Xp22.31 Microdeletion due to Microhomology-Mediated Break-Induced Replication in a Boy with Contiguous Gene Deletion Syndrome

Abstract

The Xp22.31 region is characterized by a low frequency of interspersed repeats and a low GC content. Submicroscopic deletions at Xp22.31 involving STS and ANOS1 (alias KAL1) underlie X-linked ichthyosis and Kallmann syndrome, respectively. Of the known microdeletions at Xp22.31, a common approximately 1.5-Mb deletion encompassing STS was ascribed to nonallelic homologous recombination, while 2 ANOS1-containing deletions were attributed to nonhomologous end-joining. However, the genomic bases of other microdeletions within the Xp22.31 region remain to be elucidated. Here, we identified a 2,735,696-bp deletion encompassing STS and ANOS1 in a boy with X-linked ichthyosis and Kallmann syndrome. The breakpoints of the deletion were located within Alu repeats and shared 2-bp microhomology. The fusion junction was not associated with nucleotide stretches, and the breakpoint-flanking regions harbored no palindromes or noncanonical DNA motifs. These results indicate that microhomology-mediated break-induced replication (MMBIR) can cause deletions at Xp22.31, resulting in contiguous gene deletion syndrome. It appears that interspersed repeats without other known rearrangement-inducing DNA features or high GC contents are sufficient to stimulate MMBIR at Xp22.31.

Novel Microdeletion in the X Chromosome Leads to Kallmann Syndrome, Ichthyosis, Obesity, and Strabismus

“…Although both patients had NLGN4X and VCX-A deletions, neither had speech defects, intellectual disability, autism, or social disorders. Previous observations also indicated that the deletion of NLGN4X may be associated with normal mental development (Khelifa et al, 2013;Nagai et al, 2017). VCX-A deletion is associated with XLI (Van Esch et al, 2005;Cuevas-Covarrubias and González-Huerta, 2008), poor sperm production, and sexual development abnormalities (Zou et al, 2003).…”

“…Another patient who had a deletion of NLGN4X demonstrated normal mental development (Khelifa et al, 2013). Renal agenesis occurred in 8 of the 20 patients, which may be caused by an ANOS1 deletion (Martul et al, 1995;Krishnamurthy et al, 2007;Macarov et al, 2007;Trevisson et al, 2015;Xu et al, 2015;Nagai et al, 2017). Previous literature also noted that patients with KS harboring a deletion in Xp22.3 were more likely to exhibit renal agenesis (Kirk et al, 1994).…”

“…The Xp 22.31 region contains several genes, including STS, ANOS1, NLGN4X, HDHD1 (PUDP), PNPLA4, and the VCX cluster. Submicroscopic deletions of STS and ANOS1 may lead to KS and XLI (Nagai et al, 2017). However, the genomic bases of other microdeletions within the Xp22.31 region remain unclear.…”

Validation of preimplantation genetic tests for aneuploidy (PGT-A) with DNA from spent culture media (SCM): concordance assessment and implication

“…Due to small sample size, we cannot robustly ascertain whether a low GC-content sequence would be more vulnerable to DNA breakpoints than a high GC-content sequence. However, utilizing GC content and reciprocal sub-chromosomal arm gain-loss complementary as a reference may prove a more e cient tool in distinguishing real DNA segments from NGS data noise generated from a sample of DNA in SCM [19,32] .…”

Exacerbation of ichthyosis vulgaris phenotype by co-inheritance of STS and FLG mutations in a Chinese family with ichthyosis: a case report

“…STS deficiency results in accumulation of cholesterol sulfate in the outer layers of the skin, inducing intercellular cohesion and scaling in XLI [ 13 ]. Up to 90% of the XLI patients presented complete deletion of the entire STS gene, and deletions could even extend to neighboring genes sometimes, leading to continuous gene syndromes [ 6 , 14 ]. Less frequent point mutations have been reported as well [ 15 , 16 ].…”