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

Ye, Zimeng; Lin, Sufang; Zhao, Xia; Bennet, Mark F.; Brown, Natasha J; Wallis, Mathew; Gao, Xinyi; Sun, Li; Wu, Jiarui; Vedururu, Ravikiran; Witkowski, Tom; Gardiner, Fiona; Stutterd, Chloe; Duan, Jing; Mullen, Saul A.; McGillivray, George; Bodek, Simon; Valente, Giulia; Reagan, Matthew T.; 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.

doi:10.1002/humu.24454

Cited by 13 publications

(5 citation statements)

References 35 publications

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“…Mirroring UDP-Vic [22], families were considered solved when a molecular diagnosis in an established disease gene was made, or when a strong candidate for novel gene discovery was identi ed. For molecular diagnoses in established disease genes, the variant needed to reach criteria for the American College of Medical Genetics and Genomics (ACMG) classi cation of pathogenic or likely pathogenic (P/LP) [39]. For novel disease-gene variants and new phenotypes in known disease genes, we adopted the same 'strong candidate diagnosis' approach as UDP-Vic [22].…”

Section: Report Generation and Return Of Resultsmentioning

confidence: 99%

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Experience of the first adult-focussed undiagnosed disease program in Australia (AHA-UDP): Solving rare and puzzling genetic disorders is ageless.

Wallis,

Bodek,

Munro

et al. 2023

Preprint

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Background Significant recent efforts have facilitated increased access to clinical genetics assessment and genomic sequencing for children with rare diseases in many centres, but there remains a service gap for adults. The Austin Health Adult Undiagnosed Disease Program (AHA-UDP) was designed to complement existing UDP programs that focus on paediatric rare diseases and address an area of unmet diagnostic need for adults with undiagnosed rare conditions in Victoria, Australia. It was conducted at a large Victorian hospital to demonstrate the benefits of bringing genomic techniques currently used predominantly in a research setting into hospital clinical practice, and identify the benefits of enrolling adults with undiagnosed rare diseases into a UDP program. The main objectives were to identify the causal mutation for a variety of diseases of individuals and families enrolled, and to discover novel disease genes. Methods Unsolved patients in whom standard genomic diagnostic techniques such as targeted gene panel, exome-wide next generation sequencing (NGS), and/or chromosomal microarray, had already been performed were recruited. Genome sequencing (GS) and enhanced genomic analysis from the research setting were applied to aid novel gene discovery. Results In total, 16/50 (32%) families/cases were solved. One or more candidate variants of uncertain significance (VUS) were detected in 18/50 (36%) families. No candidate variants were identified in 16/50 (32%) families. Two novel disease genes (TOP3B, PRKACB) and two novel genotype-phenotype correlations (NARS, and KMT2C genes) were identified. Three out of eight patients with suspected mosaic tuberous sclerosis complex had their diagnosis confirmed which provided reproductive options for two patients. The utility of confirming diagnoses for patients with mosaic conditions (using high read depth sequencing and ddPCR) was not specifically envisaged at the onset of the project, but the flexibility to offer recruitment and analyses on an as-needed basis proved to be a strength of the AHA-UDP. Conclusion AHA-UDP demonstrates the utility of a UDP approach applying genome sequencing approaches in diagnosing adults with rare diseases who have had uninformative conventional genetic analysis, informing clinical management, recurrence risk, and recommendations for relatives.

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Section: Report Generation and Return Of Resultsmentioning

confidence: 99%

“…Somatic variants in the KMT2C gene are often identi ed in renal cell cancer [47]; however, none of the families reported with germline alterations in this gene have had renal cancer. This variant is classi ed as pathogenic according to the ACMG criteria [39] (PVS1, PM2, PS2).…”

Section: Kmt2c (Ah016)mentioning

confidence: 99%

Experience of the first adult-focussed undiagnosed disease program in Australia (AHA-UDP): Solving rare and puzzling genetic disorders is ageless.

Wallis,

Bodek,

Munro

et al. 2023

Preprint

Self Cite

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“…Namely, those with higher VAF in clinically accessible samples were more likely to present with a greater number of TSC features [ 105 ]. However, the opposite was found in another study of 31 NMI TSC patients, where blood, saliva, and buccal VAF in the 16 mosaic patients were not associated with the number of major clinical features [ 106 ]. Yet, the study did find that VAFs from saliva and buccal samples correlated with tuber load.…”

Section: Updates To Genotype–phenotype Correlations In Tsc: Mosaicism...mentioning

confidence: 89%

“…However, it is unclear whether mosaicism in isolated brain cell populations or even lower VAFs in the brain cause MCD or associated symptomatology [ 66 ]. In clinically accessible samples, VAFs do not always correlate with those in affected tissue such as the brain, as organs affected depend on the embryonic lineage affected as well as the timing of the initial variant [ 65 , 106 , 109 , 110 , 111 ]. This can be exemplified by a case study in which two individuals with TSC2 VAFs of ≤25% in blood showed severe, multiorgan TSC phenotypes [ 112 ].…”

