Allelic heterogeneity in the COH1 gene explains clinical variability in Cohen syndrome.
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.
Hennies
Hans Christian
HC
Gene Mapping Centre and Department of Molecular Genetics, Max Delbrück Centre for Molecular Medicine, Berlin, Germany.
Rauch
Anita
A
Seifert
Wenke
W
Schumi
Christian
C
Moser
Elisabeth
E
Al-Taji
Eva
E
Tariverdian
Gholamali
G
Chrzanowska
Krystyna H
KH
Krajewska-Walasek
Malgorzata
M
Rajab
Anna
A
Giugliani
Roberto
R
Neumann
Thomas E
TE
Eckl
Katja M
KM
Karbasiyan
Mohsen
M
Reis
André
A
Horn
Denise
D
D000015:Abnormalities, Multiple / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D002658:Developmental Disabilities / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008831:Microcephaly / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D018895:Microsatellite Repeats; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010802:Phylogeny; D013577:Syndrome; D033921:Vesicular Transport Proteins
D008565:Membrane Proteins; C475722:VPS13B protein, human; D033921:Vesicular Transport Proteins