INHERITED INTERSTITIAL DUPLICATIONS OF PROXIMAL 15Q - GENOTYPE-PHENOTYPE CORRELATIONS

We present the cytogenetic, molecular cytogenetic, and molecular genet ic results on 20 unrelated patients with an interstitial duplication o f 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 dela y. The duplication was also found in two affected but not in three una ffected sibs of one of these patients. All four probands had inherited their duplication from their mothers, three of whom were also affecte d. Two of the affected mothers also carried a maternally inherited dup lication, whereas the duplication in the unaffected mother and in an u naffected grandmother was paternal in origin, raising the possibility of a parental-origin effect. The PWACR was not duplicated in the remai ning 16 patients, of whom 4 were referred with developmental delay. In the 14 families for which parental samples were available, the duplic ation 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 discrimina tes between a large group of duplications of no apparent clinical sign ificance and a smaller group, in which a maternally derived PWACR dupl ication is consistently associated with developmental delay and speech difficulties but not with overt features of either Prader-Willi syndr ome or Angelman syndrome.