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

2022-12

Ye, Zimeng

Lin, Sufang

Zhao, Xia

Bennett, Mark F

Brown, Natasha J

Wallis, Mathew J

Gao, Xinyi

Sun, Li

Wu, Jiarui

Vedururu, Ravikiran

Witkowski, Tom

Gardiner, Fiona

Stutterd, Chloe A

Duan, Jing

Mullen, Saul A

McGillivray, George

Bodek, Simon

Valente, Giulia M

Reagan, Matthew

Yao, Yi

Li, Lin

Chen, Li

Boys, Amber

Adikari, Thiuni N

Cao, Dezhi

Hu, Zhanqi

Beshay, Victoria

Zhang, Victor W

Berkovic, Samuel F

Scheffer, Ingrid E

Liao, Jianxiang

Hildebrand, Michael S

high-depth sequencing

mosaic mutations

parental mosaicism

tuberous sclerosis complex

Journal Article

0000-0002-5578-9374

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10.1002/humu.24454

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.

link

Human Mutation 2022; 43(12)

Human Mutation

1098-1004