A Novel Variant in VPS13B Underlying Cohen Syndrome

Abstract

Pathogenic variants in vacuolar protein sorting 13 homolog B (VPS13B) cause Cohen syndrome (CS), a clinically diverse neurodevelopmental disorder. We used whole exome and Sanger sequencing to identify disease-causing variants in a Pakistani family with intellectual disability, microcephaly, facial dysmorphism, neutropenia, truncal obesity, speech delay, motor delay, and insomnia. We identified a novel homozygous nonsense variant c.8841G > A: p.(W2947^∗) in VPS13B (NM_017890.5) which segregated with the disease. Sleep disturbances are commonly seen in neurodevelopmental disorders and can exacerbate medical issues if left untreated. We demonstrate that individuals with Cohen syndrome may also be affected by sleep disturbances. In conclusion, we expand the genetic and phenotypic features of Cohen syndrome in the Pakistani population.

Figure 1

(a) The autosomal recessive consanguineous pedigree studied here and the segregation of the VPS13B [c.8841G > A: p.(W2947^∗)] variant. Squares symbolize the male individuals, circles denote female individuals, and filled square and circle indicates the affected individuals. Double lines denote a consanguineous marriage, and the crossed line specifies the deceased individual. (b) Facial images of the affected individuals. All individuals shared facial dysmorphism features such as a bulbous nasal tip, a prominent nose root, a short philtrum, narrow (mouth) roof (palate), prominent upper incisors, large ears, thick eyebrows, long thick eyelashes, and wave-shaped eyelids. Eye misalignment is seen in V : 1 and VI : 2 individuals only.

Figure 2

(a) Prediction of membrane topology and domains of VPS13B. The identified variant in the CS patients is shown by a black arrow. (b) The human VPS13B protein sequence (2941-2953) aligned with orthologous protein sequences of different species indicating evolutionary conservation of the C-terminal domain of VPS13B.