Parent of Origin, Mosaicism, and Recurrence Risk: Probabilistic Modeling Explains the Broken Symmetry of Transmission Genetics

Abstract

Most new mutations are observed to arise in fathers, and increasing paternal age positively correlates with the risk of new variants. Interestingly, new mutations in X-linked recessive disease show elevated familial recurrence rates. In male offspring, these mutations must be inherited from mothers. We previously developed a simulation model to consider parental mosaicism as a source of transmitted mutations. In this paper, we extend and formalize the model to provide analytical results and flexible formulas. The results implicate parent of origin and parental mosaicism as central variables in recurrence risk. Consistent with empirical data, our model predicts that more transmitted mutations arise in fathers and that this tendency increases as fathers age. Notably, the lack of expansion later in the male germline determines relatively lower variance in the proportion of mutants, which decreases with paternal age. Subsequently, observation of a transmitted mutation has less impact on the expected risk for future offspring. Conversely, for the female germline, which arrests after clonal expansion in early development, variance in the mutant proportion is higher, and observation of a transmitted mutation dramatically increases the expected risk of recurrence in another pregnancy. Parental somatic mosaicism considerably elevates risk for both parents. These findings have important implications for genetic counseling and for understanding patterns of recurrence in transmission genetics. We provide a convenient online tool and source code implementing our analytical results. These tools permit varying the underlying parameters that influence recurrence risk and could be useful for analyzing risk in diverse family structures.

Clinical and Molecular Aspects of MBD5-Associated Neurodevelopmental Disorder (MAND)

“…Gonadal mosaicism, while not yet reported for MBD5 deletions, is a possibility and should be communicated to the families. 23 Although the theoretical risk for recurrence in sibs of a proband is very low, several multi-generation families exist. 2,6 Prenatal diagnosis through CMA for pregnancies at increased risk can be done if the genetic diagnosis has been established in a previously affected family member.…”

Post-zygotic Point Mutations Are an Underrecognized Source of De Novo Genomic Variation

“…29 Considering this, the presence of parental mosaicism in 4 out of 50 individuals of our cohort stresses the importance of a thorough follow-up in families affected by a disorder due to a de novo mutation. 30 Notably, the lower limit of detection by Sanger sequencing has been reported to be close to only 10%, 25 whereas the highest level of parental mosaicism here detected was only 6.15% and could not be identified by Sanger sequencing ( Figure S6).…”

Assessment of parental mosaicism in SCN1A-related epilepsy by single-molecule molecular inversion probes and next-generation sequencing

“…A recurrence risk of 1% is often counselled to parents in the case of a presumed de novo genetic disorder34; recurrence risks, however, rise when father or mother are shown to carry variant alleles as well. Parents may make different choices regarding prenatal diagnostics when this knowledge is available.…”