Mosaicism in tuberous sclerosis complex: Lowering the threshold for clinical reporting

Ye, Z; Lin, S; Zhao, X; Bennett, MF; Brown, NJ; Wallis, M; Gao, X; Sun, L; Wu, J; Vedururu, R; Witkowski, T; Gardiner, F; Stutterd, C; Duan, J; Mullen, SA; McGillivray, G; Bodek, S; Valente, G; Reagan, M; Yao, Y; Li, L; Chen, L; Boys, A; Adikari, TN; Cao, D; Hu, Z; Beshay, V; Zhang, VW; Berkovic, SF; Scheffer, IE; Liao, J; Hildebrand, MS

Author(s): Ye, Z; Lin, S; Zhao, X; Bennett, MF; Brown, NJ; Wallis, M; Gao, X; Sun, L; Wu, J; Vedururu, R; Witkowski, T; Gardiner, F; Stutterd, C; Duan, J; Mullen, SA; McGillivray, G; Bodek, S; Valente, G; Reagan, M; Yao, Y; Li, L; Chen, L; Boys, A; Adikari, TN; Cao, D; Hu, Z; Beshay, V; Zhang, VW; Berkovic, SF; Scheffer, IE; Liao, J; Hildebrand, MS;
Details: Publication Year 2022-12,Volume 43,Issue #12,Page 1956-1969
Journal Title: Human Mutation
Publication Type: Research article
Abstract: 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.
Keywords: Humans; *Tuberous Sclerosis/diagnosis/genetics/pathology; Tuberous Sclerosis Complex 2 Protein/genetics; Tuberous Sclerosis Complex 1 Protein/genetics; Tumor Suppressor Proteins/genetics; Mosaicism; Mutation; high-depth sequencing; mosaic mutations; parental mosaicism; tuberous sclerosis complex
Department(s): Pathology
PubMed ID: 36030538
Publisher's Version: https://doi.org/10.1002/humu.24454
Open Access at Publisher's Site: https://doi.org/10.1002/humu.24454
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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