Abstract
Chromosome 16 is one of the most gene-rich chromosomes of our genome, and 10% of its sequence consists of segmental duplications, which give instability and predisposition to rearrangement by the recurrent mechanism of non-allelic homologous recombination. Microarray technologies have allowed for the analysis of copy number variations (CNVs) that can contribute to the risk of developing complex diseases. By array comparative genomic hybridization (CGH) screening of 1476 patients, we detected 27 cases with CNVs on chromosome 16. We identified four smallest regions of overlapping (SROs): one at 16p13.11 was found in seven patients; one at 16p12.2 was found in four patients; two close SROs at 16p11.2 were found in twelve patients; finally, six patients were found with atypical rearrangements. Although phenotypic variability was observed, we identified a male bias for Childhood Apraxia of Speech associated to 16p11.2 microdeletions. We also reported an elevated frequency of second-site genomic alterations, supporting the model of the second hit to explain the clinical variability associated with CNV syndromes. Our goal was to contribute to the building of a chromosome 16 disease-map based on disease susceptibility regions. The role of the CNVs of chromosome 16 was increasingly made clear in the determination of developmental delay. We also found that in some cases a second-site CNV could explain the phenotypic heterogeneity by a simple additive effect or a pejorative synergistic effect.
Highlights
Human chromosome 16 is a metacentric small-size chromosome belonging to the E group that spans 90.4 Mb with large numbers of repeats and variants localized mostly to the centromeric heterochromatin [1]
There are 2260 genes according to Vega Genome Browser release 68–2017 and 2006 genes according to NCBI, National Center for Biotechnology Information, Annotation Release 109–2018, while there are 463 pseudogenes according to Vega Genome Browser release 68–2017
As a matter of fact, chromosome 16 contains several immunoglobin-like paralogues—a type of gene for which it is clearly evolutionarily adaptive to undergo rapid duplication followed by random mutation, as they play a role in adapting to potential antigens
Summary
Human chromosome 16 is a metacentric small-size chromosome belonging to the E group that spans 90.4 Mb with large numbers of repeats and variants localized mostly to the centromeric heterochromatin [1]. Advancements in chromosomal microarray technologies have allowed for the analysis of copy number variations (CNVs) that promote genetic variability in humans, but can contribute to Mendelian [6] and complex disease risk. In this context, the clinical association between the 593 Kb proximal deletions and duplications at 16p11.2 and Neurodevelopmental Disorders (NDs) is well known [7], even if the deletions and duplications are observed in normal individuals [8]. One possible explanation for variable expressivity in these genomic alterations emerges from a recent study that proposed a “two-hit” model in which the compound effect of a relatively small number of rare variants of large effect contributes to the phenotypic heterogeneity of genomic disorders [22]
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