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

Hum Mutat. 2020 Jan;41(1):150-168. doi: 10.1002/humu.23902. Epub 2019 Nov 14.


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.

Keywords: BEX3; PLP1; TCEAL1; contiguous gene deletion syndrome; intrachromosomal repeats; sex limited traits.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • Child, Preschool
  • Chromosome Breakpoints
  • Chromosome Deletion*
  • Chromosome Mapping
  • Chromosomes, Human, X*
  • Comparative Genomic Hybridization
  • Female
  • Genetic Association Studies* / methods
  • Genetic Predisposition to Disease*
  • Humans
  • Male
  • Nervous System Diseases / diagnosis*
  • Nervous System Diseases / genetics*
  • Pedigree
  • Phenotype
  • Quantitative Trait, Heritable*
  • Repetitive Sequences, Nucleic Acid
  • Sex Factors
  • Syndrome
  • X Chromosome Inactivation