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

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.