6q22.1 microdeletion and susceptibility to pediatric epilepsy.
Genomic copy-number variations (CNVs) constitute an important cause of epilepsies and other human neurological disorders. Recent advancement of technologies integrating genome-wide CNV mapping and sequencing is rapidly expanding the molecular field of pediatric neurodevelopmental disorders. In a previous study, a novel epilepsy locus was identified on 6q16.3q22.31 by linkage analysis in a large pedigree. Subsequent array comparative genomic hybridization (array CGH) analysis of four unrelated cases narrowed this region to ∼5 Mb on 6q22.1q22.31. We sought to further narrow the critical region on chromosome 6q22. Array CGH analysis was used in genome-wide screen for CNVs of a large cohort of patients with neurological abnormalities. Long-range PCR and DNA sequencing were applied to precisely map chromosomal deletion breakpoints. Finally, real-time qPCR was used to estimate relative expression in the brain of the candidate genes. We identified six unrelated patients with overlapping microdeletions within 6q22.1q22.31 region, three of whom manifested seizures. Deletions were found to be de novo in 5/6 cases, including all subjects presenting with seizures. We sequenced the deletion breakpoints in four patients and narrowed the critical region to a ∼250-kb segment at 6q22.1 that includes NUS1, several expressed sequence tags (ESTs) that are highly expressed in the brain, and putative regulatory sequences of SLC35F1. Our findings indicate that dosage alteration in particular, of NUS1, EST AI858607, or SLC35F1 are important contributors to the neurodevelopmental phenotype associated with 6q22 deletion, including epilepsy and tremors.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Przemyslaw
P
Szafranski
Division of Child and Adolescent Neurology, Department of Pediatrics, University of Texas Health Science Center at Houston, TX, USA.
Gretchen K
GK
Von Allmen
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Brett H
BH
Graham
Department of Pediatric Neurology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
Angus A
AA
Wilfong
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Sung-Hae L
SH
Kang
Department of Pediatrics, University of South Florida, Tampa, FL, USA.
Jose A
JA
Ferreira
Section of Medical Genetics, Department of Pediatrics, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.
Sheila J
SJ
Upton
Section of Medical Genetics, Department of Pediatrics, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.
John B
JB
Moeschler
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Weimin
W
Bi
Signature Genomic Laboratories, PerkinElmer Inc., Spokane, WA, USA.
Jill A
JA
Rosenfeld
Paw Print Genetics, Genetic Veterinary Sciences Inc., Spokane, WA, USA.
Lisa G
LG
Shaffer
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Sau
S
Wai Cheung
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Paweł
P
Stankiewicz
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Seema R
SR
Lalani
D002675:Child, Preschool; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics
D026901:Membrane Transport Proteins; C512614:NUS1 protein, human; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; C000601577:SLC35F1 protein, human