First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with Tuberous Sclerosis Complex reveals numerous novel pathogenic variants

Abstract

echavarría 4 , carlos G. todd-Quiñones 5,6 & Ariadna González-del Angel 1* the aim of this study was to improve knowledge of the mutational spectrum causing tuberous sclerosis complex (tSc) in a sample of Mexican patients, given the limited information available regarding this disease in Mexico and Latin America. Four different molecular techniques were implemented to identify from single nucleotide variants to large rearrangements in the TSC1 and TSC2 genes of 66 unrelated Mexican-descent patients that clinically fulfilled the criteria for a definitive TSC diagnosis. The mutation detection rate was 94%, TSC2 pathogenic variants (pV) prevailed over TSC1 PV (77% vs. 23%) and a recurrent mutation site (hotspot) was observed in TSC1 exon 15. Interestingly, 40% of the identified mutations had not been previously reported. The wide range of novels PV made it difficult to establish any genotype-phenotype correlation, but most of the pV conditioned neurological involvement (intellectual disability and epilepsy). Our 3D protein modeling of two variants classified as likely pathogenic demonstrated that they could alter the structure and function of the hamartin (TSC1) or tuberin (TSC2) proteins. Molecular analyses of parents and first-degree affected family members of the index cases enabled us to distinguish familial (18%) from sporadic (82%) cases and to identify one case of apparent gonadal mosaicism. Tuberous sclerosis complex (TSC; MIM #191100, MIM #613254) is an autosomal dominant syndrome characterized by the presence of multiple hamartomas in different organs and systems. The incidence is about 0.1-1/10,000 births and the prevalence varies from 1/6,000 to 1/10,000 among different populations 1-3. The manifestations of TSC are highly variable among individuals and even within the same family 4 , but the most common clinical features are localized in skin and central nervous system 5-7. TSC is caused by pathogenic variants (PV) in the tumor suppressor-genes, TSC1 (tuberous sclerosis complex 1, MIM *605284, 9q34.13) and TSC2 (tuberous sclerosis complex 2, MIM *191092, 16p13.3). These PV can be detected by various molecular techniques, such as single-strand conformational polymorphism (SSCP), direct Sanger sequencing (SS), multiplex ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS). There are currently more than 2,000 pathogenic TSC1/TSC2 variants described in the Leiden Open Variation Database (www.lovd.nl/TSC1 and www.lovd.nl/TSC2) 8 ; of them, 21-26% are located in TSC1 and 69-79% in TSC2 9,10. In approximately 5-25% of the analyzed TSC cases, a PV could not be identified in either gene 9,11,12. The emergence of new techniques, such as NGS, has significantly increased the mutation detection rate

The association of neurodevelopmental abnormalities, congenital heart and renal defects in a tuberous sclerosis complex patient cohort

“…The findings from this study also corroborate with these previous studies, indicating a significant majority of TSC patients with a mutation at the TSC2 genetic locus, with a TSC1 : TSC2 mutation ratio of 2.8 TSC2 patients for every TSC1 patient, or TSC1 and TSC2 mutation rates amongst the cohort at 25% and 72%, respectively. Furthermore, the detection rate of TSC mutations was determined as 97%, superseding previous studies where the detection rate ranged from 82 to 94% [ 41 – 44 ].…”

TSC1loss-of-function increases risk for tauopathy by inducing tau acetylation and preventing autophagy-mediated tau clearance

“…LOF pathogenic variants in the TSC1 gene leading to TSC1/hamartin haploinsufficiency have previously been associated with the juvenile-onset lysosomal storage disease TSC (12,51,52).…”

“…7 ). LOF pathogenic variants in the TSC1 gene leading to TSC1/hamartin haploinsuffíciency have previously been associated with the juvenile-onset lysosomal storage disease TSC ( 12, 51, 52 ). In earlier clinical-translational studies, we have shown a linkage between TSC1 gene and age-related tauopathies ( 11, 15 ).…”

Νευροψυχιατρικές Και Συστηματικές Διαταραχές Σχετιζόμενες Με Οζώδη Σκλήρυνση

“…Συγκεκριμένα, δεδομένα από πολλές μελέτες αναφέρουν ότι η συχνότητα ανεύρεσης μετάλλαξης του TSC2 γονιδίου κυμαίνεται μεταξύ 46-85% και του TSC1 μεταξύ 12-33%. [40][41][42][43]54,[58][59][60][61][62][63][64][65][66][67][68][69] Παρόμοια ποσοστά προέκυψαν κι από τον γονιδιακό έλεγχο 902 ασθενών της βάσης δεδομένων TOSCA, όπου το 63.3% των ασθενών έφερε μετάλλαξη στο TSC2 γονίδιο και το 19.7% των ασθενών στο TSC1 γονίδιο. 44 Ειδικότερα στον ελλαδικό χώρο, σε δύο πρόσφατες μελέτες του 2018 και 2017, η συχνότητα μετάλλαξης του ΤSC2 γονιδίου ήταν μεταξύ 53-75% και του TSC1 25-47%.…”

“…41,42,65,72 Τα τελευταία χρόνια η χρήση περισσότερο ευαίσθητων μεθόδων όπως το NGS, η MLPA και πρόσφατα η μέθοδος MPS οδήγησε στην ανίχνευση νέων ΠΜ μειώνοντας το ποσοστό μη ανιχνεύσιμων ΠΜ <10%. 64,69,70,73 PRR5/Protor). [108][109][110] Σε αντίθεση με το μονοπάτι του mTORC1, το σηματοδοτικό μονοπάτι του mTORC2 δεν έχει πλήρως καθορισθεί.…”