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

• Published in: American journal of human genetics Vol. 61; no. 6; pp. 1342 - 1352
• Main Authors: Browne, C.E., Dennis, N.R., Maher, E., Long, F.L., Nicholson, J.C., Sillibourne, J., Barber, J.C.K.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01-12-1997; University of Chicago Press
• Subjects: Adult; Angelman syndrome; Angelman Syndrome - genetics; Biological and medical sciences; Child, Preschool; Chromosome 15; Chromosome aberrations; Chromosomes, Human, Pair 15 - genetics; Chromosomes, Human, Pair 15 - ultrastructure; Cosmids; Diseases in Twins; Duplication(s), interstitial; Female; Fetal Diseases - genetics; Genomic Imprinting; Genotype-phenotype correlation(s); Humans; In Situ Hybridization, Fluorescence; Infant; Intellectual Disability - genetics; Male; Medical genetics; Medical sciences; Multigene Family; Pedigree; Phenotype; Polymerase Chain Reaction; Prader-Willi syndrome; Prader-Willi Syndrome - genetics; Angelman syndrome; Prader-Willi syndrome; Chromosome 15; Duplication(s), interstitial; Genotype-phenotype correlation(s); Chromosomal aberration; Human; Nervous system diseases; Correlation; Maternal origin; Long arm; Pathogenesis; Genotype; Developmental disorder; Genetic determinism; Language disorder; Genomic imprinting; Phenotype; Abnormal chromosome D15; Cytogenetics; Abnormal chromosome; Chromosome duplication
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/301624

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.