Cohen syndrome resulting from a novel large intragenic COH1 deletion segregating in an isolated Greek island population

Abstract

Cohen syndrome, caused by mutations in the COH1 gene, is an autosomal recessive disorder consisting of mental retardation, microcephaly, growth delay, severe myopia, progressive chorioretinal dystrophy, facial anomalies, slender limbs with narrow hands and feet, tapered fingers, short stature, kyphosis and/or scoliosis, pectus carinatum, joint hypermobility, pes calcaneovalgus, and, variably, truncal obesity. Here, we describe the clinical and molecular findings in 14 patients from an isolated Greek island population. The clinical phenotype was fairly homogeneous, although microcephaly was not constant, and some patients had severe visual disability. All patients were homozygous for a novel intragenic COH1 deletion spanning exon 6 to exon 16, suggesting a founder effect. The discovery of this mutation has made carrier detection and prenatal diagnosis possible in this population.

High frequency of COH1 intragenic deletions and duplications detected by MLPA in patients with Cohen syndrome

“…10 In four patients from three families, MLPA identified a COH1 large deletion sharing the same extent with one previously reported in an isolated Greek Island population, spanning from exons 6 to 16. 16 In our patients, the deletion was heterozygous in two families and homozygous in an apparently non-consanguineous family. 10 Interestingly, this latter patient displays the same constellation of facial features reported in Greek patients with homozygous deletion including thick hair with low hairline, strabism, lack of nasofrontal angle, short upturned philtrum and prominent maxillary central incisors (patient 5, Figure 1).…”

“…10 Copy number changes in COH1 have been previously investigated in patients with Cohen syndrome by qPCR using probes designed on a 1 2 3 3 4 5 7 8 9 10 11 12 13 15 16 16 17 17 18 19 20 21 22 23 24 24 25 26 27 28 29 30 31 31 32 33 34 34 35 35 36 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 limited number of exons. 10,16 Only recently, a targeted oligonucleotide array with a median resolution of 200 bp was designed within the gene, which considerably increased the mutation detection rate. 11 Using this technique, the authors identified COH1 large deletions in nine patients from seven families, showing that they represent an important cause of Cohen syndrome.…”

“…A set of 10 markers covering a region of about 4 Mb encompassing the COH1 gene were used for haplotype analysis (Supplementary Table 2) in three of our cases with the 6-16 deletion (case 5, 8 and 9A) and one member of the large Greek consanguineous family reported by Bugiani et al 16 harboring the 6-16 deletion in homozygous state. Haplotype analysis was also performed in all available family members of the 6-16 deleted patients and in 50 Italian control individuals.…”

“…To investigate a founder effect for the recurrent deletion of exons 6-16, we performed haplotype analysis in three of our cases and one additional case belonging to a large Greek consanguineous family reported by Bugiani et al 16 A founder effect is expected to result in sharing of allelic sequence polymorphisms in the vicinity of the deletion. We examined 10 microsatellite markers within a region of about 4 Mb encompassing the COH1 gene (Supplementary Table 2, Table 3).…”

Síndrome de Cohen diagnosticado con hibridación genómica comparativa por microarreglos

“…Se han descrito mutaciones puntuales, deleciones y duplicaciones del locus 8q22-q23 que incluyen este gen y se traducen en alteraciones de una proteína transmembranal de función desconocida (1). El fenotipo característico consiste en discapacidad intelectual, microcefalia, facies característica, anormalidades oftálmicas, obesidad central e hipotonía (2,3).…”