Mutational spectrum of COH1 and clinical heterogeneity in Cohen syndrome
W Seifert, H C Hennies, Cologne Center for Genomics, Universität zu Köln, Köln, Germany
W Seifert, Faculty of Biology, Chemistry, and Pharmacy, Free University of Berlin, Germany
M Holder‐Espinasse, Hôpital Jeanne de Flandre, Génétique médicale, CHRU, Lille, France
S Spranger, Praxis für Humangenetik, Bremen, Germany
M Hoeltzenbein, Max Planck Institute for Molecular Genetics, Berlin, Germany
E Rossier, Department of Human Genetics, University of Ulm, Germany
H Dollfus, Centre de Référence pour les Affections Génétique Ophtalmologiques, Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
D Lacombe, Service de Génétique Médicale, Hôpital Pellegrin‐Enfants, Bordeaux, France
A Verloes, Unit of Clinical Genetics, Hôpital Robert Debré and INSERM U676, Paris, France
K H Chrzanowska, Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland
G H B Maegawa, D Chitayat, Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
D Kotzot, Division of Clinical Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Austria
D Huhle, Praxis für humangenetische Beratung und Diagnostik, Wetzlar, Germany
P Meinecke, Altonaer Kinderkrankenhaus, Hamburg, Germany
B Albrecht, Institut für Humangenetik, Universität Essen, Essen, Germany
I Mathijssen, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
B Leheup, Hôpital de Brabois, Service de Génétique, Nancy, France
K Raile, Department of Pediatric Endocrinology, University of Leipzig, Leipzig, Germany
D Horn, Institute of Medical Genetics, Charité, University Medicine of Berlin, Germany
Received November 28, 2005; Revised January 25, 2006; Accepted January 25, 2006.
Cohen syndrome (CS; MIM #216550) is an uncommon autosomal recessive disorder with variability in the clinical manifestations including psychomotor retardation, microcephaly, typical facial dysmorphism, progressive pigmentary retinopathy appearing at mid‐childhood, early onset and severe myopia, and intermittent neutropenia.1,2,3,4
The characteristic craniofacial appearance includes downwards slanting and wave shaped palpebral fissures, short philtrum, heavy eyebrows, thick hair, and prominent nasal base. Finnish patients present with a homogeneous phenotype as result of a specific allele. However, a broad clinical spectrum in non‐Finnish cases and the age dependent appearance of some clinical signs may contribute to a delay in making the diagnosis.
Recently, the CS phenotype was found to be associated with mutations in the gene COH1
in different populations.5,6,7,8COH1
maps to chromosome 8q22 and codes for various splice forms. It comprises up to 62 exons and its longest transcript is 14
093 nucleotides in length with an open reading frame of 4022 codons.5COH1
encodes a potential transmembrane protein presumably involved in vesicle mediated sorting and intracellular protein transport.5,9,10
The mouse homologue of COH1
is widely expressed in neurones of the postnatal and adult brain suggesting a role in neuronal differentiation.8
This suggests that COH1 primarily has a function in postmitotic cells, which may be the reason for the postnatal microcephaly seen in CS.8
Overall, more than 50 COH1 mutations have been reported in association with CS. Most are termination mutations and predicted to result in a null allele, while missense mutations and larger deletions are less common.
To determine the variability of the clinical manifestations and the spectrum of mutations associated with this condition we investigated 24 patients with CS from 16 families, with a wide range of geographical and ethnic origins.