Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome.
Hadia HijaziFernanda S CoelhoClaudia Gonzaga-JaureguiLaura BernardiniSoe S MarMelanie A ManningAndrea Hanson-KahnSakkuBai NaiduSiddharth SrivastavaJennifer A LeeJulie R JonesMichael J FriezThomas AlbericoBarbara TorresPing FangSau Wai CheungXiaofei SongAngelique Davis-WilliamsCarly JornlinPatricia A WightPankaj PatyalJennifer TaubeAndrea PorettiKen InoueFeng ZhangDavut PehlivanCláudia M B CarvalhoGrace M HobsonJames R. LupskiPublished in: Human mutation (2019)
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.
Keyphrases
- early onset
- genome wide
- late onset
- copy number
- intellectual disability
- high density
- dna methylation
- end stage renal disease
- chronic kidney disease
- single cell
- randomized controlled trial
- ejection fraction
- high resolution
- mass spectrometry
- gene expression
- electronic health record
- climate change
- transcription factor
- peritoneal dialysis
- deep learning
- circulating tumor
- nucleic acid
- genome wide analysis
- upper limb