Allelic Heterogeneity in the COH1 Gene Explains Clinical Variabilityin Cohen Syndrome
Open accessAbstract
Cohen syndrome is a rare autosomal recessive disorder with a variable clinical picture mainly characterized by developmental delay, mental retardation, microcephaly, typical facial dysmorphism, progressive pigmentary retinopathy, severe myopia, and intermittent neutropenia. A Cohen syndrome locus was mapped to chromosome 8q22 in Finnish patients, and, recently, mutations in the gene COH1 were reported in patients with Cohen syndrome from Finland and other parts of northern and western Europe. Here, we describe clinical and molecular findings in 20 patients with Cohen syndrome from 12 families, originating from Brazil, Germany, Lebanon, Oman, Poland, and Turkey. All patients were homozygous or compound heterozygous for mutations in COH1. We identified a total of 17 novel mutations, mostly resulting in premature termination codons. The clinical presentation was highly variable. Developmental delay of varying degree, early-onset myopia, joint laxity, and facial dysmorphism were the only features present in all patients; however, retinopathy at school age, microcephaly, and neutropenia are not requisite symptoms of Cohen syndrome. The identification of novel mutations in COH1 in an ethnically diverse group of patients demonstrates extensive allelic heterogeneity and explains the intriguing clinical variability in Cohen syndrome.
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One consanguineous family had a single affected child homozygous for a rare VPS13B p.S824A missense variant; the proband had some but not all features of Cohen syndrome, including autism, mild facial dysmorphism, and joint laxity, consistent with mild previously reported versions.
“Finally, in another consanguineous family, the single affected child was homozygous for a rare missense variant (p.S824A) in VPS13B (Table 1B; Figure S4). The proband had in retrospect some but not all features of Cohen syndrome (autism with mild facial dysmorphism and joint laxity), consistent with mild versions reported previously (Hennies et al., 2004).”
From Using Whole-Exome Sequencing to Identify Inherited Causes of Autism (2013) · cites this paper as Hennies et al., 2004
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- Authors
- Hennies, H. C., Rauch, A., Seifert, W., Schumi, C., Moser, E., Al-Taji, E., Tariverdian, G., Chrzanowska, K. H., Krajewska-Walasek, M., Rajab, A., Giugliani, R., Neumann, T. E., Eckl, K. M., Karbasiyan, M., Reis, A., & Horn, D.
- Affiliations
- Max Delbrück Center (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of Vienna (AT)
- Heidelberg University (DE)
- Ministry of Health (OM)
- Hospital de Clínicas de Porto Alegre (BR)
- University of Münster (DE)
- Charité – Universitätsmedizin Berlin (DE)
- Corresponding author
- Horn, Denise
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2004-07
- Volume
- 75
- Issue
- 1
- Pages
- 138-145
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC1181997
- OpenAlex
- W1970564587
- Cited by
- 90
- References
- 22
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 4 · 2023: 1 · 2022: 5 · 2021: 3 · 2020: 6 · 2019: 5 · 2018: 5 · 2017: 2 · 2015: 2 · 2014: 3 · 2013: 4 · 2012: 5
- FWCI
- 3.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by-nc-nd)
- Edge Hill University Research Information Repository (Edge Hill University) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- Cohen syndrome, allelic heterogeneity, clinical heterogeneity, novel mutations, premature stop codon, compound heterozygosity, autosomal recessive disorder, developmental delay, myopia, facial dysmorphism, neutropenia, retinopathy, microcephaly
- MeSH terms
- Abnormalities, Multiple, Adolescent, Adult, Child, Developmental Disabilities, Child, Preschool, Chromosomes, Human, Pair 8, Female, Gene Frequency, Genotype, Humans, Male, Membrane Proteins, Intellectual Disability, Microcephaly, Mutation, Pedigree, Phylogeny, Syndrome, Genetic Variation, Microsatellite Repeats, Craniofacial Abnormalities, Vesicular Transport Proteins
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