Cohen Syndrome via the VPS13B (COH1) Gene

Cohen syndrome (OMIM 216550) is characterized clinically by developmental delay, early-onset myopia, joint laxity, and a characteristic facies (Hennies et al. Am J Hum Genet 75:138-145, 2004). In the Finnish population, where Cohen syndrome is relatively more common, patients uniformly exhibit microcephaly, developmental delay, retinal dystrophy, neutropenia, joint laxity, and characteristic facies (Kolehmainen et al. Am J Hum Genet 72:1359-1369, 2003). In patients from a more diverse geographic region, however, microcephaly, neutropenia, retinopathy in school-aged children, and the typical facies are not constant findings (Hennies et al., 2004; Seifert et al. J Med Genet 43:e22, 2006). Developmental delay varies in severity from profound to mild mental retardation (Kivitie-Kallio and Norio. Am J Med Genet 102:125-135, 2001), and most patients have a cheerful disposition. Patients also have motor clumsiness, muscle weakness, and hypotonia beyond infancy. Microcephaly, when present is of postnatal onset. Facial dysmorphism includes high, arched eyelids; mildly downslanting palpebral fissures; a short philtrum; open mouth with prominent upper incisors; high, arched narrow palate; and large ears. Other features sometimes occurring in Cohen syndrome include slender fingers, thick hair with low hairline, delayed puberty, and a high-pitched voice. Obesity in Cohen syndrome patients has been found to be unremarkable (Kolehmainen et al., 2003).

Cohen syndrome is inherited as an autosomal recessive disorder, most often involving private variants. Allelic heterogeneity underlies the variability in observed clinical phenotypes. Truncating VPS13B (COH1) variants are the most abundant class of variant and they are distributed throughout the gene.

Clinical sensitivity of the VPS13B (COH1) sequencing test has been shown to be high in patients from wide geographic origins with highly variable clinical phenotypes. For example, Hennies et al. (2004) found two variants in probands from all twelve families originating from countries in Eastern and Southern Europe, South America, and the Middle East. Similarly, Seifert et al. (2006) found two variants in all but one proband from sixteen families with diverse ethnic origins. A single mutant VPS13B allele was found in the other proband.

This test is performed using Next-Generation sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the VPS13B gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.