A total of five Wolf-Hirschhorn syndrome (WHS) patient with a 4p16.3 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.
Lingua originaleEnglish
pagine (da-a)797-804
Numero di pagine8
RivistaEuropean Journal of Human Genetics
Stato di pubblicazionePubblicato - 2004


  • Abnormalities, Multiple
  • Adolescent
  • Adult
  • Child, Preschool
  • Chromosomal Instability
  • Chromosome Deletion
  • Chromosome Disorders
  • Chromosome Painting
  • Chromosomes, Human, Pair 4
  • Chromosomes, Human, Pair 8
  • Female
  • Genotype
  • Humans
  • Infant
  • Male
  • Microsatellite Repeats
  • Muscle Hypotonia
  • Phenotype
  • Seizures
  • Syndrome
  • Translocation, Genetic


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