Prader-Willi syndrome and a deletion/duplication within the 15q11-q13 region.

Prader-Willi syndrome (PWS) is characterised by infantile hypotonia, feeding difficulties, hypogonadism, small hands and feet, mental deficiency, obesity in early childhood, a particular facial appearance, and a paternally derived 15q11-q13 deletion (approximately 4 million bp in size) in about 70% of subjects, maternal disomy 15 (both 15s from the mother) in 25% of subjects, or an imprinting mutation in 2-5% of subjects. PWS syndrome is considered to be the most common genetic cause of marked obesity in humans. Two breakpoint clusters have been reported centromeric to locus ZNF127 with the most proximal breakpoint (BP1) accounting for 44% of cytogenetic deletions while 56% of deletions occur at the second proximal breakpoint (BP2). 6 The second breakpoint (BP2) lies between loci D15S541/S542 and D15S543 and breakpoint BP1 is proximal to D15S541/ S542. 6 A third breakpoint (BP3) is distally located within the 15q11-q13 region and mapped telomeric to the P locus (involved in hypopigmentation) in nearly all deletion subjects studied. The apparent genetic instability in the 15q11-q13 region may be attributed to DNA sequences identified in low copy repeats in the vicinity of the common breakpoints occurring in patients with PWS. These END repeats are derived from large genomic duplications of a novel gene (HERC2). 12 The END repeats flanking the 15q11-q13 region may be involved with interand intrachromosomal misalignment and homologous recombination resulting in the common PWS deletion and facilitated by active transcription of the END repeats in male and female gametogenesis. 14 Duplication, triplication, and tetrasomy of the 15q11-q13 region have been reported with varying degrees of clinical manifestation. Generally, duplications of maternal origin have been associated with developmental delay and autistic behaviour. Paternal duplications have no apparent impact on the phenotype although a patient reported by Mohandas et al with an interstitial duplication of proximal 15q of paternal origin had non-specific developmental delay and partial agenesis of the corpus callosum. In addition, Ungaro et al reported molecular characterisation of four subjects presenting with mild to severe mental retardation and features of PWS or Angelman syndrome along with intrachromosomal triplications of the chromosome region 15q11-q14. Here, we present a patient with the typical 15q11-q13 deletion seen in PWS who also carried a familial duplication of centromerically located 15q11-q13 loci. The paternally derived deletion of 15q11-q13 occurred at breakpoints BP2 and BP3 and the paternal duplication was centromeric to breakpoint BP2.