Parental Somatic Mosaicism Detected During Prenatal Diagnosis

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.

FIGURE 1

A comparison of Sanger sequencing and PCR capture next generation sequencing results of parental and affected proband genomic DNA samples for selected cases ((A)—Case 6; (B)—Case 4; (C)—Case 7; (D)—Case 14); see Supporting Information S1: Figures 1–3 for all cases. For the Sanger sequencing traces, all variants occur at the middle peak in each image. The middle panel in each figure shows traces from the sample tested, the other sequence trace is from a normal control sample (either top or bottom depending on if forward or reverse) and the other panel is the electropherogram traces comparing the peaks detected in the sample trace in comparison to the normal control. Red arrows indicate signs of mosaicism and black arrows indicate background noise causing mosaicism to be missed. PCR capture Next Generation Sequencing results are given as the number of reads for the wild type and variant sequences. The percentage VAF has also been calculated using the values in red indicating somatic mosaicism.