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SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenic mechanism
  1. W Borozdin1,
  2. D Boehm2,
  3. M Leipoldt1,
  4. C Wilhelm1,
  5. W Reardon3,
  6. J Clayton-Smith4,
  7. K Becker5,
  8. H Mühlendyck6,
  9. R Winter7,
  10. Ö Giray8,
  11. F Silan9,
  12. J Kohlhase1
  1. 1Institut für Humangenetik und Anthropologie, Universität Freiburg, Freiburg, Germany
  2. 2Institut für Humangenetik, Universität Göttingen, Göttingen, Germany
  3. 3National Centre for Medical Genetics, Our Lady’s Hospital for Sick Children, Crumlin, Dublin, Republic of Ireland
  4. 4Department of Clinical Genetics, St Mary’s Hospital, Manchester, UK
  5. 5Kennedy-Galton Centre, Northwick Park Hospital, Harrow, UK
  6. 6Department of Neuro-ophthalmology, University of Göttingen, Göttingen, Germany
  7. 7Institute for Child Health, University College London Medical School, London, UK
  8. 8Department of Paediatrics, Division of Genetics, Dokuz Eylul University, Izmir, Turkey
  9. 9Medical Biology and Genetics Department, Abant Izzet Baysal University Medical School, Duzce, Turkey
  1. Correspondence to:
 Dr J Kohlhase
 Institut für Humangenetik und Anthropologie, Universität Freiburg, Breisacher Str 33, D-79106 Freiburg, Germany;

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The SALL genes, similar to the Drosophila gene spalt,1 probably encode zinc-finger transcription factors. In humans, four such genes have been identified to date. Mutations at SALL1 on chromosome 16q12.1 have been associated with Townes-Brocks syndrome and related phenotypes,2,3 and mutations at SALL4 have been shown to be causative in patients with Okihiro/Duane-radial ray syndrome (OMIM No 607323).4,5SALL26 and SALL37 have not yet been associated with human disease.

We previously reported frameshift and nonsense mutations in SALL4 in five of eight families segregating the Okihiro syndrome phenotype.5 A further report4 identified two frameshift mutations and one nonsense mutation in three affected kindreds, including the family reported by Okihiro et al.8 In a recent study of patients with the clinical diagnosis of Holt-Oram syndrome (OMIM No 142900), one additional frameshift mutation was reported from a family which turned out to have Okihiro syndrome rather than Holt-Oram syndrome.9 Furthermore, we reported three novel and one already identified SALL4 mutations in patients originally diagnosed as either Holt-Oram syndrome (later revised as Okihiro syndrome on the basis of the observation of a Duane anomaly in at least one of the affected family members in each family), acro-renal-ocular syndrome (OMIM No 102490), and Holt-Oram syndrome versus thalidomide embryopathy.10

In contrast to the report of Al-Baradie et al,4 we found no SALL4 mutations in three of eight families with clear Okihiro syndrome, the diagnosis being based on the presence of radial ray malformations in combination with a Duane anomaly. This finding led to the assumption that either mutations of another yet unidentified locus were responsible for the phenotype in those families, or that mutations within the SALL4 gene were present but outside the region analysed (that is, they were …

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  • Conflicts of interest: none declared