Parental Somatic Mosaicism Detected During Prenatal Diagnosis

Overview

Journal Prenat Diagn

Publisher Wiley

Specialty Gynecology & Obstetrics

Date 2024 Nov 25

PMID 39586789

Authors

Natalie J Chandler

Elizabeth Scotchman

Fiona McKay

Vijaya Ramachandran

Lyn S Chitty

Affiliations

Soon will be listed here.

Abstract

Objective: Accurate recurrence risks are essential for genomic counselling and parental reproductive choices. Historically, Sanger sequencing was used to test parental samples, which has a limited sensitivity of ∼ 10% for detecting somatic mosaicism. Next generation sequencing (NGS) methods, utilised for non-invasive prenatal diagnosis (NIPD) and trio prenatal exome sequencing in our laboratory, have greater sensitivity. Here we review the cases of parental somatic mosaicism we have detected and discuss its impact on management.

Method: Laboratory databases from 1 January 2015 to 30 September 2022 were reviewed to identify all cases where parental somatic mosaicism was detected during NIPD and prenatal exome testing.

Results: During the development of NIPD testing, we identified 10/131 (7.6%) families with parental somatic mosaicism. In six cases where NGS detected levels between 0.37% and 8.82%, prior testing with Sanger sequencing had not detected mosaicism. In our exome sequencing cohort, we detected parental mosaicism in 4/101 (3.96%) cases. Clinical features of the condition were identified in 2/14 parents.

Conclusion: The sensitivity of the testing technique needs to be considered when counselling parents on recurrence risk. Parents need to be aware that modern approaches to prenatal diagnosis may allow identification of mosaicism, which may have implications for their own health and change recurrence risks for future pregnancies.

References

Mellis R, Chandler N, Chitty L . Next-generation sequencing and the impact on prenatal diagnosis. Expert Rev Mol Diagn. 2018; 18(8):689-699. DOI: 10.1080/14737159.2018.1493924. View

Chen Z, Moran K, Richards-Yutz J, Toorens E, Gerhart D, Ganguly T . Enhanced sensitivity for detection of low-level germline mosaic RB1 mutations in sporadic retinoblastoma cases using deep semiconductor sequencing. Hum Mutat. 2013; 35(3):384-91. PMC: 4112364. DOI: 10.1002/humu.22488. View

Domogala D, Gambin T, Zemet R, Wu C, Schulze K, Yang Y . Detection of low-level parental somatic mosaicism for clinically relevant SNVs and indels identified in a large exome sequencing dataset. Hum Genomics. 2021; 15(1):72. PMC: 8686574. DOI: 10.1186/s40246-021-00369-6. View

Jonsson H, Sulem P, Arnadottir G, Palsson G, Eggertsson H, Kristmundsdottir S . Multiple transmissions of de novo mutations in families. Nat Genet. 2018; 50(12):1674-1680. DOI: 10.1038/s41588-018-0259-9. View

Chitty L, Mason S, Barrett A, McKay F, Lench N, Daley R . Non-invasive prenatal diagnosis of achondroplasia and thanatophoric dysplasia: next-generation sequencing allows for a safer, more accurate, and comprehensive approach. Prenat Diagn. 2015; 35(7):656-62. PMC: 4657458. DOI: 10.1002/pd.4583. View

Miceikaite I, Fagerberg C, Brasch-Andersen C, Torring P, Kristiansen B, Hao Q . Comprehensive prenatal diagnostics: Exome versus genome sequencing. Prenat Diagn. 2023; 43(9):1132-1141. DOI: 10.1002/pd.6402. View

Brewer C, Gillespie M, Fierro J, Scaringe W, Li J, Lee C . The Value of Parental Testing by Next-Generation Sequencing Includes the Detection of Germline Mosaicism. J Mol Diagn. 2020; 22(5):670-678. DOI: 10.1016/j.jmoldx.2020.02.001. View

Jenkins L, Deans Z, Lewis C, Allen S . Delivering an accredited non-invasive prenatal diagnosis service for monogenic disorders and recommendations for best practice. Prenat Diagn. 2017; 38(1):44-51. DOI: 10.1002/pd.5197. View

Chandler N, Scotchman E, Mellis R, Ramachandran V, Roberts R, Chitty L . Lessons learnt from prenatal exome sequencing. Prenat Diagn. 2022; 42(7):831-844. PMC: 9325487. DOI: 10.1002/pd.6165. View

10.

