8p23.1 duplication syndrome; a novel genomic condition with unexpected complexity revealed by array CGH

Abstract

The 8p23.1 deletion syndrome is established but not an equivalent duplication syndrome. Here, we report five patients; a de novo prenatal case and two families in which 8p23.1 duplications have been directly transmitted from mothers to children. Dual-colour fluorescent in situ hybridisation, multiplex ligation-dependent probe amplification analysis and customised oligonucleotide array comparative genomic hybridisation (oaCGH) indicated an approximately 3.75 Mb duplication of most of band 8p23.1 between the olfactory receptor/defensin repeats (ORDRs) in all cases. However, oaCGH revealed an additional duplication of 500 kb adjacent to the proximal ORDR in Family 1 and an additional deletion of 3.14 Mb within the Nablus Mask-Like Facial Syndrome region of 8q22.1 in Family 2. Copy number variation at introns 4-5 of the GATA4 gene was also identified. This 8p23.1 duplication syndrome is associated with a characteristic facial phenotype including a prominent forehead and arched eyebrows. Adrenal insufficiency, Tetralogy of Fallot, partial 2/3 syndactyly of the toes and cleft palate in some individuals may be explained by ascertainment bias, incomplete penetrance and/or the presence of the microdeletion in Family 2. The duplication is compatible with normal early childhood development but, although our adult cases live independent lives with varying degrees of support, learning difficulties have been experienced by some family members. We conclude that the 8p23.1 duplication syndrome is a genomic condition with an emerging but variable phenotype that may be under-diagnosed. Our results demonstrate that direct transmission does not distinguish genuine duplications from euchromatic variants and illustrate the power of array CGH to reveal unexpected additional imbalances in affected patients.

Genomic profile of copy number variants on the short arm of human chromosome 8

“…On the basis of the finding of three probands with 8p23.1 duplication in this study, or a 0.31% detection rate, we suspect that the 8p23.1 duplication may be more common than previously suspected. 7 Rare genomic abnormalities reveal the possible existence of multiple hotspots leading to variable genomic rearrangements on 8p The specific genomic abnormalities of patients 1 and 7-10 in this study have not been previously reported. However, these rare genomic abnormalities reveal the occurrence of several unstable regions leading to recurrent genomic rearrangements on 8p.…”

“…7,42 Three probands (patients 4-6) in this study were observed to have the 8p23.1 duplication (Table 1; Figure 1; Supplementary Figure S1b). The 8p23.1 duplication in patient 4 was inherited from the affected mother.…”

“…This B5.0 Mb duplication of 8p23.1 is flanked by REPD and REPP, which share a high level of identity of complex genomic repeats involving retroviral elements, olfactory repeat regions, and variable copy numbers of defensin genes. 4,7,8,42 The 8p23.1 duplication is likely caused by intrachromosomal recombination between REPD and REPP within the 8p23.1 region through LCR-mediated nonallelic homologous misalignment and unequal recombination (NAHR) during meiosis. [6][7][8][9]43,44 The copy numbers of different types of defensin and olfactory receptor genes in the REPD and REPP regions are highly variable, leading to cytogenetically visible euchromatic variants if the copies are sufficiently high.…”

“…4,7,8,42 The 8p23.1 duplication is likely caused by intrachromosomal recombination between REPD and REPP within the 8p23.1 region through LCR-mediated nonallelic homologous misalignment and unequal recombination (NAHR) during meiosis. [6][7][8][9]43,44 The copy numbers of different types of defensin and olfactory receptor genes in the REPD and REPP regions are highly variable, leading to cytogenetically visible euchromatic variants if the copies are sufficiently high. 4,45,46 However, these euchromatic variants are indistinguishable from the genuine 8p23.1 duplication under a light microscope.…”

“…[2][3][4][5][6] These REPD-and/or REPP-related 8p genomic rearrangements include (1) the 8p23.1 deletion or duplication between REPD and REPP, [6][7][8][9] (2) the 8p23.1 paracentric inversion between REPD and REPP, 8,10 (3) the pericentric inversion (inv(8)(p23.1q22.1)) and recombinant chromosome 8 (rec (8)dup(8q)inv(8)(p23.1q22.1)), 11 (4) the 8p interstitial inverted duplication with associated terminal deletion (inv dup del(8p)), 5,6,8,10,[12][13][14][15][16][17][18][19][20][21][22][23][24] (5) the 8p translocations involving the 8p23.1, 25,26 and (6) different types of supernumerary chromosome 8 (SMC (8)) involving the breakpoints within 8p23.1. 4,27 In addition to these defined 8p genomic abnormalities, other pathogenic genomic changes have been identified, [28][29][30] whereas numerous genomic imbalances on 8p are still described as copy number variants (CNVs) of unknown clinical significance or CNVs without apparent clinical significance (benign CNVs) (http://projects.tcag.ca/variation).…”