A novel approach using long-read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders
- Resource Type
- Authors
- Maria, Wilbe; Sanna, Gudmundsson; Josefin, Johansson; Adam, Ameur; Eva-Lena, Stattin; Göran, Annerén; Helena, Malmgren; Carina, Frykholm; Marie-Louise, Bondeson
- Source
- Prenatal Diagnosis
- Subject
- Male
Mosaicism
DNA Mutational Analysis
Noonan Syndrome
Nuclear Proteins
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Original Articles
Phosphoproteins
Risk Assessment
Pregnancy
Humans
Female
Original Article
Mandibulofacial Dysostosis
Preimplantation Diagnosis
- Language
- ISSN
- 1097-0223
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 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.
What's already known about this topic? De novo mutations contribute significantly to severe early‐onset genetic disorders. what does this study add? A novel successful strategy to identify the parental origin of de novo mutations and to investigate the recurrence risk by SMRT sequencing and ddPCR.