The int22h1/int22h2-Mediated Xq28 Duplication Syndrome: An Intersection between Neurodevelopment, Immunology, and Cancer

Abstract

The int22h1/int22h2-mediated Xq28 duplication syndrome is a rare X-linked intellectual disability syndrome (XLIDS) arising from a duplication of the segment between intron 22 homologous regions 1 and 2, on the q28 subregion of the X chromosome. The main clinical features of the syndrome include intellectual disability, neurobehavioral abnormalities, and dysmorphic facial features. Due to the X-linked nature of the syndrome, affected males exhibit more severe phenotypes compared with heterozygous females. A unique distinguishing feature of the syndrome across the sexes, however, is a peculiar combination of recurrent sinopulmonary infections and atopy exclusively seen in a subset of affected males. In addition to the 'typical' 0.5 Mb duplication detected in most cases reported to date with the syndrome, a shortened centromeric version, and another 0.2 Mb telomerically shifted one, have been recently identified, with most detected duplications being maternally inherited, except for three recent cases found to have de novo duplications. Interestingly, a recently reported case of an affected male suggests a possible association of the syndrome with multiple malignancies, an observation that has been recently replicated in two pediatric patients. As a result, a better understanding of the pathogenesis of int22h1/int22h2-mediated Xq28 duplication syndrome may grant us a better understanding of the sex-specific differences in immunological responses, as well as the potential role of the genes involved by the duplication, in oncogenesis.

Keywords: BRCC3; CLIC2; MECP2; RAB39B; VBP1; XLID; gene dosage.

Figure 1

Schematic illustration of the duplicated chromosomal segment in int22h1/int22h2-mediated Xq28 duplication syndrome. The figure highlights the classical duplication detected in most patients diagnosed to date with the syndrome, as well as two atypical duplications recently detected: (a) a shorter duplicated segment that spans only the centromeric half of the typical duplication (~0.26 Mb), identified in a male subject, and (b) a 0.2 Mb-telomerically shifted duplication extending beyond the int22h2 locus, detected in two siblings.