Paternally derived de novo interstitial duplication of proximal 15q in a patient with developmental delay

Abstract

Interstitial duplications of proximal 15q containing the Prader-Willi syndrome/Angelman syndrome (PWS/AS) region have been found in patients with autism or atypical autism. In these cases with an abnormal phenotype, the duplications were maternally derived. Paternal origin of the duplication has been associated with a normal phenotype. We report on a patient who presented with nonspecific developmental delay and partial agenesis of the rostral corpus callosum. Fluorescence in situ hybridization (FISH) studies using probes specific for the PWS/AS region demonstrated a double signal on one chromosome 15, indicating the presence of an interstitial duplication of proximal 15q involving the PWS/ AS region in the patient. Parental chromosomes were normal with FISH studies. Methylation analysis at exon alpha of the SNRPN locus showed a maternal band at 4.2 kb and a paternal band of apparent double intensity at 0.9 kb, suggestive of one copy of the maternal allele and two copies of the paternal allele in the patient. Microsatellite analysis was informative at the GABRB3 locus in the family, which showed the inheritance of two different paternal alleles and a maternal allele in the patient consistent with the origin of this duplication from an unequal crossing over between the two chromosome 15 homologs in the father. This is the first report of an abnormal phenotype associated with a paternally derived duplication of proximal 15q shown to contain the PWS/AS region by molecular techniques.

Characterisation of interstitial duplications and triplications of chromosome 15q11–q13

“…Interestingly, in one proband, the duplication was paternal in origin. Paternal duplications are only rarely associated with an abnormal phenotype (Mao and Jalal 2000;Mohandas et al 1999). However, the identification of an additional case suggests that this association may not be coincidental.…”

“…Abnormal phenotypes have previously been reported for two paternal duplications (Mao and Jalal 2000;Mohandas et al 1999) and two paternal triplications (Cassidy et al 1996;Ungaro et al 2001). There is further evidence from our families that additional paternal copies of the PWACR may cause an abnormal phenotype.…”

“…Additional maternal copies of the PWACR produce an abnormal phenotype that is distinct from both PWS and AS and includes developmental delay, particularly with regard to speech and language problems, and behavioural problems sometimes falling within the autistic spectrum, with only mild or no dysmorphic features (Bolton et al 2001). In contrast, paternal duplication carriers are generally unaffected (Browne et al 1997;Cook et al 1997;Bolton et al 2001) and are only rarely associated with an abnormal phenotype (Mao and Jalal 2000;Mohandas et al 1999).…”

A Paternally Inherited Duplication in the Prader-Willi/ Angelman Syndrome Critical Region: A Case and Family Study

“…There have been very few reports of 15q11-13 duplications involving the paternally inherited chromosome, and most of these cases have been identified after testing the extended family of cases with maternally inherited duplications (Bolton et al, 2001;Cook et al, 1997;Mohandas et al, 1999;Schroer et al, 1998). Individuals with paternal duplications have usually been reported to be mildly affected or unaffected.…”

“…The limited available evidence has also suggested that the phenotypic manifestations of inherited duplications that involve the PWACR may result in developmental delay without ASD (Bolton et al, 2001;Mohandas et al, 1999) and may be dependent on the parental origin of the duplication with more marked impairments when the duplication is maternally derived (Bolton et al, 2001;Browne et al, 1997;Cook et al, 1997).…”