The cases described here indicate a wide range of complexity of duplication chromosomes derived from chromosome 15. In patient 00.16, the two der(15) were dicentric and each appeared to carry one extra copy of the region between BP2-BP3. This was further supported by the dosage measurements derived array CGH, which were consistent with overall tetrasomy of the duplicated region. However using array CGH without cytogenetic analyses would have missed the structural anomalies for the der(15)s. The molecular mechanisms that generated these idic(15) chromosomes are speculated to involve an interchromosomal exchange during meiosis, with a subsequent segregation error early in development, leading to two apparently identical idic(15) chromosomes.
Cases 99.30 and 03.46 have internal rearrangements within the der(15) that led to partial hexasomy for the involved segments. For 99.30, the increase in dosage for the region within the BP3-BP4 region was clearly detected by the array CGH studies and subsequently confirmed using FISH. Notably, at diagnosis, the complexity of the der(15) was not identified because the FISH probe used detected only the proximal BP2-BP3 region that was not included in the hexasomic segment. Phenotypically, this child performs on the lower end of the cognitive spectrum by comparison with other cases of idic(15) and is microcephalic (OFC < 2nd
centile for age), which is not typical of the syndrome. The der(15) carried by 03.46 is distinctive in that it appears to include 4 tandemly arranged segments, each of which includes the region proximal to BP1. While this region is typically included twice in the region between the centromere and BP1 in a typical idic(15) chromosome, it is unexpected that it would be included in the internally rearranged segments, indicating that the mechanisms that gave rise to this der(15) involved unique recombination events that lie outside the LCR. Pairing of the der(15) chromosomes in neurons has not previously been described. The proximity of the duplication chromosomes with the normal homologues is consistent with maintenance of perinucleolar organization of 15q11-13, despite the lack of the ribosomal RNA gene clusters in the der(15) chromosome. Homologous pairing of 15q11-13 is predicted to be important for the maintenance of biallelic expression of GABAA
receptor genes (Hogart et al, 2007), but the effect of der(15) chromosomes on GABAA
receptor gene expression is currently unknown. Previous expression studies in lymphocytes that demonstrated maternal expression of the UBE3A
gene on idic(15) chromosomes[14
For the family of 99.10, the large r(15) that was identified in the mother likely contributed to the subsequent abnormal crossover during oogenesis that led to the formation of the idic(15) in her daughter. The mother in this family is phenotypically normal, which likely reflects her low level mosaicism and may also represent a paternal origin of the r(15). Because grandparental samples were not available, it is not possible to determine the origin of the r(15). Array CGH performed with the prior knowledge of the r(15) was able to detect the presence of the r(15) however the low level dosage increase would not be expected to be detected clinically.
In two probands, 00.16 and 99.30, a shift in biallelic and monoallelic maternal contributions were observed, with change occurring in the BP2-BP3 interval in a region that has previously been identified as a recombination hotspot on chromosome 15q11-q12 in females. For 00.16, this likely represents an recombination event on the normal maternal homologue, although this cannot be definitively confirmed based on morphology of the der(15) chomosomes. For case 99.30, this shift between monoallelic and biallelic maternal contribution occurs in the region where the internal rearrangement of the der(15) is detected, hence increasing the likelihood a complex interchromosome and intrachromosomal exchange was involved in the generation of the the idic(15) chromosome. In summary, the cases described here indicate that not all der(15) chromosomes arise through nonhomologous allelic recombinations mediated by LCR present within the chromosome 15q11-q13 region.