Mosaicism in tuberous sclerosis complex: Lowering the threshold for clinical reporting.
high-depth sequencing
mosaic mutations
parental mosaicism
tuberous sclerosis complex
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
revised:
20
07
2022
received:
10
03
2022
accepted:
21
08
2022
pubmed:
29
8
2022
medline:
15
12
2022
entrez:
28
8
2022
Statut:
ppublish
Résumé
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.
Substances chimiques
Tuberous Sclerosis Complex 2 Protein
0
Tuberous Sclerosis Complex 1 Protein
0
Tumor Suppressor Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1956-1969Informations de copyright
© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.
Références
Au, K. S., Williams, A. T., Gambello, M. J., & Northrup, H. (2004). Molecular genetic basis of tuberous sclerosis complex: From bench to bedside. Journal of Child Neurology (St. Louis, MO), 19(9), 699-709. https://doi.org/10.1177/08830738040190091101
Au, K. S., Williams, A. T., Roach, E. S., Batchelor, L., Sparagana, S. P., Delgado, M. R., Wheless, J. W., Baumgartner, J. E., Roa, B. B., Wilson, C. M., Smith-Knuppel, T. K., Cheung, M. Y., Whittemore, V. H., King, T. M., & Northrup, H. (2007). Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genetics in Medicine, 9(2), 88-100. https://doi.org/10.1097/gim.0b013e31803068c7
Batalini, F., Peacock, E. G., Stobie, L., Robertson, A., Garber, J., Weitzel, J. N., & Tung, N. M. (2019). Li-Fraumeni syndrome: Not a straightforward diagnosis anymore-the interpretation of pathogenic variants of low allele frequency and the differences between germline PVs, mosaicism, and clonal hematopoiesis. Breast Cancer Research, 21(1), 107. https://doi.org/10.1186/s13058-019-1193-1
Baybis, M., Yu, J., Lee, A., Golden, J. A., Weiner, H., McKhann, G., 2nd, Aronica, E., & Crino, P. B. (2004). mTOR cascade activation distinguishes tubers from focal cortical dysplasia. Annals of Neurology, 56(4), 478-487. https://doi.org/10.1002/ana.20211
Caban, C., Khan, N., Hasbani, D. M., & Crino, P. B. (2017). Genetics of tuberous sclerosis complex: Implications for clinical practice. The Application of Clinical Genetics, 10, 1-8. https://doi.org/10.2147/TACG.S90262
Curatolo, P., Moavero, R., Roberto, D., & Graziola, F. (2015). Genotype/Phenotype correlations in tuberous sclerosis complex. Seminars in Pediatric Neurology, 22(4), 259-273. https://doi.org/10.1016/j.spen.2015.10.002
Curatolo, P., Moavero, R., van Scheppingen, J., & Aronica, E. (2018). mTOR dysregulation and tuberous sclerosis-related epilepsy. Expert Review of Neurotherapeutics, 18(3), 185-201. https://doi.org/10.1080/14737175.2018.1428562
Curatolo, P., Moavero, R., & de Vries, P. J. (2015). Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurology, 14(7), 733-745. https://doi.org/10.1016/S1474-4422(15)00069-1
Dabora, S. L., Jozwiak, S., Franz, D. N., Roberts, P. S., Nieto, A., Chung, J., Choy, Y. S., Reeve, M. P., Thiele, E., Egelhoff, J. C., Kasprzyk-Obara, J., Domanska-Pakiela, D., & Kwiatkowski, D. J. (2001). Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. American Journal of Human Genetics, 68(1), 64-80. https://doi.org/10.1086/316951
Damiano, J. A., Do, H., Ozturk, E., Burgess, R., Kalnins, R., Jones, N. C., Dobrovic, A., Berkovic, S. F., & Hildebrand, M. S. (2017). Sensitive quantitative detection of somatic mosaic mutation in “double cortex” syndrome. Epileptic Disorders, 19(4), 450-455. https://doi.org/10.1684/epd.2017.0944
Feng, Y., Chen, D., Wang, G. L., Zhang, V. W., & Wong, L. J. (2015). Improved molecular diagnosis by the detection of exonic deletions with target gene capture and deep sequencing. Genetics in Medicine, 17(2), 99-107. https://doi.org/10.1038/gim.2014.80
