期刊
HUMAN MUTATION
卷 43, 期 12, 页码 1956-1969出版社
WILEY-HINDAWI
DOI: 10.1002/humu.24454
关键词
high-depth sequencing; mosaic mutations; parental mosaicism; tuberous sclerosis complex
资金
- CURE Epilepsy
- Australia National Health and Medical Research Council
- Victorian State Government Operational Infrastructure Support
- Epilepsy Foundation of Victoria
- Sanming Project of Medicine in Shenzhen
This study investigated the contribution of low-level mosaic TSC1/TSC2 mutations in unsolved sporadic patients and families with TSC. The findings highlight the need to change laboratory practice to improve diagnostic yield.
Tuberous sclerosis complex (TSC) is a multi-system genetic disorder. Most patients have germline mutations in TSC1 or TSC2 but, 10%-15% patients do not have TSC1/TSC2 mutations detected on routine clinical genetic testing. We investigated the contribution of low-level mosaic TSC1/TSC2 mutations in unsolved sporadic patients and families with TSC. Thirty-one sporadic TSC patients negative on routine testing and eight families with suspected parental mosaicism were sequenced using deep panel sequencing followed by droplet digital polymerase chain reaction. Pathogenic variants were found in 22/31 (71%) unsolved sporadic patients, 16 were mosaic (median variant allele fraction [VAF] 6.8% in blood) and 6 had missed germline mutations. Parental mosaicism was detected in 5/8 families (median VAF 1% in blood). Clinical testing laboratories typically only report pathogenic variants with allele fractions above 10%. Our findings highlight the critical need to change laboratory practice by implementing higher sensitivity assays to improve diagnostic yield, inform patient management and guide reproductive counseling.
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