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2035-01-01
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XQ22 DELETIONS AND CORRELATION WITH DISTINCT NEUROLOGICAL DISEASE TRAITS IN FEMALES: FURTHER EVIDENCE FOR A CONTIGUOUS GENE SYNDROME
PLP1
TCEAL1
Contiguous gene deletion syndrome
Intrachromosomal repeats
Xex limited traits
Author
Hijazi, Hadia
Coelho, Fernanda Sales
Gonzaga Jauregui, Claudia
Bernardini, Laura
Mar, Soe S.
Manning, Melanie A.
Hanson-Kahn, 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
Davis-Williams, 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.
Coelho, Fernanda Sales
Gonzaga Jauregui, Claudia
Bernardini, Laura
Mar, Soe S.
Manning, Melanie A.
Hanson-Kahn, 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
Davis-Williams, 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.
Affilliation
Department of Molecular and Human Genetics. Baylor College of Medicine.Houston, Texas, USA.
Universidade Federal de Minas Gerais. Departamento de Biologia Geral. Programa de Pós-Graduação em Genética. Belo Horizonte, MG, Brasil / Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.
Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA.
Medical Genetics Division. IRCCS "Casa Sollievo della Sofferenza" Foundation. San Giovanni Rotondo (FG), Italy.
Department of Neurology. Washington University School of Medicine.St. Louis, Missouri, USA.
Division of Medical Genetics. Department of Pediatrics. Stanford University School of Medicine. Palo Alto, California, USA / Department of Pathology. Stanford University School of Medicine. Palo Alto, California, USA.
Division of Medical Genetics. Department of Pediatrics. Stanford University School of Medicine. Palo Alto, California, USA / Department of Genetics. Stanford University School of Medicine. Palo Alto, California, USA.
Departments of Neurology and Pediatrics. Johns Hopkins University School of Medicine. Baltimore, Maryland, USA / Department of Neurogenetics. Kennedy Krieger Institute. Baltimore, Maryland, USA.
Department of Neurology. Boston Children's Hospital. Boston, Massachusetts, USA.
Molecular Diagnostic Laboratory. Greenwood Genetic Center. Greenwood, South Carolina, USA.
Molecular Diagnostic Laboratory. Greenwood Genetic Center. Greenwood, South Carolina, USA.
Molecular Diagnostic Laboratory. Greenwood Genetic Center. Greenwood, South Carolina, USA.
Nemours Biomedical Research. Nemours/Alfred I. duPont Hospital for Children. Wilmington, Delaware, USA.
Medical Genetics Division. IRCCS "Casa Sollievo della Sofferenza" Foundation. San Giovanni Rotondo (FG), Italy.
Clinical Genomics. WuXi NextCODE. Cambridge, Massachusetts, USA.
Department of Molecular and Human Genetics. Baylor College of Medicine.Houston, Texas, USA.
Department of Molecular and Human Genetics. Baylor College of Medicine.Houston, Texas, USA.
Nemours Biomedical Research. Nemours/Alfred I. duPont Hospital for Children. Wilmington, Delaware, USA.
Nemours Biomedical Research. Nemours/Alfred I. duPont Hospital for Children. Wilmington, Delaware, USA.
Department of Physiology and Biophysics. College of Medicine. University of Arkansas for Medical Sciences. Little Rock, Arkansas, USA.
Department of Physiology and Biophysics. College of Medicine. University of Arkansas for Medical Sciences. Little Rock, Arkansas, USA.
Nemours Biomedical Research. Nemours/Alfred I. duPont Hospital for Children. Wilmington, Delaware, USA.
Departments of Neurology and Pediatrics. Johns Hopkins University School of Medicine. Baltimore, Maryland, USA.
Department of Mental Retardation and Birth Defect Research. National Institute of Neuroscience. National Center of Neurology and Psychiatry. Kodaira, Japan.
State Key Laboratory of Genetic Engineering at School of Life Sciences. Obstetrics and Gynecology Hospital. Institute of Reproduction and Development. Fudan University. Shanghai, China.
Department of Molecular and Human Genetics. Baylor College of Medicine.Houston, Texas/Section of Neurology. Department of Pediatrics. Baylor College of Medicine. Houston, Texas, USA.
Department of Molecular and Human Genetics. Baylor College of Medicine.Houston, Texas, USA.
