Deletions flanked by breakpoints 3 and 4 on 15q13 may contribute to abnormal phenotypes

Abstract

Non-allelic homologous recombination (NAHR) between segmental duplications in proximal chromosome 15q breakpoint (BP) regions can lead to microdeletions and microduplications. Several individuals with deletions flanked by BP3 and BP4 on 15q13, immediately distal to, and not including the Prader-Willi/Angelman syndrome (PW/AS) critical region and proximal to the BP4-BP5 15q13.3 microdeletion syndrome region, have been reported; however, because the deletion has also been found in normal relatives, the significance of these alterations is unclear. We have identified six individuals with deletions limited to the BP3-BP4 interval and an additional four individuals with deletions of the BP3-BP5 interval from 34 046 samples submitted for clinical testing by microarray-based comparative genomic hybridization (aCGH). Of four individuals with BP3-BP4 deletions for whom parental testing was conducted, two were apparently de novo and two were maternally inherited. A comparison of clinical features, available for five individuals in our study (four with deletions within BP3-BP4 and one with a BP3-BP5 deletion), with those in the literature show common features of short stature and/or failure to thrive, microcephaly, hypotonia, and premature breast development in some individuals. Although the BP3-BP4 deletion does not yet demonstrate statistically significant enrichment in abnormal populations compared with control populations, the presence of common clinical features among probands and the presence of genes with roles in development and nervous system function in the deletion region suggest that this deletion may have a role in abnormal phenotypes in some individuals.

Figure 1

Summary of microarray analysis of individuals with deletions of 15q13. At the top of the figure is a partial idiogram showing chromosome bands 15q13.1q14, with genomic coordinates corresponding to the hg18 build of the human genome. Plots show the deletions in 10 individuals with microdeletions at 15q13. Eight out of the 10 deletions were defined using a high-density 105-K oligonucleotide microarray (subjects 1–6, 9, 10), and two deletions were defined using a high-density 135-K oligonucleotide microarray (subjects 7 and 8). Vertical dashed lines indicate the approximate deletion sizes in the individuals. Red boxes represent segmental duplication blocks BP3, BP4, and BP5 that flank the BPs. Black, blue, and green arrows represent small- and medium-sized homologous duplicons contained within the segmental duplication blocks. The complex segmental duplication structure of this region has been simplified for illustrative purposes, and the orientations shown are according to the human reference genome. Blue boxes represent all known genes annotated in the Reference Sequence database in the deletion regions.

Figure 2

(a) Subject 1 at 10 years. Note frontal bossing, bifrontal narrowing, hypertelorism, broad nasal tip with upturned nares, large and low-set ears, and downslanting palpebral fissures. (b and c) Subject 3 at 6 years. Note macrocephaly, prominent forehead, bifrontal prominence, long and oval face, and triangular chin. (d and e) Subject 4 at 8 years. Note microcephaly, short forehead, and deep-set eyes. (f) Subject 5 at 26 months. Note microcephaly, small facial structure, prominent ears, and deep-set eyes.