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Multi-omics analysis reveals multiple mechanisms causing Prader-Willi like syndrome in a family with a X;15 translocation

Eisfeldt, Jesper ; Rezayee, Fatemah ; Pettersson, Maria LU ; Lagerstedt, Kristina ; Malmgren, Helena ; Falk, Anna LU ; Grigelioniene, Giedre and Lindstrand, Anna (2022) In Human Mutation 43(11). p.1567-1575
Abstract

Prader-Willi syndrome (PWS; MIM# 176270) is a neurodevelopmental disorder caused by the loss of expression of paternally imprinted genes within the PWS region located on 15q11.2. It is usually caused by either maternal uniparental disomy of chromosome 15 (UPD15) or 15q11.2 recurrent deletion(s). Here, we report a healthy carrier of a balanced X;15 translocation and her two daughters, both with the karyotype 45,X,der(X)t(X;15)(p22;q11.2),-15. Both daughters display symptoms consistent with haploinsufficiency of the SHOX gene and PWS. We explored the architecture of the derivative chromosomes and investigated effects on gene expression in patient-derived neural cells. First, a multiplex ligation-dependent probe amplification methylation... (More)

Prader-Willi syndrome (PWS; MIM# 176270) is a neurodevelopmental disorder caused by the loss of expression of paternally imprinted genes within the PWS region located on 15q11.2. It is usually caused by either maternal uniparental disomy of chromosome 15 (UPD15) or 15q11.2 recurrent deletion(s). Here, we report a healthy carrier of a balanced X;15 translocation and her two daughters, both with the karyotype 45,X,der(X)t(X;15)(p22;q11.2),-15. Both daughters display symptoms consistent with haploinsufficiency of the SHOX gene and PWS. We explored the architecture of the derivative chromosomes and investigated effects on gene expression in patient-derived neural cells. First, a multiplex ligation-dependent probe amplification methylation assay was used to determine the methylation status of the PWS-region revealing maternal UPD15 in daughter 2, explaining her clinical symptoms. Next, short read whole genome sequencing and 10X genomics linked read sequencing was used to pinpoint the exact breakpoints of the translocation. Finally, we performed transcriptome sequencing on neuroepithelial stem cells from the mother and from daughter 1 and observed biallelic expression of genes in the PWS region (including SNRPN) in daughter 1. In summary, our multi-omics analysis highlights two different PWS mechanisms in one family and provide an example of how structural variation can affect imprinting through long-range interactions.

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author
; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Mutation
volume
43
issue
11
pages
1567 - 1575
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85135005399
  • pmid:35842787
ISSN
1059-7794
DOI
10.1002/humu.24440
language
English
LU publication?
no
additional info
© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.
id
307263fc-2762-4fa1-a06c-d9736b55daab
date added to LUP
2022-09-20 14:08:49
date last changed
2024-06-27 20:53:59
@article{307263fc-2762-4fa1-a06c-d9736b55daab,
  abstract     = {{<p>Prader-Willi syndrome (PWS; MIM# 176270) is a neurodevelopmental disorder caused by the loss of expression of paternally imprinted genes within the PWS region located on 15q11.2. It is usually caused by either maternal uniparental disomy of chromosome 15 (UPD15) or 15q11.2 recurrent deletion(s). Here, we report a healthy carrier of a balanced X;15 translocation and her two daughters, both with the karyotype 45,X,der(X)t(X;15)(p22;q11.2),-15. Both daughters display symptoms consistent with haploinsufficiency of the SHOX gene and PWS. We explored the architecture of the derivative chromosomes and investigated effects on gene expression in patient-derived neural cells. First, a multiplex ligation-dependent probe amplification methylation assay was used to determine the methylation status of the PWS-region revealing maternal UPD15 in daughter 2, explaining her clinical symptoms. Next, short read whole genome sequencing and 10X genomics linked read sequencing was used to pinpoint the exact breakpoints of the translocation. Finally, we performed transcriptome sequencing on neuroepithelial stem cells from the mother and from daughter 1 and observed biallelic expression of genes in the PWS region (including SNRPN) in daughter 1. In summary, our multi-omics analysis highlights two different PWS mechanisms in one family and provide an example of how structural variation can affect imprinting through long-range interactions.</p>}},
  author       = {{Eisfeldt, Jesper and Rezayee, Fatemah and Pettersson, Maria and Lagerstedt, Kristina and Malmgren, Helena and Falk, Anna and Grigelioniene, Giedre and Lindstrand, Anna}},
  issn         = {{1059-7794}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{11}},
  pages        = {{1567--1575}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Human Mutation}},
  title        = {{Multi-omics analysis reveals multiple mechanisms causing Prader-Willi like syndrome in a family with a X;15 translocation}},
  url          = {{http://dx.doi.org/10.1002/humu.24440}},
  doi          = {{10.1002/humu.24440}},
  volume       = {{43}},
  year         = {{2022}},
}