Frost, M. & Hulbert, J. (2015). Clinical management of tuberous sclerosis complex over the lifetime of a patient. Pediatric Health Med Ther, 6, 139-146. https://doi.org/10.2147/PHMT.S67342
Giannikou, K., Lasseter, K. D., Grevelink, J. M., Tyburczy, M. E., Dies, K. A., Zhu, Z., Hamieh, L., Wollison, B. M., Thorner, A. R., Ruoss, S. J., Thiele, E. A., Sahin, M., & Kwiatkowski, D. J. (2019). Low-level mosaicism in tuberous sclerosis complex: Prevalence, clinical features, and risk of disease transmission. Genetics in Medicine, 21(11), 2639-2643. https://doi.org/10.1038/s41436-019-0562-6
Hildebrand, M. S., Tankard, R., Gazina, E. V., Damiano, J. A., Lawrence, K. M., Dahl, H. H., Regan, B. M., Shearer, A. E., Smith, R. J., Marini, C., Guerrini, R., Labate, A., Gambardella, A., Tinuper, P., Lichetta, L., Baldassari, S., Bisulli, F., Pippucci, T., Scheffer, I. E.,… Berkovic, S. F. (2015). PRIMA1 mutation: a new cause of nocturnal frontal lobe epilepsy. Annals of Clinical and Translational Neurology, 2(8), 821-830. https://doi.org/10.1002/acn3.224
Hodges, A. K., Li, S., Maynard, J., Parry, L., Braverman, R., Cheadle, J. P., Declue, J. E., & Sampson, J. R. (2001). Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin. Human Molecular Genetics, 10(25), 2899-2905. https://doi.org/10.1093/hmg/10.25.2899
Jones, A. C., Shyamsundar, M. M., Thomas, M. W., Maynard, J., Idziaszczyk, S., Tomkins, S., Sampson, J. R., & Cheadle, J. P. (1999). Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. American Journal of Human Genetics, 64(5), 1305-1315. https://doi.org/10.1086/302381
Kingswood, J. C., D'augères, G. B., Belousova, E., Ferreira, J. C., Carter, T., Castellana, R., Cottin, V., Curatolo, P., Dahlin, M., de Vries, P. J., Feucht, M., Fladrowski, C., Gislimberti, G., Hertzberg, C., Jozwiak, S., Lawson, J. A., Macaya, A., Nabbout, R., O'Callaghan, F., … TOSCA consortium and TOSCA, i (2017). TuberOus SClerosis registry to increase disease awareness (TOSCA) - baseline data on 2093 patients. Orphanet Journal of Rare Diseases, 12(1), 2. https://doi.org/10.1186/s13023-016-0553-5
Martin, K. R., Zhou, W., Bowman, M. J., Shih, J., Au, K. S., Dittenhafer-Reed, K. E., Sisson, K. A., Koeman, J., Weisenberger, D. J., Cottingham, S. L., DeRoos, S. T., Devinsky, O., Winn, M. E., Cherniack, A. D., Shen, H., Northrup, H., Krueger, D. A., & MacKeigan, J. P. (2017). The genomic landscape of tuberous sclerosis complex. Nature Communications, 8, 15816. https://doi.org/10.1038/ncomms15816
Mayer, K., Fonatsch, C., Wimmer, K., van den Ouweland, A. M., & Maat-Kievit, A. J. (2014). Clinical utility gene card for: Tuberous sclerosis complex (TSC1, TSC2. European Journal of Human Genetics, 22(2). https://doi.org/10.1038/ejhg.2013.129
McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M., & DePristo, M. A. (2010). The genome analysis toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Research, 20(9), 1297-1303. https://doi.org/10.1101/gr.107524.110
Northrup, H., Aronow, M. E., Bebin, E. M., Bissler, J., Darling, T. N., de Vries, P. J., Frost, M. D., Fuchs, Z., Gosnell, E. S., Gupta, N., Jansen, A. C., Jóźwiak, S., Kingswood, J. C., Knilans, T. K., McCormack, F. X., Pounders, A., Roberds, S. L., Rodriguez-Buritica, D. F., Roth, J.,… International Tuberous Sclerosis Complex Consensus, G. (2021). Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatric Neurology, 123, 50-66. https://doi.org/10.1016/j.pediatrneurol.2021.07.011
Northrup, H., Krueger, D. A., & International Tuberous Sclerosis Complex Consensus, G. (2013). Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational tuberous sclerosis complex consensus conference. Pediatric Neurology, 49(4), 243-254. https://doi.org/10.1016/j.pediatrneurol.2013.08.001
