Xq26 duplications lead to undergrowth or overgrowth via competing pathways including GPC3/GPC4

The Xq26 locus has importance in human growth with multiple genes and regions playing important roles, which potentially leads to macrosomia or microsomia if disrupted. One region of Xq26.2 comprises the genes GPC3 and GPC4; deletion or duplication of this region has been recently been shown to result in overgrowth, specifically Simpson-Golabi-Behmel syndrome. We describe a male patient with two maternally inherited Xq26 microduplications; the first was 0.8 Mb at Xq26.2 affecting only GPC3 and GPC4, and the second, a distal 0.6 Mb duplication at Xq26.3 affecting seven genes. Rather than having Simpson-Golabi-Behmel syndrome, our patient had microcephaly and undergrowth, with development that was within normal limits at 25 months of age. This finding suggests that the molecular pathway leading to overgrowth secondary to GPC3/GPC4 haploinsufficiency can be overpowered by a disruption to the distal Xq26.3 region. Of the genes in that region, we propose that SLC9A6 is the most likely to play an important role as mutations in this gene lead to Christianson syndrome, in which patients may have microcephaly and weight loss.