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A novel approach using long‐read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders
OBJECTIVE: De novo mutations contribute significantly to severe early‐onset genetic disorders. Even if the mutation is apparently de novo, there is a recurrence risk due to parental germ line mosaicism, depending on in which gonadal generation the mutation occurred. METHODS: We demonstrate the power...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725701/ https://www.ncbi.nlm.nih.gov/pubmed/28921562 http://dx.doi.org/10.1002/pd.5156 |
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author | Wilbe, Maria Gudmundsson, Sanna Johansson, Josefin Ameur, Adam Stattin, Eva‐Lena Annerén, Göran Malmgren, Helena Frykholm, Carina Bondeson, Marie‐Louise |
author_facet | Wilbe, Maria Gudmundsson, Sanna Johansson, Josefin Ameur, Adam Stattin, Eva‐Lena Annerén, Göran Malmgren, Helena Frykholm, Carina Bondeson, Marie‐Louise |
author_sort | Wilbe, Maria |
collection | PubMed |
description | OBJECTIVE: De novo mutations contribute significantly to severe early‐onset genetic disorders. Even if the mutation is apparently de novo, there is a recurrence risk due to parental germ line mosaicism, depending on in which gonadal generation the mutation occurred. METHODS: We demonstrate the power of using SMRT sequencing and ddPCR to determine parental origin and allele frequencies of de novo mutations in germ cells in two families whom had undergone assisted reproduction. RESULTS: In the first family, a TCOF1 variant c.3156C>T was identified in the proband with Treacher Collins syndrome. The variant affects splicing and was determined to be of paternal origin. It was present in <1% of the paternal germ cells, suggesting a very low recurrence risk. In the second family, the couple had undergone several unsuccessful pregnancies where a de novo mutation PTPN11 c.923A>C causing Noonan syndrome was identified. The variant was present in 40% of the paternal germ cells suggesting a high recurrence risk. CONCLUSIONS: Our findings highlight a successful strategy to identify the parental origin of mutations and to investigate the recurrence risk in couples that have undergone assisted reproduction with an unknown donor or in couples with gonadal mosaicism that will undergo preimplantation genetic diagnosis. |
format | Online Article Text |
id | pubmed-5725701 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-57257012017-12-12 A novel approach using long‐read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders Wilbe, Maria Gudmundsson, Sanna Johansson, Josefin Ameur, Adam Stattin, Eva‐Lena Annerén, Göran Malmgren, Helena Frykholm, Carina Bondeson, Marie‐Louise Prenat Diagn Original Articles OBJECTIVE: De novo mutations contribute significantly to severe early‐onset genetic disorders. Even if the mutation is apparently de novo, there is a recurrence risk due to parental germ line mosaicism, depending on in which gonadal generation the mutation occurred. METHODS: We demonstrate the power of using SMRT sequencing and ddPCR to determine parental origin and allele frequencies of de novo mutations in germ cells in two families whom had undergone assisted reproduction. RESULTS: In the first family, a TCOF1 variant c.3156C>T was identified in the proband with Treacher Collins syndrome. The variant affects splicing and was determined to be of paternal origin. It was present in <1% of the paternal germ cells, suggesting a very low recurrence risk. In the second family, the couple had undergone several unsuccessful pregnancies where a de novo mutation PTPN11 c.923A>C causing Noonan syndrome was identified. The variant was present in 40% of the paternal germ cells suggesting a high recurrence risk. CONCLUSIONS: Our findings highlight a successful strategy to identify the parental origin of mutations and to investigate the recurrence risk in couples that have undergone assisted reproduction with an unknown donor or in couples with gonadal mosaicism that will undergo preimplantation genetic diagnosis. John Wiley and Sons Inc. 2017-10-17 2017-11 /pmc/articles/PMC5725701/ /pubmed/28921562 http://dx.doi.org/10.1002/pd.5156 Text en © 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Articles Wilbe, Maria Gudmundsson, Sanna Johansson, Josefin Ameur, Adam Stattin, Eva‐Lena Annerén, Göran Malmgren, Helena Frykholm, Carina Bondeson, Marie‐Louise A novel approach using long‐read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders |
title | A novel approach using long‐read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders |
title_full | A novel approach using long‐read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders |
title_fullStr | A novel approach using long‐read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders |
title_full_unstemmed | A novel approach using long‐read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders |
title_short | A novel approach using long‐read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders |
title_sort | novel approach using long‐read sequencing and ddpcr to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725701/ https://www.ncbi.nlm.nih.gov/pubmed/28921562 http://dx.doi.org/10.1002/pd.5156 |
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