centre, Netherlands
              1. J W Innis (innis{at}umich.edu)
              1. Department of Human Genetics and Pediatrics, University of Michigan, Ann Arbor, United States
                1. T J L de Ravel (thomy.deravel{at}uz.kuleuven.ac.be)
                1. Centre for Human Genetics, University Hospital, Catholic University of Leuven, Leuven, Belgium
                  1. C L Mercer (catherine.mercer{at}suht.swest.nhs.uk)
                  1. Wessex Clinical Genetics Service, Southampton University Hospitals NHS Trust, Princess Anne Hospital, United Kingdom
                    1. M Fichera (mfichera{at}oasi.en.it)
                    1. Laboratory of Genetic Diagnosis, I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy
                      1. H Stewart (helen.stewart{at}orh.nhs.uk)
                      1. Churchill Hospital, Oxford, United Kingdom
                        1. L E Connell (lyndsey.connell{at}orh.nhs.uk)
                        1. Churchill Hospital, Oxford, United Kingdom
                          1. K Ounap (katrin.ounap{at}kliinikum.ee)
                          1. Institute of Molecular and Cell Biology, University of Tartu/Estonian Biocentre, Tartu, Estonia
                            1. K Lachlan
                            1. Wessex Clinical Genetics Service, Southampton University Hospitals NHS Trust, Princess Anne Hospital, United Kingdom
                              1. B Castle (bruce.castle{at}suht.swest.nhs.uk)
                              1. Wessex Clinical Genetics Service, Southampton University Hospitals NHS Trust, Princess Anne Hospital, United Kingdom
                                1. N Van der Aa (nathalie.van.der.aa{at}uza.be)
                                1. Department of Medical Genetics, University and University Hospital of Antwerp, Antwerp, Belgium
                                  1. C van Ravenswaaij (c.m.a.van.ravenswaaij{at}medgen.umcg.nl)
                                  1. University Medical Centre Groningen, Netherlands
                                    1. M A Nobrega (mnobrega{at}bsd.uchicago.edu)
                                    1. Department of Human Genetics, University of Chicago, Chicago, United States
                                      1. C Serra-Juhé (clara.serra{at}upf.edu)
                                      1. Genetics Unit, Universitat Pompeu Fabra, and U735 CIBERER, Barcelona, Spain
                                        1. I Simonic (ingrid.simonic{at}addenbrookes.nhs.uk)
                                        1. Department of Medical Genetics, Addenbrookes Hospital, Hills Road, Cambridge, United Kingdom
                                          1. N de Leeuw (n.deleeuw{at}antrg.umcn.nl)
                                          1. Radboud University Nijmegen Medical Centre, Netherlands
                                            1. R Pfundt (r.pfundt{at}antrg.umcn.nl)
                                            1. Radboud University Nijmegen Medical Centre, Netherlands
                                              1. E M Bongers (e.bongers{at}antrg.umcn.nl)
                                              1. Radboud University Nijmegen Medical Centre, Netherlands
                                                1. C Baker (c.baker{at}u.washington.edu)
                                                1. Department of Genome Sciences, University of Washington School of Medicine, United States
                                                  1. P Finnemore (patricia.finnemore{at}suht.swest.nhs.uk)
                                                  1. Wessex Clinical Genetics Service, Southampton University Hospitals NHS Trust, Princess Anne Hospital, United Kingdom
                                                    1. S Huang (shuwen.huang{at}salisbury.nhs.uk)
                                                    1. National Genetics Reference Laboratory (Wessex), United Kingdom
                                                      1. V K Maloney (viv.maloney{at}salisbury.nhs.uk)
                                                      1. Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, United Kingdom
                                                        1. J A Crolla (john.crolla{at}salisbury.nhs.uk)
                                                        1. Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, United Kingdom
                                                          1. M van Kalmthout (m.vankalmthout{at}cello-zorg.nl)
                                                          1. Radboud University Nijmegen Medical Centre, Netherlands
                                                            1. M Elia (melia{at}oasi.en.it)
                                                            1. Unit of Neurology and Clinical Neurophysiology, I.R.C.C.S. Associazione Oasi Maria Santis, Italy
                                                              1. G Vandeweyer (geert.vandeweyer2{at}ua.ac.be)
                                                              1. Department of Medical Genetics, University and University Hospital of Antwerp, Antwerp, Belgium
                                                                1. J P Fryns (jean-pierre.fryns{at}uz.kuleuven.ac.be)
                                                                1. Centre for Human Genetics, University Hospital, Catholic University of Leuven, Leuven, Belgium
                                                                  1. S Janssens (sandra.janssens{at}ugent.be)
                                                                  1. Centre for Medical Genetics and Centre for Developmental Disorders, Ghent University Hospital, Belgium
                                                                    1. N Foulds (nicola.foulds{at}suht.swest.nhs.uk)
                                                                    1. Wessex Clinical Genetics Service, Southampton University Hospitals NHS Trust, Princess Anne Hospital, United Kingdom
                                                                      1. S Reitano (sreitano{at}oasi.en.it)
                                                                      1. Unit of Pediatrics and Medical Genetics . I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy
                                                                        1. K Smith (kim.smith{at}orh.nhs.uk)
                                                                        1. Oxford Regional Cytogenetics Laboratory Oxford Radcliffe Hospitals NHS Trust, Churchill Hospital, United Kingdom
                                                                          1. S Parkel (sven.parkel{at}gmail.com)
                                                                          1. Institute of Molecular and Cell Biology, University of Tartu/Estonian Biocentre, Tartu, Estonia
                                                                            1. B Loeys (bart.loeys{at}ugent.be)
                                                                            1. Centre for Medical Genetics and Centre for Developmental Disorders, Ghent University Hospital, Belgium
                                                                              1. C G Woods (cw347{at}hermes.cam.ac.uk)
                                                                              1. Department of Medical Genetics, Addenbrookes Hospital, Hills Road, Cambridge, United Kingdom
                                                                                1. A Oostra (ann.oostra{at}cosgent.be)
                                                                                1. Centre for Medical Genetics and Centre for Developmental Disorders, Ghent University Hospital, Belgium
                                                                                  1. F Speleman (franki.speleman{at}ugent.be)
                                                                                  1. Centre for Medical Genetics and Centre for Developmental Disorders, Ghent University Hospital, Belgium
                                                                                    1. A C C Pereira (alexandre.pereira{at}incor.usp.br)
                                                                                    1. Heart Institute, University of São Paulo Medical School, São Paulo, Brazil
                                                                                      1. A Kurg (akurg{at}ebc.ee)
                                                                                      1. Institute of Molecular and Cell Biology, University of Tartu/Estonian Biocentre, Tartu, Estonia
                                                                                        1. Lionel Willatt (lionel.willatt{at}addenbrookes.nhs.uk)
                                                                                        1. Department of Medical Genetics, Addenbrookes Hospital, Hills Road, Cambridge, United Kingdom
                                                                                          1. S J L Knight (sknight{at}well.ox.ac.uk)
                                                                                          1. Oxford Partnership Comprehensive Biomedical Research Centre, The Wellcome Trust Centre for Human Gen, United Kingdom
                                                                                            1. J R Vermeesch (joris.vermeesch{at}uz.kuleuven.ac.be)
                                                                                            1. Centre for Human Genetics, University Hospital, Catholic University of Leuven, Leuven, Belgium
                                                                                              1. C Romano (cromano{at}oasi.en.it)
                                                                                              1. Unit of Pediatrics and Medical Genetics . I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy
                                                                                                1. J C Barber (john.barber{at}salisbury.nhs.uk)
                                                                                                1. Human Genetics Division, School of Medicine, Southampton University Hospitals NHS Trust, United Kingdom
                                                                                                  1. G Mortier (geert.mortier{at}ugent.be)
                                                                                                  1. Centre for Medical Genetics and Centre for Developmental Disorders, Ghent University Hospital, Belgium
                                                                                                    1. L A Perez-Jurado (luis.perez{at}upf.edu)
                                                                                                    1. Genetics Unit, Universitat Pompeu Fabra, and U735 CIBERER, Barcelona, Spain
                                                                                                      1. F Kooy (frank.kooy{at}ua.ac.be)
                                                                                                      1. Department of Medical Genetics, University and University Hospital of Antwerp, Belgium
                                                                                                        1. H G Brunner (h.brunner{at}antrg.umcn.nl)
                                                                                                        1. Radboud University Nijmegen Medical Centre, Netherlands
                                                                                                          1. E E Eichler (eee{at}gs.washington.edu)
                                                                                                          1. Howard Hughes Medical Institute, Seattle, WA, United States
                                                                                                            1. T Kleefstra (t.kleefstra{at}antrg.umcn.nl)
                                                                                                            1. Radboud University Nijmegen Medical Centre, Netherlands
                                                                                                              1. B B A de Vries (b.devries{at}antrg.umcn.nl)
                                                                                                              1. Radboud University Nijmegen Medical Centre, Netherlands

