BACKGROUND: Sotos syndrome is characterised by learning difficulties, 
overgrowth, and a typical facial appearance. Microdeletions at 5q35.3, 
encompassing NSD1, are responsible for approximately 10% of non-Japanese cases 
of Sotos. In contrast, a recurrent approximately 2 Mb microdeletion has been 
reported as responsible for approximately 50% of Japanese cases of Sotos.
METHODS: We screened 471 cases for NSD1 mutations and deletions and identified 
23 with 5q35 microdeletions. We investigated the deletion size, parent of 
origin, and mechanism of generation in these and a further 10 cases identified 
from published reports. We used "in silico" analyses to investigate whether 
repetitive elements that could generate microdeletions flank NSD1.
RESULTS: Three repetitive elements flanking NSD1, designated REPcen, REPmid, and 
REPtel, were identified. Up to 18 cases may have the same sized deletion, but at 
least eight unique deletion sizes were identified, ranging from 0.4 to 5 Mb. In 
most instances, the microdeletion arose through interchromosomal rearrangements 
of the paternally inherited chromosome.
CONCLUSIONS: Frequency, size, and mechanism of generation of 5q35 microdeletions 
differ between Japanese and non-Japanese cases of Sotos. Our microdeletions were 
identified from a large case series with a broad range of phenotypes, suggesting 
that sample selection variability is unlikely as a sole explanation for these 
differences and that variation in genomic architecture might be a contributory 
factor. Non-allelic homologous recombination between REPcen and REPtel may have 
generated up to 18 microdeletion cases in our series. However, at least 15 
cannot be mediated by these repeats, including at least seven deletions of 
different sizes, implicating multiple mechanisms in the generation of 5q35 
microdeletions.