The phenotypic and genomic similarities between our two patients suggest a novel syndrome of microcephaly, short stature, developmental delay and delayed bone maturation, in the absence of facial or osseous dysmorphism, caused by duplications of the Sotos syndrome critical region. Remarkably, the observed phenotype is reciprocal to that of patients with Sotos syndrome, who commonly present with macrocephaly, overgrowth and advanced bone age.
The breakpoints of the duplication in both patients map to the proximal and distal LCRs that flank the Sotos critical region (), strongly suggesting NAHR as the underlying mechanism of their genomic imbalance and indicating that the predicted duplication reciprocal to the common deletion of this region can indeed be found in human populations.
The previously reported patient with a duplication involving this and adjacent regions of the genome (, bottom) had a more severe phenotype than did our patients, including brachydactyly, abnormally shaped fifth digits, strabismus, bilateral inguinal hernias and facial dysmorphism, in addition to microcephaly, short stature and developmental delay.20
A patient with a smaller (520–650
kb) duplication within the Sotos syndrome critical region, also encompassing the NSD1
gene but not reciprocal to the common deletion (, top), had microcephaly and short stature in addition to mild facial dysmorphism.21
This suggests that the gene dosage effect that seems to be responsible for this phenotype is limited to a region smaller than the 1.1
Mb minimum-duplicated fragment found in our patients, and that it is likely to involve the NSD1
A reciprocal phenotype between deletion and duplication cases has been observed in some,7
but not all, genomic disorders reported to date. The striking reciprocity of the phenotype between deletion and duplication cases in the Sotos syndrome critical region suggests a strong dosage effect of the NSD1
gene. Although the exact physiological functions of NSD1
remain largely unknown, our data support the hypothesis of a role for this gene as a regulator of somatic growth in humans. Functional studies and animal models may help to further clarify this.
When systematically studied, a majority of point mutations in the NSD1
gene in patients with Sotos syndrome are nonsense or frameshift mutations.27
Our data raise the possibility of gain-of-function mutations at this locus being a cause of microcephaly, short stature and developmental delay.
The paucity of dysmorphic features in our patients may help explain, at least in part, why deletions in this region are a well-known cause of human disease, whereas the phenotype associated with the reciprocal duplication is only now being uncovered. Given the population distribution of the common Sotos syndrome microdeletion, for example, one would expect the frequency of its reciprocal duplication to be relatively high in people of Japanese ancestry. We advocate the clinical use of techniques that allow the detection of copy number changes not visible by standard cytogenetic techniques, such as aCGH and MLPA, in patients with microcephaly and/or developmental delay, in the absence of other dysmorphic features. This should allow other cases to be uncovered, providing further insight into the clinical manifestations of this novel syndrome.