title: Microarray and FISH-based genotype-phenotype analysis of 22 Japanese patients with Wolf-Hirschhorn syndrome.
abstract: Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion syndrome of the distal 4p chromosome, characterized by craniofacial features, growth impairment, intellectual disability, and seizures. Although genotype-phenotype correlation studies have previously been published, several important issues remain to be elucidated including seizure severity. We present detailed clinical and molecular-cytogenetic findings from a microarray and fluorescence in situ hybridization (FISH)-based genotype-phenotype analysis of 22 Japanese WHS patients, the first large non-Western series. 4p deletions were terminal in 20 patients and interstitial in two, with deletion sizes ranging from 2.06 to 29.42 Mb. The new Wolf-Hirschhorn syndrome critical region (WHSCR2) was deleted in all cases, and duplication of other chromosomal regions occurred in four. Complex mosaicism was identified in two cases: two different 4p terminal deletions; a simple 4p terminal deletion and an unbalanced translocation with the same 4p breakpoint. Seizures began in infancy in 33% (2/6) of cases with small (<6 Mb) deletions and in 86% (12/14) of cases with larger deletions (>6 Mb). Status epilepticus occurred in 17% (1/6) with small deletions and in 87% (13/15) with larger deletions. Renal hypoplasia or dysplasia and structural ocular anomalies were more prevalent in those with larger deletions. A new susceptible region for seizure occurrence is suggested between 0.76 and 1.3 Mb from 4 pter, encompassing CTBP1 and CPLX1, and distal to the previously-supposed candidate gene LETM1. The usefulness of bromide therapy for seizures and additional clinical features including hypercholesterolemia are also described.
authors.affiliation: Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan; Division of Medical Genetics, Saitama Children's Medical Center, Saitama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Shimizu
authors.forename: Keiko
authors.initials: K
authors.lastname: Wakui
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kosho
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Okamoto
authors.forename: Seiji
authors.initials: S
authors.lastname: Mizuno
authors.forename: Kazuya
authors.initials: K
authors.lastname: Itomi
authors.forename: Shigeto
authors.initials: S
authors.lastname: Hattori
authors.forename: Kimio
authors.initials: K
authors.lastname: Nishio
authors.forename: Osamu
authors.initials: O
authors.lastname: Samura
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kako
authors.forename: Takashi
authors.initials: T
authors.lastname: Arai
authors.forename: Oh-ishi
authors.initials: OI
authors.lastname: Tsutomu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawame
authors.forename: Yoko
authors.initials: Y
authors.lastname: Narumi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ohashi
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Fukushima
mesh_terms: D000293:Adolescent; D044466:Asian People / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002871:Chromosome Banding; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D007223:Infant; D007564:Japan; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010641:Phenotype; D054877:Wolf-Hirschhorn Syndrome / Q000175:diagnosis* / Q000235:genetics*
keywords: 4p deletion; Wolf-Hirschhorn syndrome; fluorescence in situ hybridization (FISH); genotype-phenotype correlation; microarray analysis; mosaicism; seizures