Nemours Biomedical Research. Nemours/Alfred I. duPont Hospital for Children. Wilmington, Delaware, USA.
Department of Molecular and Human Genetics. Baylor College of Medicine.Houston, Texas, USA / Human Genome Sequencing Center. Baylor College of Medicine. Houston, Texas, USA / Department of Pediatrics. Baylor College of Medicine. Houston, Texas, USA / Texas Children's Hospital. Houston, Texas, USA.
Universidade Federal de Minas Gerais. Departamento de Biologia Geral. Programa de Pós-Graduação em Genética. Belo Horizonte, MG, Brasil / Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.
Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA.
Medical Genetics Division. IRCCS "Casa Sollievo della Sofferenza" Foundation. San Giovanni Rotondo (FG), Italy.
Department of Neurology. Washington University School of Medicine.St. Louis, Missouri, USA.
Division of Medical Genetics. Department of Pediatrics. Stanford University School of Medicine. Palo Alto, California, USA / Department of Pathology. Stanford University School of Medicine. Palo Alto, California, USA.
Division of Medical Genetics. Department of Pediatrics. Stanford University School of Medicine. Palo Alto, California, USA / Department of Genetics. Stanford University School of Medicine. Palo Alto, California, USA.
Departments of Neurology and Pediatrics. Johns Hopkins University School of Medicine. Baltimore, Maryland, USA / Department of Neurogenetics. Kennedy Krieger Institute. Baltimore, Maryland, USA.
Department of Neurology. Boston Children's Hospital. Boston, Massachusetts, USA.
Molecular Diagnostic Laboratory. Greenwood Genetic Center. Greenwood, South Carolina, USA.
Molecular Diagnostic Laboratory. Greenwood Genetic Center. Greenwood, South Carolina, USA.
Molecular Diagnostic Laboratory. Greenwood Genetic Center. Greenwood, South Carolina, USA.
Nemours Biomedical Research. Nemours/Alfred I. duPont Hospital for Children. Wilmington, Delaware, USA.
Medical Genetics Division. IRCCS "Casa Sollievo della Sofferenza" Foundation. San Giovanni Rotondo (FG), Italy.
Clinical Genomics. WuXi NextCODE. Cambridge, Massachusetts, USA.
Department of Molecular and Human Genetics. Baylor College of Medicine.Houston, Texas, USA.
Department of Molecular and Human Genetics. Baylor College of Medicine.Houston, Texas, USA.
Nemours Biomedical Research. Nemours/Alfred I. duPont Hospital for Children. Wilmington, Delaware, USA.
Nemours Biomedical Research. Nemours/Alfred I. duPont Hospital for Children. Wilmington, Delaware, USA.
Department of Physiology and Biophysics. College of Medicine. University of Arkansas for Medical Sciences. Little Rock, Arkansas, USA.
Department of Physiology and Biophysics. College of Medicine. University of Arkansas for Medical Sciences. Little Rock, Arkansas, USA.
Nemours Biomedical Research. Nemours/Alfred I. duPont Hospital for Children. Wilmington, Delaware, USA.
Departments of Neurology and Pediatrics. Johns Hopkins University School of Medicine. Baltimore, Maryland, USA.
Department of Mental Retardation and Birth Defect Research. National Institute of Neuroscience. National Center of Neurology and Psychiatry. Kodaira, Japan.
State Key Laboratory of Genetic Engineering at School of Life Sciences. Obstetrics and Gynecology Hospital. Institute of Reproduction and Development. Fudan University. Shanghai, China.
Department of Molecular and Human Genetics. Baylor College of Medicine.Houston, Texas/Section of Neurology. Department of Pediatrics. Baylor College of Medicine. Houston, Texas, USA.
Department of Molecular and Human Genetics. Baylor College of Medicine.Houston, Texas, USA.
Nemours Biomedical Research. Nemours/Alfred I. duPont Hospital for Children. Wilmington, Delaware, USA.
Department of Molecular and Human Genetics. Baylor College of Medicine.Houston, Texas, USA / Human Genome Sequencing Center. Baylor College of Medicine. Houston, Texas, USA / Department of Pediatrics. Baylor College of Medicine. Houston, Texas, USA / Texas Children's Hospital. Houston, Texas, USA.
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.
Keywords
BEX3PLP1
TCEAL1
Contiguous gene deletion syndrome
Intrachromosomal repeats
Xex limited traits
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