Mutation Spectrum of Tuberous Sclerosis Complex Patients in Indian Population

Abstract

Tuberous sclerosis complex (TSC) is a multiorgan disorder characterized by formation of hamartomas and broad phenotypic spectrum including seizures, mental retardation, renal dysfunction, skin manifestations and brain tubers. It is inherited in an autosomal dominant pattern, caused due to mutation in either TSC1 or TSC2 genes. Seizures are one of the major presenting symptoms of TSC that helps in early diagnosis. The present study describes the mutation spectrum in TSC1 and TSC2 genes in TSC patients and their association with neurocognitive-behavioral phenotypes. Ninety-eight TSC patients were enrolled for TSC genetic testing after detailed clinical and neurobehavioral assessment. Large genomic rearrangement testing was performed by multiplex ligation-dependent probe amplification (MLPA) technique for all cases and Sanger sequencing was performed for MLPA negative cases. Large rearrangements were identified in approximately 1% in TSC1 and 14.3% in TSC2 genes. The present study observed the presence of duplications in two (2%) cases, both involving TSC2/PKD1 contiguous genes which to the best of our knowledge is reported for the first time. 8.1% of small variants were identified in the TSC1 gene and 85.7% in TSC2 gene, out of which 23 were novel variations and no variants were found in six (6.1%) cases. This study provides a representative picture of the distribution of variants in the TSC1 and TSC2 genes in Indian population along with the detailed assessment of neurological symptoms. This is the largest cohort study from India providing an overview of comprehensive clinical and molecular spectrum.

Keywords

tuberous sclerosis complex - subependymal nodules - white matter lesions - subependymal giant cell astrocytomas - multiplex ligation-dependent probe amplification - renal manifestation

Publication History

Received: 22 April 2020

Accepted: 24 July 2020

Article published online:
07 September 2020

• References

• 1 Caban C, Khan N, Hasbani DM, Crino PB. Genetics of tuberous sclerosis complex: implications for clinical practice. Appl Clin Genet 2016; 10: 1-8
• 2 Northrup DA. Krueger, and on behalf of the International Tuberous Sclerosis Complex Consensus Group Tuberous Sclerosis Complex Diagnostic Criteria Update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013; 49 (04) 243-254
• 3 Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJ. The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc 2015; 10 (06) 845-858
• 4 Richards S, Aziz N, Bale S. ACMG Laboratory Quality Assurance Committee. et al; Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
• 5 Sudarshan S, Kumar M, Kaur P. et al. Decoding of novel missense TSC2 gene variants using in-silico methods. BMC Med Genet 2019; 20 (01) 164
• 6 Rosset C, Netto CBO, Ashton-Prolla P. TSC1 and TSC2 gene mutations and their implications for treatment in Tuberous Sclerosis Complex: a review. Genet Mol Biol 2017; 40 (01) 69-79
• 7 Au KS, Williams AT, Roach ES. et al. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet Med 2007; 9 (02) 88-100
• 8 Kwiatkowski DJ. Tuberous sclerosis: from tubers to mTOR. Ann Hum Genet 2003; 67 (Pt 1): 87-96
• 9 Ridler K, Suckling J, Higgins N, Bolton P, Bullmore E. Standardized whole brain mapping of tubers and subependymal nodules in tuberous sclerosis complex. J Child Neurol 2004; 19 (09) 658-665
• 10 Bolton PF, Park RJ, Higgins JN, Griffiths PD, Pickles A. Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Brain 2002; 125 (Pt 6): 1247-1255
• 11 O'Callaghan FJ, Harris T, Joinson C. et al. The relation of infantile spasms, tubers, and intelligence in tuberous sclerosis complex. Arch Dis Child 2004; 89 (06) 530-533
• 12 Takanashi J, Sugita K, Fujii K, Niimi H. MR evaluation of tuberous sclerosis: increased sensitivity with fluid-attenuated inversion recovery and relation to severity of seizures and mental retardation. AJNR Am J Neuroradiol 1995; 16 (09) 1923-1928
• 13 Hamano S, Tanaka M, Imai M, Nara T, Maekawa K. Topography, size and number of cortical tubers in tuberous sclerosis with West syndrome. No To Hattatsu 1998; 30 (02) 152-158
• 14 Husain AM, Foley CM, Legido A, Chandler DA, Miles DK, Grover WD. Tuberous sclerosis complex and epilepsy: prognostic significance of electroencephalography and magnetic resonance imaging. J Child Neurol 2000; 15 (02) 81-83
• 15 Dabora SL, Jozwiak S, Franz DN. et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 2001; 68 (01) 64-80
• 16 Sancak O, Nellist M, Goedbloed M. et al. Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype–phenotype correlations and comparison of diagnostic DNA techniques in tuberous sclerosis complex. Eur J Hum Genet 2005; 13 (06) 731-741
• 17 Jones AC, Shyamsundar MM, Thomas MW. et al. Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am J Hum Genet 1999; 64 (05) 1305-1315
• 18 Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 2002; 30: e57
• 19 Kozlowski P, Roberts P, Dabora S. et al. Identification of 54 large deletions/duplications in TSC1 and TSC2 using MLPA, and genotype-phenotype correlations. Hum Genet 2007; 121 (3-4): 389-400
• 20 Ramandi H, Ghaderian SMH, Toosi P, Tonekaboni SH, Ebrahimi A, Hatamnejadian N. TSC2 deletions and duplications: a descriptive study in Iranian patients affected with tuberous sclerosis. Am J Mol Biol 2014; 4: 163-167
• 21 Boehm D, Bacher J, Neumann HP. Gross genomic rearrangement involving the TSC2-PKD1 contiguous deletion syndrome: characterization of the deletion event by quantitative polymerase chain reaction deletion assay. Am J Kidney Dis 2007; 49 (01) e11-e21
• 22 Blennow E, Lagerstedt K, Malmgren H, Sahlén S, Schoumans J, Anderlid B. Concurrent microdeletion and duplication of 22q11.2. Clin Genet 2008; 74 (01) 61-67
• 23 Lee JS, Lim BC, Chae J-H. et al. Mutational analysis of paediatric patients with tuberous sclerosis complex in Korea: genotype and epilepsy. Epileptic Disord 2014; 16 (04) 449-455
• 24 Hung C-C, Su Y-N, Chien S-C. et al. Molecular and clinical analyses of 84 patients with tuberous sclerosis complex. BMC Med Genet 2006; 7: 72
• 25 Rosset C, Vairo F, Bandeira IC. et al. Molecular analysis of TSC1 and TSC2 genes and phenotypic correlations in Brazilian families with tuberous sclerosis. PLoS One 2017; 12 (10) e0185713
• 26 Yang G, Shi ZN, Meng Y. et al. Phenotypic and genotypic characterization of Chinese children diagnosed with tuberous sclerosis complex. Clin Genet 2017; 91 (05) 764-768
• 27 Rendtorff ND, Bjerregaard B, Frödin M. Danish Tuberous Sclerosis Group. et al; Analysis of 65 tuberous sclerosis complex (TSC) patients by TSC2 DGGE, TSC1/TSC2 MLPA, and TSC1 long-range PCR sequencing, and report of 28 novel mutations. Hum Mutat 2005; 26 (04) 374-383