Exome sequencing identifies pathogenic variants of VPS13B in a patient with familial 16p11.2 duplication

Abstract

Background: The recurrent microduplication of 16p11.2 (dup16p11.2) is associated with a broad spectrum of neurodevelopmental disorders (NDD) confounded by incomplete penetrance and variable expressivity. This inter- and intra-familial clinical variability highlights the importance of personalized genetic counselling in individuals at-risk.

Case presentation: In this study, we performed whole exome sequencing (WES) to look for other genomic alterations that could explain the clinical variability in a family with a boy presenting with NDD who inherited the dup16p11.2 from his apparently healthy mother. We identified novel splicing variants of VPS13B (8q22.2) in the proband with compound heterozygous inheritance. Two VPS13B mutations abolished the canonical splice sites resulting in low RNA expression in transformed lymphoblasts of the proband. VPS13B mutation causes Cohen syndrome (CS) consistent with the proband's phenotype (intellectual disability (ID), microcephaly, facial gestalt, retinal dystrophy, joint hypermobility and neutropenia). The new diagnosis of CS has important health implication for the proband, provides the opportunity for more meaningful and accurate genetic counselling for the family; and underscores the importance of longitudinally following patients for evolving phenotypic features.

Conclusions: This is the first report of a co-occurrence of pathogenic variants with familial dup16p11.2. Our finding suggests that the variable expressivity among carriers of rare putatively pathogenic CNVs such as dup16p11.2 warrants further study by WES and individualized genetic counselling of families with such CNVs.

Keywords: 16p11.2 duplication; Case report; Cohen syndrome; Neuro-developmental disorders; Variable expressivity; Whole exome sequencing.

Fig. 1

a Family pedigree. b Sanger sequencing analysis of VPS13B variants. I) Proband and his mother are carriers of splicing mutation of c.1426-1G > A. II) Proband and his father are carriers of splicing mutation of c.4157 + 1G > T (sequences of reverse strands are shown)

Fig. 2

Sanger sequencing of RT-PCR products of proband and control, using primers covering exons 9–12 and 26–29 of VPS13B. a The variant of c.1426-1G > A disrupted the following sequences and caused frameshift in the proband. The orange arrow shows the first bp of exon 11 in the normal control. b The variant of 4157 + 1G > T disrupted following sequences, and caused frameshift in the proband. The orange arrow shows the first bp of exon 27 in the normal control

Fig. 3

Expression study of VPS13B gene. The mean RNA expression of VPS13B calculated from three different time-series of RNA extraction in the proband, his mother and two normal controls. The relative expression of VPS13B is <0.5 fold in the proband and >0.6 fold in his mother. Error bars indicate standard errors from three replicates