Cao Y, Tokita M, Chen E, Ghosh R, Chen T, Feng Y . A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing. Genome Med. 2019; 11(1):48. PMC: 6660700. DOI: 10.1186/s13073-019-0658-2. View

11.

Chandler N, Ahlfors H, Drury S, Mellis R, Hill M, McKay F . Noninvasive Prenatal Diagnosis for Cystic Fibrosis: Implementation, Uptake, Outcome, and Implications. Clin Chem. 2019; 66(1):207-216. DOI: 10.1373/clinchem.2019.305011. View

12.

Xu X, Yang X, Wu Q, Liu A, Yang X, Ye A . Amplicon Resequencing Identified Parental Mosaicism for Approximately 10% of "de novo" SCN1A Mutations in Children with Dravet Syndrome. Hum Mutat. 2015; 36(9):861-72. PMC: 5034833. DOI: 10.1002/humu.22819. View

13.

Qin L, Wang J, Tian X, Yu H, Truong C, Mitchell J . Detection and Quantification of Mosaic Mutations in Disease Genes by Next-Generation Sequencing. J Mol Diagn. 2016; 18(3):446-453. DOI: 10.1016/j.jmoldx.2016.01.002. View

14.

Preka E, Ellershaw D, Chandler N, Ahlfors H, Spencer H, Chitty L . Cell-Free DNA in Pediatric Solid Organ Transplantation Using a New Detection Method of Separating Donor-Derived from Recipient Cell-Free DNA. Clin Chem. 2020; 66(10):1300-1309. DOI: 10.1093/clinchem/hvaa173. View

15.

Mellis R, Chandler N, Jenkins L, Chitty L . The role of sonographic phenotyping in delivering an efficient noninvasive prenatal diagnosis service for FGFR3-related skeletal dysplasias. Prenat Diagn. 2020; 40(7):785-791. DOI: 10.1002/pd.5687. View

16.

Cook C, Armstrong L, Boerkoel C, Clarke L, du Souich C, Demos M . Somatic mosaicism detected by genome-wide sequencing in 500 parent-child trios with suspected genetic disease: clinical and genetic counseling implications. Cold Spring Harb Mol Case Stud. 2021; 7(6). PMC: 8751411. DOI: 10.1101/mcs.a006125. View

17.

Wright C, Prigmore E, Rajan D, Handsaker J, McRae J, Kaplanis J . Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data. Nat Commun. 2019; 10(1):2985. PMC: 6611863. DOI: 10.1038/s41467-019-11059-2. View

18.

Bernkopf M, Abdullah U, Bush S, Wood K, Ghaffari S, Giannoulatou E . Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation. Nat Commun. 2023; 14(1):853. PMC: 9932158. DOI: 10.1038/s41467-023-36606-w. View

19.

Rahbari R, Wuster A, Lindsay S, Hardwick R, Alexandrov L, Al Turki S . Timing, rates and spectra of human germline mutation. Nat Genet. 2015; 48(2):126-133. PMC: 4731925. DOI: 10.1038/ng.3469. View

20.

Hill M, Twiss P, Verhoef T, Drury S, McKay F, Mason S . Non-invasive prenatal diagnosis for cystic fibrosis: detection of paternal mutations, exploration of patient preferences and cost analysis. Prenat Diagn. 2015; 35(10):950-8. PMC: 4672687. DOI: 10.1002/pd.4585. View