Author
Affilliation
Abstract
Background: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain.
There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates. Objective: To characterise genetic and clinical findings in patients with SIX3 mutations.
Methods: Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed.
The results were correlated with a mutation-specific functional assay in zebrafish. Results: In a cohort of patients (n = 800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of nonchromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial 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, as shown by functional studies using animal models.
Publisher
BMJ Publishing Group
Citation
LACBAWAN, F. et al. Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function. Journal of Medical Genetics, v. 46, p. 389-398, 2009.
DOI
10.1136/jmg.2008.063818
ISSN
0022-2593
Notes
K. El-Jaick. Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Documento produzido em parceria ou por autor vinculado à Fiocruz, mas não consta a informação no documento.
1 Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; 2 Department of Pathology, State University of New York-Downstate Medical Center, Brooklyn, NY, USA; 3 Department of Clinical Genetics, Royal Liverpool Children’s Hospital (Alder Hey), Liverpool, UK; 4 Department of Genetics, Maine Medical Center, Portland, ME, USA; 5 Department of Neonatalogy, College of Human Medicine, Michigan State University, MI, USA; 6 Departments of Pediatrics and Genetics, San Antonio Military Medical Center, San Antonio, TX, USA; 7 Department of Clinical Genetics, Greenwood Genetic Center, Columbia, SC, USA; 8 Department of Neurology, Texas Scottish Rite Hospital for Children, University of Texas Southwestern Medical Center, Dallas, TX, USA; 9 Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD, USA; 10 Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA; 11 Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; 12 Academic Department of Medical Genetics and Regional Genetic Services, St Mary’s Hospital, University of Manchester, Manchester, UK; 13 Division of Genetics, Department of Pediatrics, Tufts University School of Medicine, Boston, MA, USA; 14 Department of Paediatrics, Haukeland University Hospital, Bergen, Norway; 15 Department of Clinical Medicine, University of Bergen, Bergen, Norway; 16 Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands; 17 Division of Medical Genetics, University of Utah Medical Center, Salt Lake City, UT, USA; 18 Department of Human Genetics, University of Regensburg, Regensburg, Germany; 19 Center for Human Genetics, University of Bremen, Bremen, Germany; 20 Institute of Human Genetics, University of Munster, Munster, Germany; 21 Department of Clinical Genetics, Academic Medical Center, Amsterdam, Netherlands; 22 Institute of Child Health, Great Ormond Street Hospital for Children, London, UK; 23 Department of Medical Genetics, University Medical Centre Utrecht, Netherlands; 24 Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands; 25 Department of Clinical Genetics, Academic Hospital Maastricht, Maastricht, Netherlands; 26 Division of Clinical Genetics, Innsbruck Medical University, Innsbruck, Austria; 27 Prenatal Diagnostics and Medical Genetics, Mt. Sinai Hospital, Toronto, ON, Canada; 28 Department of Neurology, Stanford University School of Medicine, Palo Alto, CA, USA; 29 Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; 30 Departments of Human Genetics, Neurology and Pediatrics, The University of Chicago, Chicago, IL, USA.
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