Molecular characterisation of four cases of intrachromosomal triplication of chromosome 15q11-q14

Abstract

Context-Chromosomalabnormalities that involve the proximal region of chromosome 15q occur relatively frequently in the human population. However, interstitial triplications involving one 15 homologue are very rare with three cases reported to date. Objective-To provide a detailed molecular characterisation of four additional patients with interstitial triplications of chromosome 15q11-q14. Design-Molecular analyses were performed using DNA markers and probes specific for the 15q11-q14 region. Setting-Molecular cytogenetics laboratory at the University of Chicago. (15)). In all patients the orientation of the triplicated segments was normalinverted-normal, suggesting that a common mechanism of rearrangement may have been involved. Microsatellite analysis showed the parental origin of the trip(15) to be maternal in three cases and paternal in one case. The paternal triplication patient had features similar to PWS, one maternal triplication patient had features similar to AS, and the other two maternal triplication patients had non-specific findings including hypotonia and mental retardation. Methylation analysis at exon 1 of the SNRPN locus showed increased dosage of either the paternal or maternal bands in the paternal or maternal triplication patients, respectively, suggesting that the methylation pattern shows a dose dependent increase that correlates with the parental origin of the triplication. In addition, the expression of SNRPN was analysed by northern blotting and expression levels were consistent with dosage and parental origin of the triplication. Conclusions-These four additional cases of trip(15) will provide additional information towards understanding the phenotypic eVects of this abnormality and aid in understanding the mechanism of formation of other chromosome 15 rearrangements. (J Med Genet 2001;38:26-34)

Recurrent rearrangements in the proximal 15q11–q14 region: a new breakpoint cluster specific to unbalanced translocations

“…BP4 has been mapped between markers D15S1019 and D15S165 and BP5 between markers D15S165 and D15S144. 10,12,18,34 Indeed, a BP located distal to the marker D15S144 had previously been hypothesized, 18,34 but neither characterized nor delineated. Our results demonstrated that such a BP distal to BP5 exists and may be specific to translocations.…”

“…It was initially located between markers D15S12 and D15S24 ( 33 , for review) and has been subsequently more precisely located between markers D15S931 and D15S1019. 12,20,31 Two other distal BPs, BP4 and BP5, which have not been fully characterized, are involved in cases of large 15q11 -q14 interstitial triplications and inv dup (15) chromosomes. BP4 has been mapped between markers D15S1019 and D15S165 and BP5 between markers D15S165 and D15S144.…”

Low-copy repeats at the human VIPR2 gene predispose to recurrent and nonrecurrent rearrangements

“…Alternatively, the triplications could form by U-type exchanges between three chromatids. [26][27][28][29] One exchange between homologous chromatids would take place at the distal breakpoint region, the other at the proximal breakpoint region, between either sister chromatids or homologous chromosomes. Brewer et al 23 proposed a replicationbased mechanism, supported by yeast observations, involving the generation of a dimeric inverted circular intermediate.…”

Human chromosome 15q11-q14 regions of rearrangements contain clusters of LCR15 duplicons

“…D15S144). 9,22 These observations would suggest the existence of different repeat sequences involved in rearrangements affecting these regions.…”

“…19 ± 21 Two other breakpoint regions named BP4 and BP5 have been mapped distally to BP3, between markers D15S24 and D15S144, and seem to be implicated in cases of large 15q11-q14 duplications or triplications. 4,5,9,18,20,21 These distal regions appear to be more complex since breakpoint variability has been described (BP located distal to Figure 1 15q11-q14 chromosome rearrangements, breakpoint regions, and LCR15s clusters and copies. BP1 to BP5 breakpoints and class I (BP1) and class II (BP2) PWS/AS deletion types are shown.…”