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Clinical Spectrum of SIX3-Associated Mutations in Holoprosencephaly: Correlation between Genotype, Phenotype, and Function.
  1. Felicitas Lacbawan
  1. NHGRI; State University of New York - Downstate, United States
    1. Benjamin D Solomon
    1. National Human Genome Research Institute, United States
      1. Erich Roessler
      1. National Human Genome Research Institute, United States
        1. Kenia El-Jaick
        1. National Human Genome Research Institute, United States
          1. Sabina Domené
          1. National Human Genome Research Institute, United States
            1. Jorge I Velez
            1. National Human Genome Research Institute, United States
              1. Nan Zhou
              1. National Human Genome Research Institute, United States
                1. Donald Hadley
                1. National Human Genome Research Institute, United States
                  1. Joan Z Balog
                  1. National Human Genome Research Institute, United States
                    1. Robert Long
                    1. National Human Genome Research Institute, United States
                      1. Alan Fryer
                      1. Royal Liverpool Children's Hospital, United Kingdom
                        1. Wendy Smith
                        1. Maine Medical Center, United Kingdom
                          1. Said Omar
                          1. Michigan State University College of Human Medicine, United States
                            1. Scott D McLean
                            1. San Antonio Military Medical Center, United States
                              1. Kate Clarkson
                              1. Greenwood Genetic Center, United States
                                1. Angie Lichty
                                1. Greenwood Genetic Center, United States
                                  1. Nancy J Clegg
                                  1. Texas Scottish Rite Hospital for Children, United States
                                    1. Mauricio R Delgado
                                    1. Texas Scottish Rite Hospital for Children, United States
                                      1. Eric Levey
                                      1. Kennedy Krieger Institute, United States
                                        1. Elaine Stashinko
                                        1. Kennedy Krieger Institute, United States
                                          1. Lorraine Potocki
                                          1. Baylor College of Medicine, United States
                                            1. Margot I Van Allen
                                            1. University of British Columbia Faculty of Medicine, Canada
                                              1. Jill Clayton-Smith
                                              1. St. Mary's Hospital, United Kingdom
                                                1. Dian Donnai
                                                1. St. Mary's Hospital, United Kingdom
                                                  1. Diana W Bianchi
                                                  1. Tuft's University School of Medicine, United States
                                                    1. Pétur B Juliusson
                                                    1. Haukeland University Hospital, Norway
                                                      1. Pål Rasmus Njølstad
                                                      1. Haukeland University Hospital; University of Bergen, Norway
                                                        1. Han G Brunner
                                                        1. Radboud University Nijmegen Medical Center, Netherlands
                                                          1. John C Carey
                                                          1. University of Utah Medical Center, United States
                                                            1. Ute Hehr
                                                            1. University of Regensburg, Germany
                                                              1. Jörg Müsebeck
                                                              1. University of Bremen, Germany
                                                                1. Peter F Wieacker
                                                                1. University of Munster, Germany
                                                                  1. Abeltje Polstra
                                                                  1. Academic Medical Centre, Amsterdam, Netherlands
                                                                    1. Raoul C M Hennekam
                                                                    1. Great Ormond Street Hospital for Children, United Kingdom
                                                                      1. Marie-Jose H van den Boogaard
                                                                      1. University Medical Centre Utrecht, Netherlands
                                                                        1. Arie van Haeringen
                                                                        1. Leiden University Medical Center, Netherlands
                                                                          1. Aimee Paulussen
                                                                          1. Academic Hospital Maastricht, Netherlands
                                                                            1. Jos Herbergs
                                                                            1. Academic Hospital Maastricht, Netherlands
                                                                              1. Constance T R M Schrander-Stumpel
                                                                              1. Academic Hospital Maastricht, Netherlands
                                                                                1. Andreas R Janecke
                                                                                1. Innsbruck Medical University, Austria
                                                                                  1. David Chitayat
                                                                                  1. Mt. Sinai Hospital, Canada
                                                                                    1. Jin Hahn
                                                                                    1. Stanford University, United States
                                                                                      1. Donna M McDonald-McGinn
                                                                                      1. University of Pennsylvania, United States
                                                                                        1. Elaine H Zackai
                                                                                        1. University of Pennsylvania, United States
                                                                                          1. William B Dobyns
                                                                                          1. University of Chicago, United States
                                                                                            1. Maximilian Muenke (mamuenke{at}mail.nih.gov)
                                                                                            1. National Human Genome Research Institute, United States

                                                                                              Abstract

                                                                                              Background: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. Among several important HPE mutational target genes, the transcription factor SIX3 encodes an early regulator of Shh, Wnt, Bmp and Nodal signaling expressed in the developing forebrain and eyes of all vertebrates.

                                                                                              Objective: To characterize genetic and clinical findings in patients with SIX3 mutations.

                                                                                              Methods: We test individuals with HPE and their family members for mutations in HPE-associated genes and analyze genetic and clinical findings, including additional cases found in the literature. We correlate results with a mutation-specific functional assay in zebrafish.

                                                                                              Results: In a cohort of patients (n≈800) with HPE, we detect SIX3 mutations in 4.7% of probands; we identify additional individuals through testing of relatives. We present data on 138 individuals, 59 of whom have not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of non-chromosomal, non-syndromic HPE. We find an over-representation of severe HPE among individuals whose mutations confer greater loss-of-function as measured through the functional zebrafish assay. The F:M ratio in this combined set of patients is 1.5:1 and maternal inheritance is almost twice as common as paternal. 14% of SIX3 mutations in probands occur de novo. There is a wide intra-familial clinical range of features and classical penetrance is estimated to be at least 62%.

                                                                                              Conclusions: Our data suggest that SIX3 mutations result in relatively severe HPE, and that there is a genotype-phenotype correlation revealed by functional studies using animal models.

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