Duplications of proximal 16q flanked by heterochromatin are not euchromatic variants and show no evidence of heterochromatic position effect

Abstract

Extra euchromatic material was found within the major heterochromatic block of chromosome 16 (16qh) in one de novo case and seven members of two families. In contrast to the euchromatic variants of chromosome 9 (9qh), which are derived from pericentromeric euchromatin, molecular cytogenetics confirmed that these duplications were of 16q11.2→q12.2 in the de novo case, of 16q11.2→q13 in three members of family 1 and 16q11.2→q12.1 in four members of family 2. The duplication had arisen as a post-zygotic mitotic event in the mother of family 1 and been transmitted paternally in family 2. An insertional mechanism of origin is proposed for the duplications in case 1 and family 1. Expression at the 16q13 matrix metalloproteinase-2 (MMP2)locus in families 1 and 2 was proportional to genomic copy number and not therefore consistent with position effect silencing due to the flanking blocks of heterochromatin. We conclude that proximal 16q duplications within 16qh are not novel euchromatic variants but associated with a variable phenotype including developmental delay, speech delay, learning difficulties and behavioural problems. The behavioural problems in families ascertained through affected children are much less severe than those encountered in previous patients ascertained as adults.

Novel deletion variants of 9q13–q21.12 and classical euchromatic variants of 9q12/qh involve deletion, duplication and triplication of large tracts of segmentally duplicated pericentromeric euchromatin

“…This is in contrast to the situation on chromosome 16, where duplications of unique sequence proximal 16q are found within the major heterochromatic block and are associated with developmental delay and behavioural problems. 24 Finally, we have confirmed the nature and extent of the duplications that underlie the 9p12 euchromatic variants of chromosome 9 which extend over the same area identified by Di Giacomo et al 10 It is interesting that the 9p12 amplification variants reported by Lecce et al 11 involve clones at both ends of the 9p12 duplication variant region ( Table 1). The pericentromeric region of chromosome 9 is thought to follow the 'domain' model established for chromosome 10 in which the centromere is surrounded by large alphoid repeat arrays which are themselves flanked by interchromosomally duplicated sequences which are, in turn, flanked by intrachromosomal duplications 25 .…”

Severe Progressive Autism Associated with Two de novo Changes: A 2.6-Mb 2q31.1 Deletion and a Balanced t(14;21)(q21.1;p11.2) Translocation with Long-Range Epigenetic Silencing of <i>LRFN5</i> Expression

“…Furthermore, in families where 16q11-q13 derived euchromatic material was duplicated and inserted within the major heterochromatin block of chromosome 16 (16qh), there was no evidence for a heterochromatin position effect, i.e. repressed gene expression from the duplicated segment [Barber et al, 2006]. Alternatively, since a centromere is likely to associate with heterochromatin at the nuclear periphery, i.e.…”

Molecular Cytogenetic Characterization of Two Cases with de novo Small Mosaic Supernumerary Marker Chromosomes Derived from Chromosome 16: Towards a Genotype/Phenotype Correlation

“…In only a few of these cases the markers have been characterized extensively, however their content seems to be limited to the centromeric and heterochromatin regions. Trisomy involving band 16q12 is usually associated with clinical impact [for review see Barber et al, 2006]. It seems that individuals with duplications of this proximal 16q do not have characteristic facies but frequently have short stature, developmental and speech delay, learning difficulties and behavioral problems which range from mild to severe [Barber et al, 2006].…”

“…Trisomy involving band 16q12 is usually associated with clinical impact [for review see Barber et al, 2006]. It seems that individuals with duplications of this proximal 16q do not have characteristic facies but frequently have short stature, developmental and speech delay, learning difficulties and behavioral problems which range from mild to severe [Barber et al, 2006]. However, a recent report showed that not all euchromatic trisomies of 16q12 have a clinical repercussion [Rodrí-guez et al, 2008].…”

“…Cases with an sSMC consisting of only these centromeric and heterochromatin regions do not show clinical manifestations [Callen et al, 1990[Callen et al, , 1991Crolla, 1998;Paoloni-Giacobino et al, 1998;Sanz et al, 2000]. However, trisomy involving band 16q12 is usually associated with a clinical impact [Barber et al, 2006].…”