MECP2 germline mosaicism plays an important part in the inheritance of Rett syndrome: a study of MECP2 germline mosaicism in males

Abstract

Background Germline mosaicisms could be inherited to offspring, which considered as “de novo” in most cases. Paternal germline MECP2 mosaicism has been reported in fathers of girls with Rett syndrome (RTT) previously. For further study, we focused on MECP2 germline mosaicism in males, not only RTT fathers. Methods Thirty-two fathers of RTT girls with MECP2 pathogenic mutations and twenty-five healthy adult males without history and family history of RTT or other genetic disorders were recruited. Sperm samples were collected and ten MECP2 hotspot mutations were detected by micro-droplet digital PCR (mDDPCR). And routine semen test was performed at the same time if the sample was sufficient. Additionally, blood samples were also detected for those with sperm MECP2 mosaicisms. Results Nine fathers with RTT daughters (28.1%, 9/32) were found to have MECP2 mosaicism in their sperm samples, with the mutant allele fractions (MAFs) ranging from 0.05% to 7.55%. Only one father with MECP2 c.806delG germline mosaicism (MAF 7.55%) was found to have mosaicism in the blood sample, with the MAF was 0.28%. In the group of healthy adult males, MECP2 mosaicism was found in 7 sperm samples (28.0%, 7/25), with the MAFs ranging from 0.05% to 0.18%. None of the healthy adult males with MECP2 germline mosaicisms were found with MECP2 mosaicism in blood samples. There were no statistical differences in age, or the incidence of asthenospermia between fathers with RTT daughters and healthy adult males with MECP2 germline mosaicisms. Additionally, there was no linear correlation between MAFs of MECP2 mosaicisms and the age of males with germline MECP2 mosaicisms. Conclusions Germline MECP2 mosaicism could be found not only in fathers with RTT daughters but also in healthy adult males without family history of RTT. As germline mosaic mutations may be passed on to offspring which commonly known as “de novo”, more attention should be paid to germline mosaicism, especially in families with a proband diagnosed with genetic disorders.

Case Report of Suspected Gonadal Mosaicism in FOXP1-Related Neurodevelopmental Disorder

“…The detection of maternal gonadal mosaicism from oocytes causes technical difficulties, since oocytes can be obtained only by invasive procedure. However, sperm analysis is a possible method of detecting paternal gonadal mosaicism that was studied recently [ 20 , 22 , 23 , 24 , 25 ]. In a Chinese Dravet syndrome cohort, Yang et al reported higher levels of SCN1A mosaicism in sperm samples compared to blood samples of mosaic fathers [ 25 ].…”

“…reported on the paternal MECP2 gonadal mosaicism of nine fathers’ daughters with Rett syndrome, and in only one of case was mosaicism identified in the blood sample. The research team also found gonadal mosaicism in the sperm samples of healthy males who had no Rett syndrome relatives, and none of these individuals had mosaicism in blood-derived DNA [ 24 ]. A Hungarian case report by Bessenyei et al reported paternal gonadal mosaicism for MED13L -related disorders.…”