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

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 (s...

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Autores principales: Strom, Samuel P., Hossain, Waheeda A., Grigorian, Melina, Li, Mickey, Fierro, Joseph, Scaringe, William, Yen, Hai-Yun, Teguh, Mirandy, Liu, Joanna, Gao, Harry, Butler, Merlin G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148043/
https://www.ncbi.nlm.nih.gov/pubmed/34046054
http://dx.doi.org/10.3389/fgene.2021.608889
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author Strom, Samuel P.
Hossain, Waheeda A.
Grigorian, Melina
Li, Mickey
Fierro, Joseph
Scaringe, William
Yen, Hai-Yun
Teguh, Mirandy
Liu, Joanna
Gao, Harry
Butler, Merlin G.
author_facet Strom, Samuel P.
Hossain, Waheeda A.
Grigorian, Melina
Li, Mickey
Fierro, Joseph
Scaringe, William
Yen, Hai-Yun
Teguh, Mirandy
Liu, Joanna
Gao, Harry
Butler, Merlin G.
author_sort Strom, Samuel P.
collection PubMed
description 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.
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spelling pubmed-81480432021-05-26 A Streamlined Approach to Prader-Willi and Angelman Syndrome Molecular Diagnostics Strom, Samuel P. Hossain, Waheeda A. Grigorian, Melina Li, Mickey Fierro, Joseph Scaringe, William Yen, Hai-Yun Teguh, Mirandy Liu, Joanna Gao, Harry Butler, Merlin G. Front Genet Genetics 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. Frontiers Media S.A. 2021-05-11 /pmc/articles/PMC8148043/ /pubmed/34046054 http://dx.doi.org/10.3389/fgene.2021.608889 Text en Copyright © 2021 Strom, Hossain, Grigorian, Li, Fierro, Scaringe, Yen, Teguh, Liu, Gao and Butler. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Strom, Samuel P.
Hossain, Waheeda A.
Grigorian, Melina
Li, Mickey
Fierro, Joseph
Scaringe, William
Yen, Hai-Yun
Teguh, Mirandy
Liu, Joanna
Gao, Harry
Butler, Merlin G.
A Streamlined Approach to Prader-Willi and Angelman Syndrome Molecular Diagnostics
title A Streamlined Approach to Prader-Willi and Angelman Syndrome Molecular Diagnostics
title_full A Streamlined Approach to Prader-Willi and Angelman Syndrome Molecular Diagnostics
title_fullStr A Streamlined Approach to Prader-Willi and Angelman Syndrome Molecular Diagnostics
title_full_unstemmed A Streamlined Approach to Prader-Willi and Angelman Syndrome Molecular Diagnostics
title_short A Streamlined Approach to Prader-Willi and Angelman Syndrome Molecular Diagnostics
title_sort streamlined approach to prader-willi and angelman syndrome molecular diagnostics
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148043/
https://www.ncbi.nlm.nih.gov/pubmed/34046054
http://dx.doi.org/10.3389/fgene.2021.608889
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