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

Hadia Hijazi, Fernanda S. Coelho, Claudia Gonzaga-Jauregui, Laura Bernardini, Soe S. Mar, Melanie A. Manning, Andrea Hanson-Kahn, Sakku Bai Naidu, Siddharth Srivastava, Jennifer A. Lee, Julie R. Jones, Michael J. Friez, Thomas Alberico, Barbara Torres, Ping Fang, Sau Wai Cheung, Xiaofei Song, Angelique Davis-Williams, Carly Jornlin, Patricia A. WightPankaj Patyal, Jennifer Taube, Andrea Poretti, Ken Inoue, Feng Zhang, Davut Pehlivan, Claudia M.B. Carvalho, Grace M. Hobson, James R. Lupski

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)150-168
Number of pages19
JournalHuman mutation
Issue number1
StatePublished - Jan 1 2020


  • BEX3
  • PLP1
  • TCEAL1
  • contiguous gene deletion syndrome
  • intrachromosomal repeats
  • sex limited traits

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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