Amplicon Resequencing Identified Parental Mosaicism for Approximately 10% of “
            <i>de novo</i>
            ”
            <i>SCN1A</i>
            Mutations in Children with Dravet Syndrome

Xu, Xiaojing; Yang, Xiaoxu; Wu, Qixi; Liu, Aijie; Yang, Xiaoling; Ye, Adam Yongxin; Huang, August Yue; Li, Jiarui; Wang, Meng; Yu, Zhe; Wang, Sheng; Zhang, Zhichao; Wu, Xiru; Wei, Liping; Zhang, Yuehua

doi:10.1002/humu.22819

Cited by 114 publications

(125 citation statements)

References 64 publications

Supporting

Mentioning

115

Contrasting

Order By: Relevance

“…All cases were confirmed in a maternally inherited pattern sharing an identical mutation with their mothers while no mutations in their father. Additionally, we confirmed no existence of a mosaic mutation in their parents using digital PCR and PGM (Xu et al, 2015). The phenotypes of the three female patients were consistent with those of RTT but the five males not.…”

Section: Discussionsupporting

confidence: 77%

Familial cases and male cases with MECP2 mutations

Zhang

Zhao

Bao

et al. 2017

American J of Med Genetics Pt B

Self Cite

View full text Add to dashboard Cite

This is the first report of Chinese familial cases with Rett syndrome (RTT) or X‐linked mental retardation (XLMR). RTT is a neurodevelopmental disorder that almost exclusively affects females. Most RTT cases are sporadic. We have studied eight cases with MECP2 mutations in six Chinese families, including three females and five males with RTT or XLMR. All shared identical MECP2 mutations with their mothers. The three females fulfilled the diagnostic criteria for RTT, while the five males were XLMR. A random X‐chromosome inactive (XCI) pattern was seen in all the three female patients and two mothers while a skewed XCI in the rest four mothers. The clinical manifestations and pathogenic gene spectrum between male and female patients were different. The different MECP2 mutations and different XCI pattern may be the determinants of the phenotypic heterogeneity between the family members.

show abstract

Section: Discussionsupporting

confidence: 77%

Familial cases and male cases with MECP2 mutations

Zhang

Zhao

Bao

et al. 2017

American J of Med Genetics Pt B

Self Cite

View full text Add to dashboard Cite

show abstract

“…No validation studies were performed, which may have led to false positive results; however, as the reported percentages of mosaicism were relatively high (16.7%–30.6%), this risk may be low. Xu et al 20 found parental mosaicism in 10% of Dravet syndrome families as well. Yang et al 21 reported an even higher incidence: parental mosaicism was detected in 25% of Dravet syndrome families.…”

Section: Discussionmentioning

confidence: 95%

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

et al. 2018

View full text Add to dashboard Cite

BackgroundDravet syndrome is a severe genetic encephalopathy, caused by pathogenic variants in SCN1A. Low-grade parental mosaicism occurs in a substantial proportion of families (7%–13%) and has important implications for recurrence risks. However, parental mosaicism can remain undetected by methods regularly used in diagnostics. In this study, we use single-molecule molecular inversion probes (smMIP), a technique with high sensitivity for detecting low-grade mosaic variants and high cost-effectiveness, to investigate the incidence of parental mosaicism of SCN1A variants in a cohort of 90 families and assess the feasibility of this technique.MethodsDeep sequencing of SCN1A was performed using smMIPs. False positive rates for each of the proband’s pathogenic variants were determined in 145 unrelated samples. If parents showed corresponding variant alleles at a significantly higher rate than the established noise ratio, mosaicism was confirmed by droplet digital PCR (ddPCR).ResultsSequence coverage of at least 100× at the location of the corresponding pathogenic variant was reached for 80 parent couples. The variant ratio was significantly higher than the established noise ratio in eight parent couples, of which four (5%) were regarded as true mosaics, based on ddPCR results. The false positive rate of smMIP analysis without ddPCR was therefore 50%. Three of these variants had previously been considered de novo in the proband by Sanger sequencing.ConclusionsmMIP technology combined withnext generation sequencing (NGS) performs better than Sanger sequencing in the detection of parental mosaicism. Because parental mosaicism has important implications for genetic counselling and recurrence risks, we stress the importance of implementing high-sensitivity NGS-based assays in standard diagnostics.

show abstract

“…These genes included SCN1A in 3 of 40 families with apparently de novo SCN1A mutations; these findings showing that approximately 10% of children with an apparently de novo SCN1A variant had a parent with mosaicism replicated those of another study. 5 In addition, one variant occurred in each of the following genes: SCN8A, GNB1, SLC6A1, DNM1, KCNT1, CACNA1A , and KCNQ2 . Owing to the small sample size, we were unable to determine whether certain genes, such as those encoding ion channels, were more prone to mosaicism.…”

Section: To the Editormentioning

confidence: 99%