Clinical spectrum of SIX3-associated mutations in holoprosencephaly: Correlation between genotype, phenotype and function

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.Fil: Lacbawan, F.. Suny Downstate Medical Center; Estados Unidos. National Human Genome Research Institute; Estados UnidosFil: Solomon, B. D.. National Human Genome Research Institute; Estados UnidosFil: Roessler, E.. National Human Genome Research Institute; Estados UnidosFil: El-Jaick, K.. National Human Genome Research Institute; Estados UnidosFil: Domene, Sabina. National Human Genome Research Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Vélez, J. I.. National Human Genome Research Institute; Estados UnidosFil: Zhou, N.. National Human Genome Research Institute; Estados UnidosFil: Hadley, D.. National Human Genome Research Institute; Estados UnidosFil: Balog, J. Z.. National Human Genome Research Institute; Estados UnidosFil: Long, R.. National Human Genome Research Institute; Estados UnidosFil: Fryer, A.. Royal Liverpool Children's Hospital; Estados UnidosFil: Smith, W.. Maine Medical Center; Estados UnidosFil: Omar, S.. Michigan State University; Estados UnidosFil: McLean, S. D.. San Antonio Military Medical Center; Estados UnidosFil: Clarkson, K.. Greenwood Genetics Center; Estados UnidosFil: Lichty, A.. Greenwood Genetics Center; Estados UnidosFil: Clegg, N. J.. Ut Southwestern Medical School; Estados UnidosFil: Delgado, M. R.. Ut Southwestern Medical School; Estados UnidosFil: Levey, E.. University Johns Hopkins; Estados UnidosFil: Stashinko, E.. University Johns Hopkins; Estados UnidosFil: Potocki, L.. Texas Children's Hospital Houston; Estados UnidosFil: VanAllen, M. I.. University of British Columbia; CanadáFil: Clayton Smith, J.. University of Manchester; Reino UnidoFil: Donnai, D.. University of Manchester; Reino UnidoFil: Bianchi, D. W.. Tufts University School Of Medicine; Estados UnidosFil: Juliusson, P. B.. Helse Bergen Haukeland University Hospital; NoruegaFil: Njølstad, P. R.. University Of Bergen; Noruega. Helse Bergen Haukeland University Hospital; NoruegaFil: Brunner, H. G.. Radboud University Nijmegen Medical Centre; Países BajosFil: Carey, J. C.. University Of Utah Health Sciences; Estados UnidosFil: Hehr, U.. Universitat Regensburg; AlemaniaFil: Müsebeck, J.. Universitat Bremen; AlemaniaFil: Wieacker, P. F.. Westfalische Wilhelms Universitat; AlemaniaFil: Postra, A.. University of Amsterdam; Países BajosFil: Hennekam, R. C. M.. Institute Of Child Health; Reino UnidoFil: Van Den Boogaard, M. J. H.. University Medical Center Utrecht; Países BajosFil: Van Haeringen, A.. Leiden University Medical Center; Países BajosFil: Paulussen, A.. Academic Hospital Maastricht; Países BajosFil: Herbergs, J.. Academic Hospital Maastricht; Países BajosFil: Schrander Stumpel, C. T. R. M.. Academic Hospital Maastricht; Países BajosFil: Janecke, A. R.. Medizinische Universitat Innsbruck; AustriaFil: Chitayat, D.. Mount Sinai Hospital Of University Of Toronto; CanadáFil: Hahn, J.. Stanford University School Of Medicine; Estados UnidosFil: McDonald McGinn, D. M.. The Children's Hospital Of Philadelphia; Estados UnidosFil: Zackai, E.H.. The Children's Hospital Of Philadelphia; Estados UnidosFil: Dobyns, W. B.. University of Chicago; Estados UnidosFil: Muenke, Maximilian. National Human Genome Research Institute; Estados Unido