Paternal origin of a small, class I inv dup(15)

The inv dup(15) is the most common supernumerary chromosome in the general population. Inv dup(15) chromosomes are cytogenetically heterogeneous and are associated with a variety of clinical phenotypes. The classification of inv dup(15)s as large or small is based on the presence or absence, respectively, of Prader-Willi and/or Angelman syndrome (PWS/AS) loci. Large inv dup(15)s are associated with a clinical phenotype that includes mental and growth retardation, seizures, and dysmorphisms [Robinson et al., 1993a,b; Cheng et al., 1994; Leana-Cox et al., 1994]. Individuals with small inv dup(15)s containing no PWS/AS loci have variable phenotypes, ranging from normal, in the majority of cases [Stetten et al., 1981; Knight et al., 1984; Webb, 1994], or with apparently coincidental mental retardation [Leana-Cox et al., 1994], to PWS or AS resulting from associated uniparental disomy (UPD) or deletion of a chromosome 15 homologue [Robinson et al., 1993a,b; Cheng et al., 1994]. Small inv dup(15)s are further grouped as class I or II based on the proximity of the breakpoint to the centromere [Huang et al., 1997], class I with a breakpoint between the centromere and the most proximal chromosome 15 loci identified to date, D15S541/D15S542, and class II with a breakpoint between the centromere and the more distal chromosome locus, D15S543. The de novo large and small class II inv dup(15)s have a maternal origin [Huang et al., 1997] and U-type exchange between non-sister chromatids has been proposed for their mechanism of formation [Schreck et al., 1977; Van Dyke et al., 1977; Wandstrat et al., 1998]. The parental origin of class I inv dup(15)s has not yet been demonstrated. Patient LD, a female, was ascertained at birth (both parents 30 years of age at delivery) because of central hypotonia and minimal dysmorphic features. A clinical diagnosis of Prader-Willi syndrome was made. Karyotype analysis showed that LD had a supernumerary bisatellited marker, identified by DA/DAPI staining as derived from chromosome 15 in each cell examined. The G-band pattern suggested that the inv dup(15) was very small, with no 15q12 or 15q13 material. The parental karyotypes were normal. LD and her father were noted to have apparently identical large satellites by Q-banding (Fig. 1), suggesting that the inv dup(15) arose as a paternal event. FISH analysis demonstrated that there were no copies of PWS/AS loci present (data not shown). The karyotype in LD was therefore designated as 47,XX,+inv dup(15)(pter-> q11.1)de novo.ish inv dup(15)15q11.2(D15S11-,SNRPN-,D15S10-,GABRB3-). Microsatellite analyses of LD and her parents demonstrated that LD has failed to inherit a paternal allele in at least two PWS loci (D15S11 and D15S113) [Mutirangura et al., 1992] (data not shown). At locus D15S542 [Christian et al., 1995] (Fig. 2), LD inherited maternal alleles 1 and 3 and no paternal allele. LD also inherited two maternal and no paternal alleles at locus D15S543 [Christian et al., 1995] (data not shown). Pedigree of LD showing paternal origin of the inv dup(15) based on chromosome 15 satellite Q-band polymorphisms. PCR analysis of patient LD and her parents with polymorphic CA repeats for locus D15S542. Alleles produced by the PCR typing are labelled to the right of each autoradiograph. Therefore, the inv dup(15) chromosome in patient LD was shown to originate from the father, based on the presence of a large polymorphic satellite in both father and daughter (Fig. 1). The lack of PWS/AS loci on the inv dup(15) and only maternal alleles at loci D15S11, D15S113, D15S542, and D15S543 supports the clinical diagnosis of PWS by maternal UPD for chromosome 15 (Fig. 2). The distinctly different satellite polymorphisms on the two ends of the inv dup(15) suggest that it resulted from a premeiotic/meiotic U-type exchange between non-sister chromatids of the paternal normal chromosome 15 homologues, followed by meiosis resulting in a gamete containing only an inv dup(15). This paternal gamete then likely fertilized a maternal gamete heterodisomic for normal chromosome 15s as a result of a maternal meiosis I non-disjunction event. The conceptus was thus “rescued” from partial chromosome 15 monosomy and ultimately resulted in PWS. These findings are consistent with and support the proposal of Robinson et al. [1993b] that uniparental disomy explains the occurrence of PWS in patients with supernumerary inv dup(15)s. Microsatellite repeat polymorphisms at loci D15S542 and D15S543 showed only maternal alleles and indicate that this is a class I small inv dup(15). To the best of our knowledge, this is the first report of the paternal origin of a small class I inv dup(15). A paternal origin of a small inv dup(15), also based on cytogenetic polymorphisms, was reported previously [Wisniewski et al., 1980], but microsatellite analysis was not available. It is would be interesting to further classify this small inv dup(15) as class I or II. The authors would like to acknowledge Dr. A.E. Chudley for referring patient LD. We would also like to gratefully acknowledge the technical expertise provided by Ms. Tracey Russnak-Redden. This work was supported by a grant from the Manitoba Health Research Council to AJD.