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

TitleXq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome.
Publication TypeJournal Article
Year of Publication2020
AuthorsHijazi, H, Coelho, FS, Gonzaga-Jauregui, C, Bernardini, L, Mar, SS, Manning, MA, Hanson-Kahn, A, Naidu, S, Srivastava, S, Lee, JA, Jones, JR, Friez, MJ, Alberico, T, Torres, B, Fang, P, Cheung, SWai, Song, X, Davis-Williams, A, Jornlin, C, Wight, PA, Patyal, P, Taube, J, Poretti, A, Inoue, K, Zhang, F, Pehlivan, D, Carvalho, CMB, Hobson, GM, Lupski, JR
JournalHum Mutat
Volume41
Issue1
Pagination150-168
Date Published2020 Jan
ISSN1098-1004
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.

DOI10.1002/humu.23902
Alternate JournalHum. Mutat.
PubMed ID31448840
Grant ListUM1 HG006542 / HG / NHGRI NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
R01 NS058978 / NS / NINDS NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
R01 GM106373 / GM / NIGMS NIH HHS / United States
/ / PMD Foundation /
P20 GM103446 / GM / NIGMS NIH HHS / United States
/ / National Human Genome Research Institute (NHGRI) /
P30 GM114736 / GM / NIGMS NIH HHS / United States
P30 GM114736 / GM / NIGMS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
P20 GM103446 / GM / NIGMS NIH HHS / United States
R01 GM106373 / GM / NIGMS NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
R01 NS058978 / NS / NINDS NIH HHS / United States