Evaluation of methylation analysis for diagnostic testing in 258 referrals suspected of Prader-Willi or Angelman syndromes |
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Authors: | Tina Buchholz Julianne Jackson Lisa Robson A Smith |
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Institution: | (1) Department of Cytogenetics, Royal Alexandra Hospital for Children, PO Box 3515, Parramatta, NSW 2124, Australia e-mail: ellies@nch.edu.au, Tel.: +61-2-9845-3222, Fax: +61-2-9845-3238, AU |
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Abstract: | Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurodevelopmental disorders with interrelated genetic
mechanisms because genomic imprinting within the chromosome 15q11–13 region affects both the PWS and the AS locus. Methylation
analysis is one method of distinguishing between the maternally and paternally inherited chromosome 15. Here we present clinical
and molecular data on a large series of 258 referred patients, evaluated with methylation analysis: 115 with suspected PWS
and 143 with suspected AS. In these patients, the clinical phenotype was graded into three groups: classical (group 1); not
classical but possible (group 2); not classical and unlikely (group 3). For PWS, a fourth group consisted of hypotonic babies.
DNA methylation analysis confirmed the diagnosis of PWS in 30 patients (26%) and AS in 28 patients (20%). For 21 PWS patients
the mechanism was established: 15 had deletions, 4 had uniparental disomy (UPD) and 2 a presumed imprinting defect. Clinically
all those with an abnormal methylation pattern had the classical phenotype and none of those with a normal methylation pattern
had classical PWS. For 23 AS patients in whom a mechanism was established, 17 had a deletion, 3 had UPD and 3 had a presumed
imprinting defect. There was greater clinical overlap in AS, with 26 classical AS patients having a normal methylation pattern
while an abnormal methylation pattern was seen in one patient from group 2. In addition, there were a further 40 patients
with a normal methylation pattern in whom AS was still a possible diagnosis. Our conclusion is that methylation analysis provides
an excellent screening test for both syndromes, providing ∼99% diagnosis for PWS and for AS, a 75% diagnostic rate, supplemented
for the remaining 25% with an essential basic starting point to further investigations.
Received: 10 February 1998 / Accepted: 7 July 1998 |
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