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

BMC Medical Genetics

Sau Wai Cheung²  Ankita Patel²  Joseph A Church³  Virginia E Kimonis⁵  Elizabeth Roeder⁴  Ping Fang²  Christian P Schaaf¹  Ayman W El-Hattab⁶ 

[1] Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA;Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS NAB 2015, Houston 77030, TX, U.S.A;Division of Clinical Immunology and Allergy, Children’s Hospital Los Angeles, and Keck School of Medicine, University of Southern California, Los Angeles, CA, USA;Section of Genetics, Department of Pediatrics, Baylor College of Medicine, Children’s Hospital of San Antonio, San Antonio, TX, USA;Division of Genetics and Genomics, Department of Pediatrics, University of California, Irvine Medical Center, Orange, CA, USA;Division of Clinical Genetics and Metabolic Disorders, Department of Pediatrics, Tawam Hospital, Al-Ain, United Arab Emirates

关键词: Chromosomal microarray analysis;    X-linked intellectual disability;    Chromosomal rearrangements;   

Others  :  1171805
DOI  :  10.1186/s12881-015-0157-2

 received in 2014-12-01, accepted in 2015-02-18,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 El-Hattab et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

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