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J Med Genet 49:713-720 doi:10.1136/jmedgenet-2012-101016
  • Developmental defects
  • Original article

Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome

  1. Tania Attié-Bitach1,2,5
  1. 1INSERM U-781, Hôpital Necker-Enfants Malades, Paris, France
  2. 2Université Paris Descartes, Paris Sorbonne Cité, Paris, France
  3. 3Department of Pediatric Genetics, Amrita Institute of Medical Sciences, Kerala, India
  4. 4Service d'Anatomie Pathologique, CHU Dijon, Dijon, France
  5. 5Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France
  6. 6Molecular Medicine Unit, University College London (UCL) Institute of Child Health, London, UK
  7. 7Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland
  8. 8Service de Gynécologie Obstétrique, Hôpital Necker Enfants Malades, AP-HP, Paris, France
  9. 9Department of Radiology, Amrita Institute of Medical Sciences, Kerala, India
  10. 10Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, Dijon, France
  11. 11EA 4271 GAD, IFR Santé – STIC, Université de Bourgogne, France
  12. 12Service de Radiologie Pédiatrique et INSERM U1000, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
  1. Correspondence to Professor Tania Attie-Bitach, Département de Génétique et Unité INSERM U-781, Hôpital Necker-Enfants Malades, 75015 Paris, France; tania.attie{at}inserm.fr
  • Received 29 April 2012
  • Accepted 21 September 2012

Abstract

Background Acrocallosal syndrome (ACLS) is a rare recessive disorder characterised by corpus callosum agenesis or hypoplasia, craniofacial dysmorphism, duplication of the hallux, postaxial polydactyly, and severe mental retardation. Recently, we identified mutations in KIF7, a key component of the Sonic hedgehog pathway, as being responsible for this syndrome.

Methods We sequenced KIF7 in five suspected ACLS cases, one fetus and four patients, based on facial dysmorphism and brain anomalies.

Results Seven mutations were identified at the KIF7 locus in these five cases, six of which are novel. We describe the first four compound heterozygous cases. In all patients, the diagnosis was suspected based on the craniofacial features, despite the absence of corpus callosum anomaly in one and of polydactyly in another. Hallux duplication was absent in 4/5 cases.

Conclusions These results show that ACLS has a variable expressivity and can be diagnosed even in the absence of the two major features, namely polydactyly or agenesis or hypoplasia of the corpus callosum. Facial dysmorphism with hypertelorism and prominent forehead in all the cases, as well as vermis dysgenesis with brainstem anomalies (molar tooth sign), strongly indicated the diagnosis. KIF7 should be tested in less typical patients in whom craniofacial features are suggestive of ACLS.