Inherited Interstitial Duplications of Proximal 15q: Genotype-Phenotype Correlations

Abstract

We present the cytogenetic, molecular cytogenetic, and molecular genetic results on 20 unrelated patients with an interstitial duplication of the proximal long arm of chromosome 15. Multiple probes showed that the Prader-Willi/Angelman critical region (PWACR) was included in the duplication in 4/20 patients, each ascertained with developmental delay. The duplication was also found in two affected but not in three unaffected sibs of one of these patients. All four probands had inherited their duplication from their mothers, three of whom were also affected. Two of the affected mothers also carried a maternally inherited duplication, whereas the duplication in the unaffected mother and in an unaffected grandmother was paternal in origin, raising the possibility of a parental-origin effect. The PWACR was not duplicated in the remaining 16 patients, of whom 4 were referred with developmental delay. In the 14 families for which parental samples were available, the duplication was inherited with equal frequency from a phenotypically normal parent, mother or father. Comparative genomic hybridization undertaken on two patients suggested that proximal 15q outside the PWACR was the origin of the duplicated material. The use of PWACR probes discriminates between a large group of duplications of no apparent clinical significance and a smaller group, in which a maternally derived PWACR duplication is consistently associated with developmental delay and speech difficulties but not with overt features of either Prader-Willi syndrome or Angelman syndrome.

Structure of Chromosomal Duplicons and their Role in Mediating Human Genomic Disorders

“…Although less common, direct duplications of proximal 15q11-15q13 have been observed (Pettigrew et al 1987;Clayton-Smith et al 1993a;Browne et al 1997;Cook et al 1997Cook et al , 1998Mohandas et al 1999), some with the same breakpoints as PWS/AS deletions, whereas others have a more distal breakpoint similar to the large inv dup(15) (Repetto et al 1998;Robinson et al 1998). Patients with maternal duplications that include at least the PWS/AS critical region show devel-opmental delay, or autism (Browne et al 1997;Cook et al 1997Cook et al , 1998Repetto et al 1998), whereas a few individuals with paternal duplications have a nonspecific developmental delay (Mohandas et al 1999).…”

“…Patients with maternal duplications that include at least the PWS/AS critical region show devel-opmental delay, or autism (Browne et al 1997;Cook et al 1997Cook et al , 1998Repetto et al 1998), whereas a few individuals with paternal duplications have a nonspecific developmental delay (Mohandas et al 1999). Finally, a few triplication cases have been reported (Schinzel et al 1994;Cassidy et al 1996;Long et al 1998;Robinson et al 1998), as well as paracentric inversions of 15q11-15q13 (Clayton-Smith et al 1993b).…”

High resolution comparative genomic hybridisation analysis reveals imbalances in dyschromosomal patients with normal or apparently balanced conventional karyotypes

“…A likewise small duplication at 15q has been described in normal individuals. 12 Since conventional banding techniques do not detect small imbalances, the extension of such chromosomal variations in normal populations is unknown, and it is possible that several types of euchromatic variants may be transmitted in families, without reproductive or clinical effect.…”

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

“…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.…”