SPG2 has a hugely variable presentation

“Neighbour” genes involved in complex, early-onset forms


Six genes adjacent to the SPG2-causing PLP1 gene contribute to a complex, early-onset form of this HSP type that ranges all the way to a mild, late-onset form.



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.


SOURCE: Hum Mutat. 2019 Aug 26. doi: 10.1002/humu.23902. [Epub ahead of print] © 2019 Wiley Periodicals, Inc. PMID: 31448840

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

Hijazi H1, Coelho FS2,3, Gonzaga-Jauregui C4, Bernardini L5, Mar SS6, Manning MA7,8, Hanson-Kahn A7,9, Naidu S10,11, Srivastava S12, Lee JA13, Jones JR13, Friez MJ13, Alberico T14, Torres B5, Fang P15, Cheung SW1, Song X1, Davis-Williams A14, Jornlin C14, Wight PA16, Patyal P16, Taube J14, Poretti A10, Inoue K17, Zhang F18, Pehlivan D1,19, Carvalho CMB1, Hobson GM14, Lupski JR1,20,21,22.

1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

2 Programa de Pós-Graduação em Genética Departmento de Biologia Geral, UFMG, Belo Horizonte, Minas Gerais, Brazil.

3 Instituto René Rachou, FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil.

4 Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc, Tarrytown, New York.

5 Medical Genetics Division, IRCCS “Casa Sollievo della Sofferenza” Foundation, San Giovanni Rotondo (FG), Italy.

6 Department of Neurology, Washington University School of Medicine, St. Louis, Missouri.

7 Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California.

8 Department of Pathology, Stanford University School of Medicine, Palo Alto, California.

9 Department of Genetics, Stanford University School of Medicine, Palo Alto, California.

10 Departments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.

11 Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland.

12 Department of Neurology, Boston Children’s Hospital, Boston, Massachusetts.

13 Molecular Diagnostic Laboratory, Greenwood Genetic Center, Greenwood, South Carolina.

14 Nemours Biomedical Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware.

15 Clinical Genomics, WuXi NextCODE, Cambridge, Massachusetts.

16 Department of Physiology and Biophysics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

17 Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.

18 State Key Laboratory of Genetic Engineering at School of Life Sciences, Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China.

19 Section of Neurology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.

20 Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.

21 Department of Pediatrics, Baylor College of Medicine, Houston, Texas.

22 Texas Children’s Hospital, Houston, Texas.

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