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

Abstract

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.

Figure 1

Facial features in individuals with int22h-1/int22h-2 -mediated Xq28 rearrangements. A: facial features of the proband in family 1, including high forehead, sparse eyebrows and scalp hair, long eyelashes, upper eyelid fullness, broad and depressed nasal bridge, anteverted nares, and long philtrum. B: facial features of the mother in family 1, including deep set eyes and thick lower lip. C: facial features of the youngest sister in family 5 including high forehead, full upper eyelid, broad nasal bridge, and thick lower lip. D: facial features of the middle sister in family 5 including high forehead, full upper eyelid, broad nasal bridge, and thick lower lip. E: facial features of the oldest sister in family 5 including high forehead, full upper eyelid, and thick lower lip. F: facial features of the mother in family 5 including high forehead, elongated face, full upper eyelid, and thick lower lip. G: facial features of the proband in family 6, including high forehead, deep-set eyes, epicanthus, and broad nasal bridge.

Figure 2

Schematic representation of the Xq28 region (154.0 – 155.3 Mb). Duplications are displayed as gray and deletions as white rectangles. Genes in the int22h-1/int22h-2-mediated Xq28 rearrangement region are displayed at the upper panel. The nucleotide position numbers are in Mb based on hg19. Andersen et al. 2014 is reference [26], Janczar et al. 2014 is reference [28], and Miskinyte et al. 2012 is reference [27].