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Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome
Author(s) -
Hijazi Hadia,
Coelho Fernanda S.,
GonzagaJauregui Claudia,
Bernardini Laura,
Mar Soe S.,
Manning Melanie A.,
HansonKahn Andrea,
Naidu SakkuBai,
Srivastava Siddharth,
Lee Jennifer A.,
Jones Julie R.,
Friez Michael J.,
Alberico Thomas,
Torres Barbara,
Fang Ping,
Cheung Sau Wai,
Song Xiaofei,
DavisWilliams Angelique,
Jornlin Carly,
Wight Patricia A.,
Patyal Pankaj,
Taube Jennifer,
Poretti Andrea,
Inoue Ken,
Zhang Feng,
Pehlivan Davut,
Carvalho Claudia M. B.,
Hobson Grace M.,
Lupski James R.
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23902
Subject(s) - biology , genetics , comparative genomic hybridization , candidate gene , gene , genome
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.