The study was funded by Canadian Institutes of Health Research (grant MOP 106467) and Michael Smith Foundation of Health Research Career Scholar salary award to ERS.

No abstract

Recurrent microduplications/microdeletions of 1q21.1 are characterized by variable phenotypes ranging from normal development to developmental delay (DD) and congenital anomalies. Their interpretation is challenging especially in families with affected and unaffected carriers. We used whole exome sequencing (WES) to look for sequence variants in two male probands with inherited 1q21.1 CNVs that could explain their more severe phenotypes. One proband had a 1q21.1 deletion transmitted from maternal grandmother, while the other had a paternal duplication. We found mutations in five genes (SMPD1, WNK3, NOS1, ATF6, and EFHC1) that could contribute to the more severe phenotype in the probands in comparison to their mildly affected or unaffected 1q21.1 CNV carrying relatives. Interestingly, all genes have roles in stress responses (oxidative/Endoplasmic Reticulum (ER)/osmotic). One of the variants was in an X-linked gene WNK3 and segregated with the developmental features and X inactivation pattern in the family with 1q21.1 deletion transmitted from maternal grandmother. In silico analysis of all rare deleterious variants in both probands identified enrichment in nervous system diseases, metabolic pathways, protein processing in the ER and protein export. Our studies suggest that rare deleterious variants outside of the 1q21.1 CNV, individually or as a pool, could contribute to phenotypic variability in carriers of this CNV. Rare deleterious variants in stress response genes are of interest and raise the possibility of susceptibility of carriers to variable environmental influences. Next generation sequencing of additional familial cases with 1q21.1 CNV could further help determine the possible causes of phenotypic variability in carriers of this CNV.

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.