Broader geographical spectrum of Cohen syndrome due to COH1 mutations.

C ohen syndrome (COH1: MIM 216550) is an autosomal recessive disorder, first described in 1973. Cardinal clinical features of Cohen syndrome include microcephaly, non-progressive mental retardation, characteristic facial features, neutropenia, and ophthalmologic findings. 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. 4 Recently, a novel gene, COH1, in this locus was shown to carry mutations in many patients with Cohen syndrome. COH1 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.