Clinical Application of an Innovative Multiplex-Fluorescent-Labeled STRs Assay for Prader-Willi Syndrome and Angelman Syndrome.

Kaihui Zhang,Haiyan Zhang,Shu Liu,Bing Feng,Zhongtao Gai,Yi Liu,Yali Yang,Rui Dong

doi:10.1371/journal.pone.0147824

Kaihui Zhang, Haiyan Zhang + Show 6 more

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https://doi.org/10.1371/journal.pone.0147824

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Abstract

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two clinically distinct neurodevelopmental disorders caused by absence of paternally or maternally expressed imprinted genes on chr15q11.2-q13.3. Three mechanisms are known to be involved in the pathogenesis: microdeletions, uniparental disomy (UPD) and imprinting defects. Both disorders are difficult to be definitely diagnosed at early age if no available molecular cytogenetic tests. In this study, we identified 5 AS patients with the maternal deletion and 26 PWS patients with paternal deletion on chr15q11-q13 by using an innovative multiplex-fluorescent-labeled short tandem repeats (STRs) assay based on linkage analysis, and validated by the methylation-specific PCR and array comparative genomic hybridization techniques. More interesting, one of these PWS patients was confirmed as maternal uniparental isodisomy by the STR linkage analysis. The phenotypic and genotypic characteristics of these individuals were also presented. Our results indicate that the new linkage analysis is much faster and easier for large-scale screening deletion and uniparental disomy, thus providing a valuable method for early diagnosis of PWS/AS patients, which is critical for genetic diagnosis, management and improvement of prognosis.

Highlights

Prader-willi syndrome (PWS) and Angelman syndrome (AS) are the first known human genomic imprinting disorders, each with an estimated prevalence of 1/15000-1/25000 in live births
A 4-year-old girl patient from the family 6 displayed two chromosome 15 alleles inherited only from one maternal chromosome 15 that was known as complete uniparental isodisomy of chromosomes 15, the patient was eventually identified as PWS with maternal uniparental disomy (mUPD) type
The results of all the patients with AS/PWS tested by short tandem repeats (STRs) linkage analysis were listed in Table 1 and S1 Table

Summary

Introduction

Prader-willi syndrome (PWS) and Angelman syndrome (AS) are the first known human genomic imprinting disorders, each with an estimated prevalence of 1/15000-1/25000 in live births. PWS and AS were initially identified by high-resolution chromosome banding, in which patients were found with an interstitial deletion in the same region of chromosome. Clinical Genetic Study for PWS and AS. There is ample evidence that a cluster of genes located in the chromosome region 15q11q13 were expressed from solely paternal or maternal chromosome. It was considered that the deficiency of UBE3A gene from the maternal chromosome could lead to AS [1,2]. While the loss of function mutation in SNORD116 snoRNAs could cause the key characteristics of the PWS phenotype [1,3]

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