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Broader geographical spectrum of Cohen syndrome due to COH1 mutations
  1. G H Mochida1,2,
  2. A Rajab3,*,
  3. W Eyaid4,*,
  4. A Lu1,5,
  5. D Al-Nouri4,
  6. K Kosaki6,
  7. M Noruzinia7,
  8. P Sarda7,
  9. J Ishihara6,8,
  10. A Bodell1,
  11. K Apse1,
  12. C A Walsh1,5
  1. 1Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, and Department of Neurology, Harvard Medical School, Boston, MA, USA
  2. 2Pediatric Neurology Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
  3. 3Genetic Unit, DGHA, Ministry of Health, Muscat, Sultanate of Oman
  4. 4Department of Genetics and Paediatric Endocrinology, King Fahad National Guard Hospital, Riyadh, Saudi Arabia
  5. 5Program in Neuroscience, Harvard Medical School, Boston, MA, USA
  6. 6Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
  7. 7Department of Human Genetics, Arnaud de Villeneuve Hospital, Montpellier, France
  8. 8Department of Pediatrics, Yokohama Citizens Hospital, Yokohama, Japan
  1. Correspondence to:
 C A Walsh MD PhD
 Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, and Department of Neurology, Harvard Medical School, 4 Blackfan Circle, HIM 816, Boston, MA 02115, USA;

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Cohen syndrome (COH1: MIM 216550) is an autosomal recessive disorder, first described in 1973.1 Cardinal clinical features of Cohen syndrome include microcephaly, non-progressive mental retardation, characteristic facial features, neutropenia, and ophthalmologic findings.2 It is overrepresented in Finland, though cases have been reported worldwide.

The genetic locus for Cohen syndrome was mapped to chromosome 8q in several Finnish pedigrees.3,4 Recently, a novel gene, COH1, in this locus was shown to carry mutations in many patients with Cohen syndrome.5COH1 is a large gene, consisting of 62 exons and encoding a protein of 4022 amino acids, whose biological function is not known. So far all the patients with reported mutation in the COH1 gene are of Finnish or other northern European origin. Therefore it has not been known if the COH1 gene is responsible for those cases of Cohen syndrome outside northern Europe.

Here we report novel mutations in the COH1 gene in four non-Finnish (Omani, Saudi Arabian, Japanese, and French) pedigrees, demonstrating that COH1 mutations are responsible for Cohen syndrome in non-Finnish populations. Variable phenotypes among these patients supports the idea that non-Finnish Cohen syndrome due to COH1 mutations has a broader clinical spectrum than the Finnish subtype. We also perform the first expression analysis of the mouse COH1 homologue, in order to investigate the pathogenesis of microcephaly in Cohen syndrome.



Four pedigrees with a total of 11 affected children from a wide geographical distribution (Omani, Saudi Arabian, Japanese, and French) were enrolled into the study of COH1 mutations. The pedigree structures are shown in figure 1. The patients were identified as having features of Cohen syndrome according to the proposed diagnostic criteria.2,6 Clinical information of the four pedigrees is presented in table 1. We studied these pedigrees according to a study protocol …

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  • GHM is supported by the Charles H. Hood Foundation as a Medical Foundation Research Fellow, and by the William Randolph Hearst Fund. CAW is supported by grants from the National Institute of Neurological Disease and Stroke (2R37NS35129 and P01NS39404), the March of Dimes, and the McKnight Foundation.

  • Conflict of interest: none declared.

  • * These authors contributed equally to this work.