                                                                                                                Abstract

                                                                                                                Recurrent 15q13.3 microdeletions were recently identified with identical proximal (BP4) and distal (BP5) breakpoints and associated with mild to moderate mental retardation and epilepsy. To further assess the clinical implications of this novel 15q13.3 microdeletion syndrome, eighteen new probands with a deletion were molecularly and clinically characterised. In addition, we evaluated the characteristics of a family with a more proximal deletion between BP3 and BP4. Finally, four patients with a duplication in the BP3-BP4-BP5 region were included in this study to ascertain the clinical significance of duplications in this region. The 15q13.3 microdeletion in our series was associated with a highly variable intra- and inter-familial phenotype. At least eleven of the eighteen deletions identified were inherited. Moreover, seven of ten siblings from four different families also had this deletion: one had a mild developmental delay, four had only learning problems during childhood, but functioned well in daily life as adults, whereas the other two had no learning problems at all. In contrast to previous findings, seizures were not a common feature in our series (only two of seventeen living probands). Three patients with deletions had cardiac defects and deletion of the KLF13 gene, located in the critical region, may contribute to these abnormalities. The limited data from the single family with the more proximal BP3-BP4 deletion suggest this deletion may have little clinical significance. Patients with duplications of the BP3-BP4-BP5 region did not share a recognizable phenotype, but psychiatric disease was noted in two of four patients. Overall, our findings broaden the phenotypic spectrum associated with 15q13.3 deletions and suggest that, in some individuals, deletion of 15q13.3 is not sufficient to cause disease. The existence of microdeletion syndromes, associated with an unpredictable and variable phenotypic outcome, will pose the clinician with diagnostic difficulties and challenge the commonly used paradigm in the diagnostic setting that aberrations inherited from a phenotypically normal parent are usually without clinical consequences.

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