Gilbert, Helen Louise; (1997) Molecular cytogenetic studies in Angelman syndrome. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are distinct neurogenetic disorders caused by the loss of function of distinct but closely linked genes on chromosome 15q11-q13, a region subject to genomic imprinting. AS and PWS most commonly arise from a de novo deletion of 15q11-q13. These deletions are maternal in origin in AS and paternal in origin in PWS. AS patients were analysed in order to find atypical deletions, which would define a critical region for the AS gene. One AS individual who had previously been identified with an apparent maternal deletion around the LS6-1 (D15S113) locus and normal DNA methylation imprints, initially appeared deleted for an LS6-1 positive cosmid by fluorescence in situ hybridisation (FISH). Further studies with overlapping cosmid and phage clones, single copy fragments and microsatellite markers, showed that this individual was not deleted for the D15S113 locus and that the original LS6-1 result was due to non-amplification of the maternal allele. A second AS individual was shown by FISH and microsatellite analysis to have an atypical deletion of 15q11-q13 such that the results obtained with PW71B (D15S63) and SNRPN appeared to conflict. A third individual who did not have the characteristic features of AS, but who had a maternally inherited deletion of 15q which included the D15S113 locus was also studied. FISH studies showed that the centromeric breakpoint was contained within a 520 kb yeast artificial chromosome (YAC) which maps between TD3-21 (D15S10) and LS6-1 (D15S113). AS individuals with no apparent maternal deletion of 15q11-q13, aberrant DNA methylation imprints and biparental inheritance of chromosome 15 were studied. Haplotypes were constructed in these individuals and their families, to localise a 'methylation control' locus. These studies were in agreement with a methylation control locus on chromosome 15q11-q13. Prenatal diagnosis was attempted in one family. The fetus had inherited the same critical maternal chromosome 15q11-q13 segment as the two affected siblings for the alleles tested, but had normal DNA methylation imprints. The mother was believed to be mosaic. FISH studies using phage clones obtained from the region on chromosome 15 designated as the 'imprinting centre' were carried out in these AS individuals, but were found to be unsuitable for diagnosing deletions of this region.

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