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Recurrent reciprocal deletions and duplications of 16p13.11: The deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant
  1. Femke D Hannes (femke.hannes{at}uz.kuleuven.ac.be)
  1. Catholic University of Leuven, Belgium
    1. Andrew J Sharp (andrew.sharp{at}medecine.unige.ch)
    1. University of Washington School of Medicine, United States
      1. Heather C Mefford (hmefford{at}u.washington.edu)
      1. University of Wahington School of Medicine, United States
        1. Thomy de Ravel (thomy.deravel{at}uzleuven.be)
        1. Catholic University of Leuven, Belgium
          1. Claudia A Ruivenkamp (c.ruivenkamp{at}lumc.nl)
          1. Leiden University Medical Center, Netherlands
            1. Martijn H Breuning (m.h.breuning{at}lumc.nl)
            1. Leiden University Medical Center, Netherlands
              1. Jean-Pierre Fryns (jean-pierre.fryns{at}med.kuleuven.be)
              1. Catholic University of Leuven, Belgium
                1. Koen Devriendt (koen.devriendt{at}med.kuleuven.be)
                1. Catholic University of Leuven, Belgium
                  1. Griet Van Buggenhout (griet.vanbuggenhout{at}uz.kuleuven.ac.be)
                  1. Catholic University of Leuven, Belgium
                    1. Annick Vogels (annick.vogels{at}uz.kuleuven.ac.be)
                    1. Catholic University of Leuven, Belgium
                      1. Helen H Stewart (helen.stewart{at}orh.nhs.uk)
                      1. Oxford Radcliffe Hospitals NHS Trust, Churchill Hospital, United Kingdom
                        1. Raoul C Hennekam (r.c.hennekam{at}amc.uva.nl)
                        1. Academic Medical Center, University of Amsterdam, Netherlands
                          1. Gregory M Cooper (coopergm{at}u.washington.edu)
                          1. University of Washington School of Medicine, United States
                            1. Regina Regan (regina{at}well.ox.ac.uk)
                            1. Wellcome Trust Centre for Human Genetics, United Kingdom
                              1. Samantha JL Knight (sknight{at}well.ox.ac.uk)
                              1. Wellcome Trust Centre for Human Genetics, United Kingdom
                                1. Evan E Eichler (eee{at}gs.washington.edu)
                                1. University of Washington School of Medicine, United States
                                  1. Joris R Vermeesch (joris.vermeesch{at}med.kuleuven.be)
                                  1. Catholic University of Leuven, Belgium

                                    Abstract

                                    Genomic disorders are frequently caused by non-allelic homologous recombination between segmental duplications. Chromosome 16 is especially rich in a chromosome 16 specific low copy repeat, termed LCR16. Our BAC array CGH screen of 1027 patients with mental retardation and/or multiple congenital anomalies (MR/MCA) detected 5 patients with deletions and 5 with apparently reciprocal duplications of 16p13 and covers 1.65 Mb, including 15 RefSeq genes. In addition, 3 atypical rearrangements overlapping or flanking this region were detected. Fine mapping by high resolution oligonucleotide arrays suggests that these deletions and duplications result from non-allelic homologous recombination (NAHR) between distinct LCR16 subunits with >99% sequence identity. Deletions and duplications were either de novo or inherited from unaffected parents. To determine whether these imbalances are associated with the MR/MCA phenotype or whether they might be benign variants, a population of 2014 normal controls was screened. The absence of deletions in the control population proves that 16p13.11 deletions are significantly associated with MR/MCA (p=0.0048). Despite phenotypic variability, common features were observed: 3 deletion patients presented with MR, microcephaly and epilepsy (2 of which had also short stature), while 2 other deletion carriers ascertained prenatally presented with cleft lip and midline defects. In contrast to its previous association with autism, the duplication appears to be a common variant in the population (5/1682, 0.29%). These findings demonstrate that deletions inherited from normal parents are likely causal for the patients' phenotype which causes a paradigm shift in (cyto)genetic counseling.

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