Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome

Abstract

Xq22 deletions that encompass PLP1 (Xq22‐PLP1‐DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late‐onset form of spastic paraplegia type 2 (MIM# 312920), sometimes associated with skewed X‐inactivation, to an early‐onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability, and behavioral abnormalities. Size and gene content of Xq22‐PLP1‐DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22‐PLP1‐DEL and performed high‐density array comparative genomic hybridization and breakpoint‐junction sequencing. Molecular characterization of Xq22‐PLP1‐DEL from 17 cases (eight herein and nine published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65%) and the clustering of ~47% of proximal breakpoints in a genomic instability hotspot with characteristic non‐B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22‐PLP1‐DEL. The correlation of Xq22‐PLP1‐DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT.

Characterization of an eutherian gene cluster generated after transposon domestication identifies Bex3 as relevant for advanced neurological functions

“…Our data show that both Bex3 mutant lines display gross brain morphological alterations and have abnormal behavioral traits and that Bex3 KO mice presented more severe phenotypes, especially in terms of memory and learning impairment. These results, together with transcriptomic and structural genomic data related to human neurological disorders (Additional file 1 : Tables S2 and S3) [ 40 – 42 ], suggest that Bex3 may function through the maintenance/renewal of specific neurons, and its absence can give rise to neurological conditions.…”

“…By analyzing publicly available human transcriptomic data of autism spectrum disorder (ASD) and schizophrenia, two well-studied neuropsychiatric disorders, we found a significant decrease in the expression of BEX/TCEAL genes in patients compared to controls in different brain regions and datasets (Additional file 1 : Table S2), being BEX but not TCEAL genes significantly enriched among the differentially expressed genes in most datasets (Additional file 1 : Table S3). Notably, BEX3 is located in the interval associated with the neurological features of patients diagnosed with early-onset neurological disease trait (EONDT), which harbor different genomic deletions encompassing BEX / TCEAL genes [ 40 – 42 ].…”

“…While functional studies for the Bex / Tceal genes have focused mainly on in vitro assays, little is known about their role at the organism level. Based on previous reports linking Bex3 to neuronal physiology [ 11 , 43 , 44 ], the analyses on patients with neurological features harboring deletions encompassing BEX / TCEAL genes [ 40 – 42 ], and its neural-enriched expression in adult and embryonic tissues, we decided to generate mouse mutant lines for this gene. We used CRISPR-Cas9 technology to generate mutant alleles for Bex3 in mice and selected two for in-depth characterization (Fig.…”

“…BEX1 and BEX3 have been recently identified among the most significantly downregulated genes in excitatory neurons of the prefrontal cortex of Alzheimer’s disease patients [ 75 ]. Furthermore, patients with severe intellectual disability, craniofacial dysmorphism, and autism have been reported to carry different genomic microdeletions in Xq22 encompassing BEX/TCEAL genes, with BEX3 pinpointed as one of the main candidates to cause these neurological features [ 40 – 42 ]. Also, a small 252-kb duplication spanning BEX3 , TCEAL4 , TCEAL9 , and RAB40A has been reported in a patient with autism (Decipher database, ID: 290829) [ 76 ].…”

Induced pluripotent stem cells established from a female patient with Xq22 deletion confirm that BEX2 escapes from X‐chromosome inactivation

“…In addition to severe intellectual disability, patients also exhibited behavioral abnormalities such as sleep disorders. Later, additional Xq22 microdeletion cases have been reported, 2 and Xq22 microdeletion‐related neurodevelopmental disorder was established as a recognizable syndrome. All the patients were female and exhibited heterozygous deletions in the Xq22 region.…”