Fetal tuberous sclerosis and diagnosis of paternal gonadal mosaicism

Tutschek, B.; Mayer, Karin; Rauch, Anita

doi:10.1002/uog.21880

Cited by 2 publications

(1 citation statement)

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“…Firstly, a germline mosaic parent may be only mildly affected or unaffected by the TSC variant [ 17 ]. For example, Tutschek and colleagues report a case in which the father of a baby born with TSC was negative for TSC variants in blood, saliva, and skin, but positive for a pathogenic TSC2 variant in 10% of tested sperm DNA [ 151 ]. Chen and colleagues report a similar case where a fetus developed rhabdomyoma from an inherited TSC2 variant with a paternal VAF of 7% in blood leukocytes and 20% in sperm [ 152 ].…”

Section: Genetic Counseling/reproductive Counseling and Management In...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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Section: Genetic Counseling/reproductive Counseling and Management In...mentioning

confidence: 99%