Characterization of a duplication in the terminal band of 4p by molecular cytogenetics

Abstract

An infant with multiple anomalies including small head, large apparently low-set ears, beaked nose, micrognathia, choanal stenosis, proptosis, atrial-septal defect, and left inguinal hernia was found, on chromosome analysis, to have a longer than normal terminal band 4p16 by G and R-banding. In situ hybridization of biotin-labeled DNA probes C39, BJ14, BJ54, BJ19, BJ7, and BJ11 showed them to be duplicated. Probes I14, A157.1, and the telomeric sequence, (TTAGGG)n, which hybridized to the more distal part of 4p16.3, were not duplicated. These results confirm the impression by G and R-banding of a duplication within band 4p16, a region extending from approximately 2.1 Mb from the telomere, proximally, to the junction of 4p16.1 and 4p15.3. This is the smallest confirmed duplication of distal 4p reported to date, with many of the classical findings of dup(4p) syndrome.

?Tandem? duplication of 4p16.1p16.3 chromosome region associated with 4p16.3pter molecular deletion resulting in Wolf-Hirschhorn syndrome phenotype

“…From literature reports [Dallapiccola et al, 1977;Gonzales et al, 1977], partial 4p trisomy appears to give rise to a distinctive MCA/MR syndrome, whose component manifestations include a characteristic facial appearance, with a ''boxer nose'' and microphthalmia, as well as an increased number of whorls on fingertips. The reported duplications usually involve a large portion of 4p, but a considerable number of clinical signs, in particular the facial appearance, are retained even in cases of small duplications [Curry et al, 1982;Wyandt et al, 1993]. The duplication detected in our patient was very similar in size to those reported by Curry et al [1982] and by Wyandt et al [1993], but the expected clinical manifestations were practically absent, although one cannot exclude that some of them might become apparent later.…”

Clinical Manifestations of Partial Trisomy 4p

“…These signs are usually observed even in cases of small terminal duplications [9]. The smallest duplicated segment leading to the dup(4p) phenotype was described by Wyandt et al [6] in an 18-month-old infant. Despite the small size of the duplication, the region 4p16.1 to 4p16.3 appears to represent the region responsible for the typical phenotype.…”

“…Such phenotypic variability may depend on the length and location of the duplicated portion of 4p. The characteristic features of partial 4p trisomy are most likely due to duplication of bands 4p15.2 to 4p16.3 [5,6]. We report on a fetus ascertained prenatally because of intrauterine growth retardation, lung and kidney hypoplasia, and congenital heart defects associated with a distal de novo trisomy of the terminal short arm of chromosome 4.…”

Benign and pathogenic copy number variation on the short arm of chromosome 4

“…Two distinct phenotypes have been associated with deletions on the short arm of chromosome 4: the Wolf-Hirschhorn syndrome, which is likely associated with terminal deletions, and the proximal 4p deletion syndrome, which is likely associated with interstitial deletions (4p16 ] p12) (Ishikawa et al, 1990;Estabrooks et al, 1993;Chitayat et al, 1995;White et al, 1995;Kozma et al, 1999;Tonk et al, 2003;South et al, 2005;Basinko et al, 2008). In addition to the deletions several duplications linked to a well-characterised chromosome disorder have been reported (Gonzalez et al, 1977;Curry et al, 1982;Keren et al, 1982;Wyandt et al, 1993;Patel et al, 1995;Sabaratnam et al, 2000;Bernardini et al, 2005;Kakinuma et al, 2007). An overview of all published pathogenic CNVs on 4p is presented in Fig.…”

“…On the short arm of chromosome 4 (4p16 ] p11), 157 pathogenic deletions and 51 pathogenic duplications have been reported as of May 2008. Wyandt et al, 1993;20) Sabaratnam et al, 2000. Since novel high resolution screening techniques paved their way in diagnostics, an increasing number of submicroscopic pathogenic CNVs have been reported. Array CGH data of patients with constitutional anomalies are collected in DECIPHER (www.sanger.ac.uk/PostGenomics/decipher); however the pathogenicity of those imbalances often remains uncertain.…”