Phenotypic manifestations of copy number variation in chromosome 16p13.11

Abstract

The widespread clinical utilization of array comparative genome hybridization, has led to the unraveling of many new copy number variations (CNVs). Although some of these CNVs are clearly pathogenic, the phenotypic consequences of others, such as those in 16p13.11 remain unclear. Whereas deletions of 16p13.11 have been associated with multiple congenital anomalies, the relevance of duplications of the region is still being debated. We report detailed clinical and molecular characterization of 10 patients with duplication and 4 patients with deletion of 16p13.11. We found that patients with duplication of the region have varied clinical features including behavioral abnormalities, cognitive impairment, congenital heart defects and skeletal manifestations, such as hypermobility, craniosynostosis and polydactyly. These features were incompletely penetrant. Patients with deletion of the region presented with microcephaly, developmental delay and behavioral abnormalities as previously described. The CNVs were of varying sizes and were likely mediated by non-allelic homologous recombination between low copy repeats. Our findings expand the repertoire of clinical features observed in patients with CNV in 16p13.11 and strengthen the hypothesis that this is a dosage sensitive region with clinical relevance.

Figure 1

Size, extent and genomic content of deletions and duplications in our cohort of patients. The similar colored bars represent the minimal possible recurrent rearrangements likely mediated by the same LCRs/NAHR. The region is very rich in LCRs and these are not represented on the array. The possible breakpoint regions are represented in the upper panel. The previously mapped recurrent rearrangement by Ullmann et al and Hannes et al, as well as the single copy regions devoid of repetitive elements termed intervals I, II and III by Ignason et al are shown at the bottom in black. Patients 1, 2, 3, 6 and 9 have duplication while patients 11–14 have deletion in the previously mapped recurrent rearrangement region. Patients 7, 8 and 10 have larger ‘atypical duplications' encompassing intervals II and III.

Figure 2

LCR structures in the proximal and distal breakpoint regions of the rearrangements in 16p13.11. Each of the colored arrows depict pairwise alignment with >98% homology. The upper panel depicts the LCRs that may have mediated the deletions in all four patients and the duplication in patients 1–6 and 9. Note that use of alternative LCRs can give rise to different size deletions. The lower panel depicts the LCRs in the breakpoint regions of the atypical duplications in patients 7, 8 and 10.