Refining the Phenotype of Recurrent Rearrangements of Chromosome 16

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.

Rare Pathogenic Copy Number Variation in the 16p11.2 (BP4–BP5) Region Associated with Neurodevelopmental and Neuropsychiatric Disorders: A Review of the Literature

“…The most immediately addressable factor with current technology and practice is that introduced by genetic variation. Several evidence-based data reported in the literature are consistent with the presence of additional rare (<0.1% frequency in control individuals) or larger CNVs as modifiers of disorder severity [37][38][39]. In fact, genetic variation and dosage imbalance at other loci could contribute to the observed phenotypic heterogeneity, resulting in an additive or synergistic effect on neurodevelopmental pathways and disease outcomes.…”

Copy number variations in ultrasonically abnormal late pregnancy fetuses with normal karyotypes

“…The only ultrasonographic manifestations in these fetuses were double kidney echo enhancements. A CNV on human chromosome 16p11.2 is associated with autism spectrum disorders 17 , 18 . We detected this known 16p11.2 deletion syndrome in four fetuses, with different ultrasonographic manifestations.…”

Formation of human long intergenic non-coding RNA genes, pseudogenes, and protein genes: Ancestral sequences are key players

“…The repeat sequence is highly prevalent in different segmental duplications or low copy repeats (LCR22) of human chromosome 22 (chr22), specifically in region 22q11.2. Chr22 has the largest number of segmental duplications per unit chromosomal length of any human chromosome [7]. These duplications are dynamic [8].…”