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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
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Uppsala, Sweden..
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0001-6085-6749
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2017 (English)In: Prenatal Diagnosis, ISSN 0197-3851, E-ISSN 1097-0223, Vol. 37, no 11, p. 1146-1154Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2017. Vol. 37, no 11, p. 1146-1154
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-342916DOI: 10.1002/pd.5156ISI: 000415897200012PubMedID: 28921562OAI: oai:DiVA.org:uu-342916DiVA, id: diva2:1185825
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Swedish Society for Medical Research (SSMF)Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-02-26Bibliographically approved

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Wilbe, MariaGudmundsson, SannaAmeur, AdamStattin, Eva-LenaAnnerén, GöranFrykholm, CarinaBondeson, Marie-Louise
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Science for Life Laboratory, SciLifeLabMedicinsk genetik och genomikDepartment of Immunology, Genetics and Pathology
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