Ogórek, B., Hamieh, L., Hulshof, H. M., Lasseter, K., Klonowska, K., Kuijf, H., Moavero, R., Hertzberg, C., Weschke, B., Riney, K., Feucht, M., Scholl, T., Krsek, P., Nabbout, R., Jansen, A. C., Benova, B., Aronica, E., Lagae, L., Curatolo, P., … Kwiatkowski, D. J. (2020). TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants: Results of the EPISTOP study. Genetics in Medicine, 22(9), 1489-1497. https://doi.org/10.1038/s41436-020-0823-4
Pedersen, B. S., Layer, R. M., & Quinlan, A. R. (2016). Vcfanno: Fast, flexible annotation of genetic variants. Genome Biology, 17(1), 118. https://doi.org/10.1186/s13059-016-0973-5
Qin, W., Kozlowski, P., Taillon, B. E., Bouffard, P., Holmes, A. J., Janne, P., Camposano, S., Thiele, E., Franz, D., & Kwiatkowski, D. J. (2010). Ultra deep sequencing detects a low rate of mosaic mutations in tuberous sclerosis complex. Human Genetics, 127(5), 573-582. https://doi.org/10.1007/s00439-010-0801-z
Rose, V. M., Au, K. S., Pollom, G., Roach, E. S., Prashner, H. R., & Northrup, H. (1999). Germ-line mosaicism in tuberous sclerosis: How common. American Journal of Human Genetics, 64(4), 986-992. https://doi.org/10.1086/302322
Sampson, J. R., Scahill, S. J., Stephenson, J. B., Mann, L., & Connor, J. M. (1989). Genetic aspects of tuberous sclerosis in the west of Scotland. Journal of Medical Genetics, 26(1), 28-31. https://doi.org/10.1136/jmg.26.1.28
Tavazoie, S. F., Alvarez, V. A., Ridenour, D. A., Kwiatkowski, D. J., & Sabatini, B. L. (2005). Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nature Neuroscience, 8(12), 1727-1734. https://doi.org/10.1038/nn1566
Treichel, A. M., Hamieh, L., Nathan, N. R., Tyburczy, M. E., Wang, J. A., Oyerinde, O., Raiciulescu, S., Julien-Williams, P., Jones, A. M., Gopalakrishnan, V., Moss, J., Kwiatkowski, D. J., & Darling, T. N. (2019). Phenotypic distinctions between mosaic forms of tuberous sclerosis complex. Genetics in Medicine, 21(11), 2594-2604. https://doi.org/10.1038/s41436-019-0520-3
Tyburczy, M. E., Dies, K. A., Glass, J., Camposano, S., Chekaluk, Y., Thorner, A. R., Lin, L., Krueger, D., Franz, D. N., Thiele, E. A., Sahin, M., & Kwiatkowski, D. J. (2015). Mosaic and intronic mutations in TSC1/TSC2 explain the majority of TSC patients with no mutation identified by conventional testing. PLoS Genetics, 11(11), e1005637. https://doi.org/10.1371/journal.pgen.1005637
Uchiyama, Y., Nakashima, M., Watanabe, S., Miyajima, M., Taguri, M., Miyatake, S., Miyake, N., Saitsu, H., Mishima, H., Kinoshita, A., Arai, H., Yoshiura, K., & Matsumoto, N. (2016). Ultra-sensitive droplet digital PCR for detecting a low-prevalence somatic GNAQ mutation in Sturge-Weber syndrome. Scientific Reports, 6, 22985. https://doi.org/10.1038/srep22985
Vadlamudi, L., Dibbens, L. M., Lawrence, K. M., Iona, X., McMahon, J. M., Murrell, W., Mackay-Sim, A., Scheffer, I. E., & Berkovic, S. F. (2010). Timing of de novo mutagenesis-A twin study of sodium-channel mutations. New England Journal of Medicine, 363(14), 1335-1340. https://doi.org/10.1056/NEJMoa0910752
Verhoef, S., Bakker, L., Tempelaars, A. M., Hesseling-Janssen, A. L., Mazurczak, T., Jozwiak, S., Fois, A., Bartalini, G., Zonnenberg, B. A., van Essen, A. J., Lindhout, D., Halley, D. J., & van den Ouweland, A. M. (1999). High rate of mosaicism in tuberous sclerosis complex. American Journal of Human Genetics, 64(6), 1632-1637. https://doi.org/10.1086/302412
Wang, K., Li, M., & Hakonarson, H. (2010). ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Research, 38(16), e164. https://doi.org/10.1093/nar/gkq603
Ye, Z., McQuillan, L., Poduri, A., Green, T. E., Matsumoto, N., Mefford, H. C., Scheffer, I. E., Berkovic, S. F., & Hildebrand, M. S. (2019). Somatic mutation: The hidden genetics of brain malformations and focal epilepsies. Epilepsy Research, 155, 106161. https://doi.org/10.1016/j.eplepsyres.2019.106161