Mosaicism of de novo pathogenic SCN1A variants in epilepsy is a frequent phenomenon that correlates with variable phenotypes

Abstract

Postzygotic mutation is a common phenomenon in SCN1A-related epilepsies. Participants with mosaicism have on average milder phenotypes, suggesting that mosaicism can be a major modifier of SCN1A-related diseases. Detection of mosaicism has important implications for genetic counseling and can be achieved by deep sequencing of unique reads.

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

“…Alternatively, mosaicism can be present at higher grades in variants that can be detected by Sanger sequencing. We have recently used smMIPs and NGS to identify high-grade mosaicism in 9% of pathogenic SCN1A variants detected in regular diagnostics, of which 9 out of 11 were previously considered heterozygous based on Sanger sequencing results 12. Similar percentages of high-grade mosaic variants in other genes have been reported previously 36–38.…”

“…Detecting high-grade mosaicism in a proband is currently the only way to virtually rule out low-grade mosaicism in a parent, since only one member of a family can be mosaic for a specific variant and all techniques can miss very small percentages of (gonadal) mosaicism. Testing probands for high-grade mosaicism therefore adds value to testing parents for low-grade mosaicism in the assessment of recurrence risks, especially because this occurs in a substantial amount of patients (9%) 12. We suggest that analysing both parents and the proband with smMIPs and NGS is currently the most cost-effective way of assessing parental mosaicism in SCN1A -related epilepsy after a pathogenic variant is found in regular diagnostics.…”

“…We suggest that analysing both parents and the proband with smMIPs and NGS is currently the most cost-effective way of assessing parental mosaicism in SCN1A -related epilepsy after a pathogenic variant is found in regular diagnostics. Since either low-grade or high-grade mosaicism could be detected in a total of 12% of families carrying pathogenic SCN1A variants in this cohort (11 probands12 and 4 parents in 122 families), a substantial amount of families will likely benefit from improved counselling this way.…”

“…In most families, parents had been assessed for carriership of the pathogenic SCN1A variant by Sanger sequencing in a regular diagnostic setting; families in which parents were shown to be heterozygous or mosaic carriers of their children’s pathogenic variants were regarded as participants themselves and excluded from additional DNA testing. Families in which mosaicism was demonstrated in the proband in previous research12 were also excluded, since this rules out parental mosaicism. Informed consent was obtained from participants, according to the Declaration of Helsinki.…”

“…However, an important part of the disease variability is still unexplained, and multiple modifying factors have been suggested 9–13. We have recently shown that mosaicism in patients is an important modifier of SCN1A -related disease severity 12. Mosaicism arises when a variant occurs postzygotically, leading to genetically distinct cell populations.…”