title: A double cryptic chromosome imbalance is an important factor to explain phenotypic variability in Wolf-Hirschhorn syndrome.
abstract: 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.
authors.affiliation: Istituto di Genetica Medica, Facoltà di Medicina A. Gemelli, UCSC, Roma, Italy. mzollino@rm.unicatt.it
authors.forename: Marcella
authors.initials: M
authors.lastname: Zollino
authors.forename: Rosetta
authors.initials: R
authors.lastname: Lecce
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.forename: Marina
authors.initials: M
authors.lastname: Murdolo
authors.forename: Irene
authors.initials: I
authors.lastname: Mancuso
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Marangi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
authors.forename: Livia
authors.initials: L
authors.lastname: Garavelli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferrarini
authors.forename: Mariano
authors.initials: M
authors.lastname: Rocchi
authors.forename: John M
authors.initials: JM
authors.lastname: Opitz
authors.forename: Giovanni
authors.initials: G
authors.lastname: Neri
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics; D000293:Adolescent; D000328:Adult; D002675:Child, Preschool; D043171:Chromosomal Instability / Q000235:genetics; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000175:diagnosis* / Q000235:genetics*; D020223:Chromosome Painting; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D009123:Muscle Hypotonia / Q000175:diagnosis / Q000235:genetics; D010641:Phenotype; D012640:Seizures / Q000175:diagnosis / Q000235:genetics; D013577:Syndrome; D014178:Translocation, Genetic