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. 2021 May 11:12:608889.
doi: 10.3389/fgene.2021.608889. eCollection 2021.

A Streamlined Approach to Prader-Willi and Angelman Syndrome Molecular Diagnostics

Samuel P Strom  1 , Waheeda A Hossain  2 , Melina Grigorian  1 , Mickey Li  1 , Joseph Fierro  1 , William Scaringe  1 , Hai-Yun Yen  1 , Mirandy Teguh  1 , Joanna Liu  1 , Harry Gao  1 , Merlin G Butler  2
Affiliations

A Streamlined Approach to Prader-Willi and Angelman Syndrome Molecular Diagnostics

Samuel P Strom et al. Front Genet. .

Abstract

Establishing or ruling out a molecular diagnosis of Prader-Willi or Angelman syndrome (PWS/AS) presents unique challenges due to the variety of different genetic alterations that can lead to these conditions. Point mutations, copy number changes, uniparental isodisomy (i-UPD) 15 of two subclasses (segmental or total isodisomy), uniparental heterodisomy (h-UPD), and defects in the chromosome 15 imprinting center can all cause PWS/AS. Here, we outline a combined approach using whole-exome sequencing (WES) and DNA methylation data with methylation-sensitive multiplex ligation-dependent probe amplification (MLPA) to establish both the disease diagnosis and the mechanism of disease with high sensitivity using current standard of care technology and improved efficiency compared to serial methods. The authors encourage the use of this approach in the clinical setting to confirm and establish the diagnosis and genetic defect which may account for the secondary genetic conditions that may be seen in those with isodisomy 15, impacting surveillance and counseling with more accurate recurrence risks. Other similarly affected individuals due to other gene disorders or cytogenetic anomalies such as Rett syndrome or microdeletions would also be identified with this streamlined approach.

Keywords: Angelman syndrome; Prader–Willi syndrome; copy number variants; methylation status; point mutations; streamlined molecular diagnostics; whole-exome sequencing.

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Conflict of interest statement

SS, MG, ML, JF, WS, H-YY, MT, JL, and HG were employees of Fulgent Genetics, a for-profit firm offering genetic testing as a fee for service. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Chromosome 15 ideogram. Genes and previously reported breakpoints (“BP”) in the 15q11-q13 region are shown in their relative genomic positions. Genes not marked with asterisk were sequenced by the whole-exome sequencing test performed.
FIGURE 2
FIGURE 2
Prader–Willi syndrome and Angelman syndrome molecular analysis workflow. The approach begins with methylation-sensitive MLPA (MS-MLPA) to determine the methylation status and copy number of the 15q11-q13 region (step 1). Based on the results of step 1, proceed to step 2, with whole-exome sequencing (WES) as illustrated in the flowchart for the determination of copy number status, sequencing of genes on chromosome 15 and elsewhere with the determination of AOH and/or LOH. UPD, uniparental disomy; PWS, Prader–Willi syndrome; AS, Angelman syndrome; AOH, absence of heterozygosity; IC, chromosome 15q11 imprinting center; LOH, loss of heterozygosity.
See this image and copyright information in PMC

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