Section: Updates To Genotype–phenotype Correlations In Tsc: Mosaicism...mentioning

confidence: 99%

The Genetics of Tuberous Sclerosis Complex and Related mTORopathies: Current Understanding and Future Directions

Man,

Di Scipio,

Grewal

et al. 2024

Genes

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The mechanistic target of rapamycin (mTOR) pathway serves as a master regulator of cell growth, proliferation, and survival. Upregulation of the mTOR pathway has been shown to cause malformations of cortical development, medically refractory epilepsies, and neurodevelopmental disorders, collectively described as mTORopathies. Tuberous sclerosis complex (TSC) serves as the prototypical mTORopathy. Characterized by the development of benign tumors in multiple organs, pathogenic variants in TSC1 or TSC2 disrupt the TSC protein complex, a negative regulator of the mTOR pathway. Variants in critical domains of the TSC complex, especially in the catalytic TSC2 subunit, correlate with increased disease severity. Variants in less crucial exons and non-coding regions, as well as those undetectable with conventional testing, may lead to milder phenotypes. Despite the assumption of complete penetrance, expressivity varies within families, and certain variants delay disease onset with milder neurological effects. Understanding these genotype–phenotype correlations is crucial for effective clinical management. Notably, 15% of patients have no mutation identified by conventional genetic testing, with the majority of cases postulated to be caused by somatic TSC1/TSC2 variants which present complex diagnostic challenges. Advancements in genetic testing, prenatal screening, and precision medicine hold promise for changing the diagnostic and treatment paradigm for TSC and related mTORopathies. Herein, we explore the genetic and molecular mechanisms of TSC and other mTORopathies, emphasizing contemporary genetic methods in understanding and diagnosing the condition.

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“…Newborn screening has successfully begun to provide an early diagnosis, even before the presentation of symptoms (Qiao et al., 2021; Su et al., 2021). However, in 10%–15% TSC patients there is no pathogenic variant identified in either TSC1 or TSC2 genes based on standard clinical testing and are generally attributed to low mosaicism, deep intronic/promoter variants, and additional causative gene loci yet to be identified (Brook‐Carter et al., 1994; Curatolo et al., 2008; Klonowska et al., 2023; Sancak et al., 2005; Ye et al., 2022). For instance, in one study, undetected somatic mosaic variants were the most common cause for undiagnosed patients with TSC with up to 51.6% (16/31) of undiagnosed patients being found to carry a disease‐causing mosaic variant (Ye et al., 2022).…”

Section: Discussionmentioning

confidence: 99%

Identification of a complex intrachromosomal inverted insertion in the long arm of chromosome 9 as a cause of tuberous sclerosis complex in a Korean family

Ryu,

Yoon,

Kim

et al. 2024

Molec Gen & Gen Med

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BackgroundTuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder, caused by a loss‐of‐function of either TSC1 or TSC2 gene. However, in 10%–15% TSC patients there is no pathogenic variant identified in either TSC1 or TSC2 genes based on standard clinical testing.MethodsIn this study, genome sequencing was performed for families with clinical diagnosis of TSC with negative results from TSC1 and TSC2 single‐gene tests.ResultsHerein, we report a family presenting a classical TSC phenotype with an unusual, complex structural variant involving the TSC1 gene: an intrachromosomal inverted insertion in the long arm of chromosome 9. We speculate that the inverted 9q33.3q34.13 region was inserted into the q31.2 region with the 3′‐end of the breakpoint of the inversion being located within the TSC1 gene, resulting in premature termination of TSC1.ConclusionsIn this study, we demonstrate the utility of genome sequencing for the identification of complex chromosomal rearrangement. Because the breakpoints are located within the deep intronic/intergenic region, this copy‐neutral variant was missed by the TSC1 and TSC2 single‐gene tests and contributed to an unknown etiology. Together, this finding suggests that complex structural variants may be underestimated causes for the etiology of TSC.

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

Cited by 13 publications

References 35 publications

Experience of the first adult-focussed undiagnosed disease program in Australia (AHA-UDP): Solving rare and puzzling genetic disorders is ageless.

Experience of the first adult-focussed undiagnosed disease program in Australia (AHA-UDP): Solving rare and puzzling genetic disorders is ageless.

The Genetics of Tuberous Sclerosis Complex and Related mTORopathies: Current Understanding and Future Directions

Identification of a complex intrachromosomal inverted insertion in the long arm of chromosome 9 as a cause of tuberous sclerosis complex in a Korean family

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