2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-<em>TSC1/TSC2</em> Mosaicism is Found in ~13% of Individuals with Tuberous Sclerosis and is Associated with a Distinctive Phenotypic Severity

TSC1/TSC2 Mosaicism is Found in ~13% of Individuals with Tuberous Sclerosis and is Associated with a Distinctive Phenotypic Severity

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This study aimed to investigate the molecular basis of tuberous sclerosis complex (TSC) in patients with no identified mutations and evaluate the rate of mosaicism in TSC patients. The pilot study involved various genetic sequencing methods on 10 individuals with TSC and no identified mutations. The complete study focused on deep-coverage sequencing of the TSC1/TSC2 genes in 200 patients and analyzing the phenotype of those with mosaicism compared to patients with heterozygous pathogenic variants. <br /><br />The results of the complete study showed that individuals with mosaic variants had a less frequent occurrence of intellectual disability, seizures, and hypomelanotic macules compared to those with heterozygous variants. However, there were no significant differences in the occurrence of cardiac rhabdomyomas, LAM, and renal angiomyolipomas between the two groups. Renal and pulmonary findings in mosaic patients were equally as severe as those without mosaicism. The study found that more than 10% of individuals with TSC carry mosaic pathogenic variants in TSC1/TSC2 genes and highlighted the need for deep-coverage sequencing in TSC patients.<br /><br />The study also provided a clinical comparison of individual patients with mosaicism and heterozygous variants, showing the presence or absence of various clinical manifestations. The authors concluded that individuals with mosaic variants have a distinctive phenotypic severity, which has important implications for prognosis, patient care, and counseling.<br /><br />Overall, this study highlights the importance of investigating the molecular basis of TSC in patients with no identified mutations and the role of mosaicism in TSC. The findings contribute to a better understanding of the phenotypic variability in TSC patients and emphasize the need for comprehensive genetic analysis in diagnosis and management.

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Presenting Author - Angela Peron, MD, PhD; Co-Author - Rosa Maria Alfano, PhD; Co-Author - Barry Moore, MS; Co-Author - Mark Nellist, PhD; Co-Author - Brent Pedersen, PhD; Co-Author - Francesca La Briola, MD; Co-Author - Luigina Spaccini, MD; Co-Author - Federica Natacci, MD; Co-Author - Maria Paola Recalcati, PhD; Co-Author - Valentina Chiesa, MD; Co-Author - Rosangela Arancio, MD; Co-Author - Ugo Cavallari, MD; Co-Author - Chiara Vannicola, MD; Co-Author - Graziella Cefalo, MD; Co-Author - Silvia Maitz, MD; Co-Author - Stefania Bigoni, MD; Co-Author - Lorenzo Gualandri, MD; Co-Author - Cristina Gervasini, PhD; Co-Author - Pierangelo Veggiotti, MD; Co-Author - Wilfred van Ijcken, PhD; Co-Author - Aglaia Vignoli, MD; Co-Author - Gaetano Pietro Bulfamante, MD; Co-Author - John C. Carey, MD; Co-Author - Maria Paola Canevini, MD;

Meta Tag

Brain/Nervous System

Cognitive Disorders

Delineation of Diseases

Genetic Testing

Genome sequencing

Genotype-Phenotype Correlations

Intellectual disability

NextGen Sequencing

Pathogenesis

Phenotype

Phenotypic delineation of disorders

Sequencing

Variant Detection

Co-Author Rosa Maria Alfano, PhD

Co-Author Barry Moore, MS

Co-Author Mark Nellist, PhD

Co-Author Brent Pedersen, PhD

Co-Author Francesca La Briola, MD

Co-Author Luigina Spaccini, MD

Co-Author Federica Natacci, MD

Co-Author Maria Paola Recalcati, PhD

Co-Author Valentina Chiesa, MD

Co-Author Rosangela Arancio, MD

Co-Author Ugo Cavallari, MD

Co-Author Chiara Vannicola, MD

Co-Author Graziella Cefalo, MD

Co-Author Silvia Maitz, MD

Co-Author Stefania Bigoni, MD

Co-Author Lorenzo Gualandri, MD

Co-Author Cristina Gervasini, PhD

Co-Author Pierangelo Veggiotti, MD

Co-Author Wilfred van Ijcken, PhD

Co-Author Aglaia Vignoli, MD

Co-Author Gaetano Pietro Bulfamante, MD

Co-Author John C. Carey, MD

Co-Author Maria Paola Canevini, MD

Presenting Author Angela Peron, MD, PhD

Keywords

tuberous sclerosis complex

mosaicism

genetic sequencing

phenotype

intellectual disability

seizures

renal angiomyolipomas

pathogenic variants

deep-coverage sequencing

prognosis