Revealing parental mosaicism: the hidden answer to the recurrence of apparent de novo variants.

Mosaicism refers to the presence of two or more populations of genetically distinct cells within an individual, all of which originate from a single zygote. Previous literature estimated the percentage of parental mosaicism ranged from 0.33 to 25.9%. In this study, parents whose children had previously been diagnosed with developmental disorders with an apparent de novo variant were recruited. Peripheral blood, buccal and semen samples were collected from these parents if available for the detection of potential parental mosaicism using droplet digital PCR, complemented with the method of blocker displacement amplification. Among the 20 families being analyzed, we report four families with parental mosaicism (4/20, 20%). Two families have maternal gonosomal mosaicism (EYA1 and EBF3) and one family has paternal gonadal mosaicism (CHD7) with a pathogenic/ likely pathogenic variant. One family has a paternal gonosomal mosaicism with a variant of uncertain significance (FLNC) with high clinical relevance. The detectable variant allele frequency in our cohort ranged from 8.7-35.9%, limit of detection 0.08-0.16% based on our in-house EBF3 assay. Detecting parental mosaicism not only informs family with a more accurate recurrence risk, but also facilitates medical teams to create appropriate plans for pregnancy and delivery, offering the most suitable care.

Meta-analysis of the diagnostic and clinical utility of exome and genome sequencing in pediatric and adult patients with rare diseases across diverse populations.

PURPOSE: This meta-analysis aims to compare the diagnostic and clinical utility of exome sequencing (ES) vs genome sequencing (GS) in pediatric and adult patients with rare diseases across diverse populations. METHODS: A meta-analysis was conducted to identify studies from 2011 to 2021. RESULTS: One hundred sixty-one studies across 31 countries/regions were eligible, featuring 50,417 probands of diverse populations. Diagnostic rates of ES (0.38, 95% CI 0.36-0.40) and GS (0.34, 95% CI 0.30-0.38) were similar (P = .1). Within-cohort comparison illustrated 1.2-times odds of diagnosis by GS over ES (95% CI 0.79-1.83, P = .38). GS studies discovered a higher range of novel genes than ES studies; yet, the rate of variant of unknown significance did not differ (P = .78). Among high-quality studies, clinical utility of GS (0.77, 95% CI 0.64-0.90) was higher than that of ES (0.44, 95% CI 0.30-0.58) (P < .01). CONCLUSION: This meta-analysis provides an important update to demonstrate the similar diagnostic rates between ES and GS and the higher clinical utility of GS over ES. With the newly published recommendations for clinical interpretation of variants found in noncoding regions of the genome and the trend of decreasing variant of unknown significance and GS cost, it is expected that GS will be more widely used in clinical settings.