Chromosomal microarray testing identifies a 4p terminal region associated with seizures in Wolf-Hirschhorn syndrome

Karen S Ho; Sarah T South; Amanda Lortz; Charles H Hensel; Mallory R Sdano; Rena J Vanzo; Megan M Martin; Andreas Peiffer; Christophe G Lambert; Amy Calhoun; John C Carey; Agatino Battaglia

doi:10.1136/jmedgenet-2015-103626

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Chromosomal microarray testing identifies a 4p terminal region associated with seizures in Wolf-Hirschhorn syndrome

Journal article

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Chromosomal microarray testing identifies a 4p terminal region associated with seizures in Wolf-Hirschhorn syndrome

Karen S Ho, Sarah T South, Amanda Lortz, Charles H Hensel, Mallory R Sdano, Rena J Vanzo, Megan M Martin, Andreas Peiffer, Christophe G Lambert, Amy Calhoun, …

Journal of medical genetics, Vol.53(4), pp.256-263

04/2016

DOI: 10.1136/jmedgenet-2015-103626

PMCID: PMC4819617

PMID: 26747863

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Abstract

Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion syndrome involving variable size deletions of the 4p16.3 region. Seizures are frequently, but not always, associated with WHS. We hypothesised that the size and location of the deleted region may correlate with seizure presentation. Using chromosomal microarray analysis, we finely mapped the breakpoints of copy number variants (CNVs) in 48 individuals with WHS. Seizure phenotype data were collected through parent-reported answers to a comprehensive questionnaire and supplemented with available medical records. We observed a significant correlation between the presence of an interstitial 4p deletion and lack of a seizure phenotype (Fisher's exact test p=3.59e-6). In our cohort, there were five individuals with interstitial deletions with a distal breakpoint at least 751 kbp proximal to the 4p terminus. Four of these individuals have never had an observable seizure, and the fifth individual had a single febrile seizure at the age of 1.5 years. All other individuals in our cohort whose deletions encompass the terminal 751 kbp region report having seizures typical of WHS. Additional examples from the literature corroborate these observations and further refine the candidate seizure susceptibility region to a region 197 kbp in size, starting 368 kbp from the terminus of chromosome 4. We identify a small terminal region of chromosome 4p that represents a seizure susceptibility region. Deletion of this region in the context of WHS is sufficient for seizure occurrence.

Chromosome Deletion

Seizures - genetics

Humans

Child, Preschool

In Situ Hybridization, Fluorescence

Infant

Male

DNA Copy Number Variations - genetics

Chromosomes, Human, Pair 4 - genetics

Seizures - pathology

Microarray Analysis

Adolescent

Adult

Epilepsy - genetics

Female

Wolf-Hirschhorn Syndrome - genetics

Wolf-Hirschhorn Syndrome - pathology

Child

Epilepsy - pathology

Details

Title: Subtitle: Chromosomal microarray testing identifies a 4p terminal region associated with seizures in Wolf-Hirschhorn syndrome
Creators: Karen S Ho - Lineagen, Inc., Salt Lake City, Utah, USA
Sarah T South - ARUP Laboratories, Salt Lake City, Utah, USA Department of Pathology, University of Utah, Salt Lake City, Utah, USA
Amanda Lortz - 4p- Support Group, Sunbury, Ohio, USA
Charles H Hensel - Lineagen, Inc., Salt Lake City, Utah, USA
Mallory R Sdano - Lineagen, Inc., Salt Lake City, Utah, USA
Rena J Vanzo - Lineagen, Inc., Salt Lake City, Utah, USA
Megan M Martin - Lineagen, Inc., Salt Lake City, Utah, USA
Andreas Peiffer - Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA
Christophe G Lambert - Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, USA
Amy Calhoun - Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
John C Carey - Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA
Agatino Battaglia - Stella Maris Clinical Research Institute for Child and Adolescent Neuropsychiatry, Pisa, Italy
Resource Type: Journal article
Publication Details: Journal of medical genetics, Vol.53(4), pp.256-263
DOI: 10.1136/jmedgenet-2015-103626
PMID: 26747863
PMCID: PMC4819617
NLM abbreviation: J Med Genet
ISSN: 0022-2593
eISSN: 1468-6244
Language: English
Date published: 04/2016
Academic Unit: Stead Family Department of Pediatrics; Medical Genetics and Genomics
Record Identifier: 9984093471302771

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