Abstract
Genomic mosaicism in parental gametes and peripheral tissues is an important consideration for genetic counseling. We studied a Chinese cohort affected by a severe epileptic disorder, Dravet syndrome (DS). There were 56 fathers who donated semen and 15 parents who donated multiple peripheral tissue samples. We used an ultra-sensitive quantification method, micro-droplet digital PCR (mDDPCR), to detect parental mosaicism of the proband’s pathogenic mutation in SCN1A, the causal gene of DS in 112 families. Ten of the 56 paternal sperm samples were found to exhibit mosaicism of the proband’s mutations, with mutant allelic fractions (MAFs) ranging from 0.03% to 39.04%. MAFs in the mosaic fathers’ sperm were significantly higher than those in their blood (p = 0.00098), even after conditional probability correction (p’ = 0.033). In three mosaic fathers, ultra-low fractions of mosaicism (MAF < 1%) were detected in the sperm samples. In 44 of 45 cases, mosaicism was also observed in other parental peripheral tissues. Hierarchical clustering showed that MAFs measured in the paternal sperm, hair follicles and urine samples were clustered closest together. Milder epileptic phenotypes were more likely to be observed in mosaic parents (p = 3.006e-06). Our study provides new insights for genetic counseling.
Highlights
Genomic mosaicism in parental gametes and peripheral tissues is an important consideration for genetic counseling
We previously identified parental mosaicism for approximately 10% of seemingly “de novo” SCN1A mutations using PGM amplicon sequencing for mosaicism (PASM)[21], which can detect mutations with mutant allelic fractions (MAFs) of 0.5%
Blood samples from the parents were available for this study from 242 families, 234 of which did not have parents carrying SCN1A mutations, and 132 of these families agreed to enroll in this study of mosaicism
Summary
Genomic mosaicism in parental gametes and peripheral tissues is an important consideration for genetic counseling. Parental mosaicism has been reported in cohorts of complex neurological and psychiatric disorders, such as autism spectrum disorder[14,15,16,17], intellectual disability[18], and epileptic encephalopathies[19] In these reported families, parents with mosaic mutations are either normal[20] or have milder clinical phenotypes[15] compared to their affected children[21]. The postzygotic single nucleotide mosaic mutation profile between paternal sperm and blood samples remains largely unknown at the cohort level for monogenic epileptic disorders caused by non-cancer genes. The differences in mutation frequencies of postzygotic single nucleotide mosaicism are not yet well understood in the context of multiple tissues or in sperm cells at the cohort level for neurological disorders. Studies using multiple samples for disorders caused by non-cancer genes, such as ATP1A335, MEFV38, PCDH1939,40, SCN1A21, and SCN5A42, were limited by their sample sizes, because the collection of a large cohort is difficult and reports tend to appear as case studies
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