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

Abstract

BackgroundThe 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 presentationIn 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.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-016-0340-0) contains supplementary material, which is available to authorized users.

CDG and immune response: From bedside to bench and back

“…In fact, a pattern of agalactosylated and asialo‐fucosylated structures, indicative of a N‐glycan maturation defect, was found in serum proteins of these patients . Intermittent congenital neutropenia is a hallmark of this disease (detected in 168/224 VPS13B‐CDG patients) . One patient had leukopenia without neutropenia while another had pancytopenia .…”

“…One patient had leukopenia without neutropenia while another had pancytopenia . Decreased neutrophil counts often coincide with infections, namely recurrent aphthous oral ulcers, gingivitis, otitis, rhinopharyngeal, pulmonary (eg, pneumonia, bronchitis), skin (eg, cellulitis) and urinary tract infections . The link between defective glycosylation and clinical manifestations in these patients remains unidentified.…”

“…234,250 Decreased neutrophil counts often coincide with infections, namely recurrent aphthous oral ulcers, gingivitis, otitis, rhinopharyngeal, pulmonary (eg, pneumonia, bronchitis), skin (eg, cellulitis) and urinary tract infections. 227,234,240,241,244,247,248 The link between defective glycosylation and clinical manifestations in these patients remains unidentified. VPS13B seems to have a major role in the Golgi integrity and trafficking, specifically, in the endosomal-lysosomal pathway.…”

A Novel Homozygous VPS13B Splice-Site Mutation Causing the Skipping of Exon 38 in a Chinese Family With Cohen Syndrome

“…The early clinical diagnosis of CS remains challenging and the diagnostic criteria are controversial due to the overlapping features with other disorders and the clinical heterogeneity of CS. The incidence rate of CS may be higher than 1:105,000 because certain clinical symptoms are insignificant during early childhood, which results in CS patients not being diagnosed in a timely manner (31).…”

Gene analysis: A rare gene disease of intellectual deficiency‐Cohen syndrome

“…Dastan J et al detected that some CS features like Truncal obesity and spine abnormality are age‐dependent and evolve later in childhood. This character also increases the difficulty of diagnosis (Dastan et al, 2016). The incidence of epilepsy in Cohen syndrome is 6%.…”