Microarray and FISH-based genotype-phenotype analysis of 22 Japanese patients with Wolf-Hirschhorn syndrome

Kenji Shimizu, Keiko Wakui, Tomoki Kosho, Nobuhiko Okamoto, Seiji Mizuno, Kazuya Itomi, Shigeto Hattori, Kimio Nishio, Osamu Samura, Yoshiyuki Kobayashi, Yuko Kako, Takashi Arai, Tsutomu Oh-ishi, Hiroshi Kawame, Yoko Narumi, Hirofumi Ohashi, Yoshimitsu Fukushima

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


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 29.42Mb. 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 (<6Mb) deletions and in 86% (12/14) of cases with larger deletions (>6Mb). 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 1.3Mb from 4pter, 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.

Original languageEnglish
Pages (from-to)597-609
Number of pages13
JournalAmerican Journal of Medical Genetics, Part A
Issue number3
Publication statusPublished - 2014 Mar


  • 4p deletion
  • Fluorescence in situ hybridization (FISH)
  • Genotype-phenotype correlation
  • Microarray analysis
  • Mosaicism
  • Seizures
  • Wolf-Hirschhorn syndrome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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