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Background   Int22h1/int22h2 -mediated Xq28 duplication syndrome is caused by ~0.5 Mb chromosomal duplications mediated by nonallelic homologous recombination between intron 22 homologous region 1 ( int22h1 ) and 2 ( int22h2 ), which, in addition to  int22h3 , are also responsible for inversions disrupting the  F8  gene in hemophilia A. This syndrome has recently been described in 9 males with cognitive impairment, behavioral problems, and distinctive facial features; and 6 females with milder phenotypes. The reciprocal deletion was previously reported in a mother and daughter. It was suggested that this deletion may not have phenotypic effects in females because of skewed chromosome X inactivation, but may be embryonic lethal in males.    Methods  Array comparative genomic hybridization analyses were performed using oligonucleotide-based chromosomal microarray. Chromosome X inactivation studies were performed at the  AR  (androgen receptor) and  FMR1  (fragile X mental retardation 1) loci.    Results  We present here 5 males and 6 females with  int22h1/int22h2 -mediated Xq28 duplication syndrome. The males manifested cognitive impairment, behavioral problems, and distinctive facial features. Two of the six females manifested mild cognitive impairment. This duplication was maternally inherited, and skewed chromosome X inactivation was observed in the majority of females carrying the duplication. We also report the reciprocal deletion in a mother and daughter with overweight, but normal cognition. In addition, we present the first case of a prenatally diagnosed  de novo int22h1/int22h2 -mediated deletion in a healthy female infant. We reviewed individuals previously reported with similar or overlapping rearrangements and evaluated the potential roles of genes in the rearrangement region.    Conclusions  The similarity of clinical features among individuals with the  int22h1/int22h2 -mediated Xq28 duplication supports the notion that this duplication causes a recognizable syndrome that affects males with females exhibiting milder phenotypes. It is suggested that the observed cognitive impairment in this syndrome results from increased dosage of  RAB39B  gene located within the duplicated region. Increased dosage of  CLIC2  may also contribute to the phenotype. The reciprocal deletion results in skewed chromosome X inactivation and no clinical phenotype in females. Review of overlapping deletions suggests that hemizygous loss of  VBP1  may be the cause for the proposed male lethality associated with this deletion.

Clinical characterization of int22h1/int22h2-mediated Xq28 duplication/deletion: new cases and literature review