Background The recurrent duplication of 16p11.2 (dup16p11.2) is associated with a broad spectrum of neurocognitive phenotypes with incomplete penetrance and variable expressivity.

Objective To explore the possibility of co-occurrence of other genetic alterations in the genome that could explain the variability in the clinical phenotypes of dup16p11.2 cases.

Methods We used whole exome sequencing with Illumina HiSeq 2000 to screen the mutational load of a trio family involving a boy with idiopathic ID/ASD who inherited dup16p11.2 from his healthy mother. Golden Helix SVS v8.1.5 software was used for data analysis. We excluded all variants outside the exonic regions (except variants at canonical splice sites), synonymous and common autosomal dominant or X-linked variants (>1% MAF), or autosomal recessive variants (>5% MAF). Seven bioinformatics tools predicted functional damaging and conservation scores of remaining variants. Their expression pattern and role in disease based in literature were also considered.

Result After filtering, two compound heterozygous variants of VPS13B (8q22.2) at canonical splice sites were detected in the proband, confirmed by Sanger sequencing. Nucleotide changes of c.1426–1 and c.4157+1 were inherited from the mother and father, respectively. VPS13B protein is required for Golgi integrity and function and involved in vesicle-mediated sorting and intracellular protein transport. Mutations and/or CNVs in VPS13B cause the autosomal recessive Cohen syndrome with which the proband’s phenotype is consistent (ID, ASD, postnatal microcephaly, facial gestalt, retinal dystrophy, body habitus, joint hypermobility and episodic neutropenia).

Conclusion Our study showed that variable expressivity among cases with 16p11.2 duplication may be due to the presence of other disease causing variants.