CNV analysis using whole exome sequencing identified biallelic CNVs of VPS13B in siblings with intellectual disability

Abstract Cohen syndromeis an autosomal recessive disease characterized by myopia, retinal dystrophy, neutropenia, short stature, microcephaly, persistent hypotonia, intellectual disability (ID), and a distinct facial appearance. Cohen syndromeis caused by mutations, such as single nucleotide variants (SNVs) and small insertions/deletions, and copy number variations(CNVs) in vacuolar protein sorting13 homolog B ( VPS13B). Here, we report Japanese siblings with ID, who were subsequently diagnosed with Cohen syndromeby whole exome sequencing(WES). The older sisterhad hypotoniaand mild to moderate ID. The younger sisterhad short stature, postnatal onset microcephaly, and developmental delay. No pathogenic mutations, including SNVs or small insertions/deletions, were found by WES. Comparative genomic hybridization(CGH)-array did not detect pathogenic copy-number variations. However, using log2-ratio values calculated from WES depth data, we detected pathogenic biallelic heterozygous CNVs in VPS13Bin both sisters: a maternally-derived exons 8–15 deletion and a paternally-derived exons 32–33 deletion. Interestingly, the sistersdid not show obvious clinical features suggestive of Cohen syndrome, including the distinct facial appearance. These results support the idea that the typical facial features of Cohen syndromedo not appear in early childhood, and that the late appearance of distinctive clinical features results in delayed diagnosis. Furthermore, these results show the possibility that CNV analysis using log2-ratio values calculated from WES depth data is a useful and effective method to detect CNVs, such as the deletion of multiple exons.