A double cryptic chromosome imbalance is an important factor to explain phenotypic variability in Wolf-Hirschhorn syndrome

Marcella Zollino, Rosetta Lecce, Angelo Selicorni, Marina Murdolo, Irene Mancuso, Giuseppe Marangi, Giuseppe Zampino, Livia Garavelli, Alessandra Ferrarini, Mariano Rocchi, John M. Opitz, Giovanni Neri

Research output: Contribution to journalArticlepeer-review


A total of five Wolf-Hirschhorn syndrome (WHS) patient with a 4p 16.3 de novo microdeletion was referred because of genotype-phenotype inconsistencies, first explained as phenotypic variability of the WHS. The actual deletion size was found to be about 12 Mb in three patients, 5 Mb in another one and 20 Mb in the last one, leading us to hypothesize the presence of an extrachromosome segment on the deleted 4p. A der(4)(4qter← p16.1::8p23← pter) chromosome, resulting from an unbalanced de novo translocation was, in fact, detected in four patients and a der(4)(4qter←q32::4p15.3←qter) in the last. Unbalanced t(4;8) translocations were maternal in origin, the rec(4p;4q) was paternal. With the purpose of verifying frequency and specificity of this phenomenon, we investigated yet another group of 20 WHS patients with de novo large deletions (n = 13) or microdeletions (n = 7) and with apparently straightforward genotype- phenotype correlations. The rearrangement was paternal in origin, and occurred as a single anomaly in 19 out of 20 patients. In the remaining patient, the deleted chromosome 4 was maternally derived and consisted of a der(4)(4qter←,4p16.3::8p23-←8pter). In conclusions, we observed that 20% (5/25) of de novo WHS-associated rearrangements were maternal in origin and 80% (20/25) were paternal. All the maternally derived rearrangements were de novo unbalanced t(4;8) translocations and showed specific clinical phenotypes. Paternally derived rearrangements were usually isolated deletions. It can be inferred that a double, cryptic chromosome imbalance is an important factor for phenotypic variability in WHS. It acts either by masking the actual deletion size or by doubling a quantitative change of the genome.

Original languageEnglish
Pages (from-to)797-804
Number of pages8
JournalEuropean Journal of Human Genetics
Issue number10
Publication statusPublished - Oct 2004


  • Phenotypic variability
  • t(4;8)de novo
  • WHS

ASJC Scopus subject areas

  • Genetics(clinical)

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