Dataset Information

Comprehensive Genetic Analysis Results of TSC1/TSC2 Genes in Patients with Clinical Suspicion of Tuberous Sclerosis Complex and Definition of 3 Novel Variants.

ABSTRACT:

Background

Tuberous Sclerosis Complex is an autosomal dominant multi-system disorder with an incidence of about 1 in 6000 live births. Defects in either TSC1 (* 605284) or TSC2 (* 191092) genes encoding the components of the Tuberous Sclerosis Complex are responsible for the disease. Therefore, consideration of TSC1/TSC2 pathogenic variations is recommended in the updated diagnostic criteria of Tuberous Sclerosis Complex.

Aims

To present the TSC1/TSC2 screening results of a mixed patient population as well as possible new variants in 23 cases from 20 different families who were referred to our Genetic Diseases Diagnosis Center with the signs and symptoms of Tuberous Sclerosis Complex.

Study design

Retrospective, cross-sectional study.

Methods

Germline TSC1/TSC2 variants were screened in DNA samples extracted from peripheral blood samples of 23 patients from 20 unrelated families using targeted high-throughput sequencing and multiplex ligation-dependent probe amplification methods. The variants identified were classified according to ACMG 2015 guidelines.

Results

In total, 5 different pathogenic/likely pathogenic changes have been defined. All these pathogenic/likely pathogenic variants were located in the TSC2 gene. Three of the pathogenic/likely pathogenic variants were novel. Two patients who are twin sisters were found to have TSC2/PKD1 contiguous deletion syndrome. One of the 3 novel variants was a mosaic in-frame deletion. We did not identify any pathogenic variants of the TSC1 gene.

Conclusion

The novelty of most of the variants found, including a mosaic likely pathogenic variant, and the presence of a large genomic rearrangement, supports the importance of a comprehensive approach in analyzing TSC1/TSC2 genes. Genetic diagnosis should be performed with caution, considering the possibility of mosaic variants with low allelic fractions.

SUBMITTER: Demir S

PROVIDER: S-EPMC8880961 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Publications

Comprehensive Genetic Analysis Results of TSC1/TSC2 Genes in Patients with Clinical Suspicion of Tuberous Sclerosis Complex and Definition of 3 Novel Variants.

Demir Selma S Yalçıntepe Sinem S Atlı Engin E Yalçın Yelda Y İkbal Atlı Emine E Eker Damla D Karal Yasemin Y Gürkan Hakan H

Balkan medical journal 20211101 6

<h4>Background</h4>Tuberous Sclerosis Complex is an autosomal dominant multi-system disorder with an incidence of about 1 in 6000 live births. Defects in either TSC1 (* 605284) or TSC2 (* 191092) genes encoding the components of the Tuberous Sclerosis Complex are responsible for the disease. Therefore, consideration of TSC1/TSC2 pathogenic variations is recommended in the updated diagnostic criteria of Tuberous Sclerosis Complex.<h4>Aims</h4>To present the TSC1/TSC2 screening results of a mixed ...[more]

PMID: 34860161

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Project description:Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that is associated with neurological symptoms, including autism spectrum disorder. Tuberous sclerosis complex is caused by pathogenic germline mutations of either the TSC1 or TSC2 gene, but somatic mutations were identified in both genes, and the combined effects of TSC1 and TSC2 mutations have been unknown. The present study investigated social behaviors by the social interaction test and three-chambered sociability tests, effects of rapamycin treatment, and gene expression profiles with a gene expression microarray in Tsc1 and Tsc2 double heterozygous mutant (TscD+/-) mice. TscD+/- mice exhibited impairments in social behaviors, and the severity of impairments was similar to Tsc2+/- mice rather than Tsc1+/- mice. Impairments in social behaviors were rescued by rapamycin treatment in all mutant mice. Gene expression profiles in the brain were greatly altered in TscD+/- mice more than in Tsc1+/- and Tsc2+/- mice. The gene expression changes compared with wild type (WT) mice were similar between TscD+/- and Tsc2+/- mice, and the overlapping genes whose expression was altered in mutant mice compared with WT mice were enriched in the neoplasm- and inflammation-related canonical pathways. The "signal transducer and activator of transcription 3, interferon regulatory factor 1, interferon regulatory factor 4, interleukin-2R α chain, and interferon-γ" signaling pathway, which is initiated from signal transducer and activator of transcription 4 and PDZ and LIM domain protein 2, was associated with impairments in social behaviors in all mutant mice. It is unclear whether the signaling pathway also plays a critical role in autism spectrum disorders not caused by Tsc1 and Tsc2 mutations. These findings suggest that TSC1 and TSC2 double mutations cause autistic behaviors similarly to TSC2 mutations, although significant changes in gene expression were attributable to the double mutations. These findings contribute to the knowledge of genotype-phenotype correlations in TSC and suggest that mutations in both the TSC1 and TSC2 genes act in concert to cause neurological symptoms, including autism spectrum disorder.

Dataset Information

Comprehensive Genetic Analysis Results of TSC1/TSC2 Genes in Patients with Clinical Suspicion of Tuberous Sclerosis Complex and Definition of 3 Novel Variants.

Background

Aims

Study design

Methods

Results

Conclusion

Publications

Comprehensive Genetic Analysis Results of TSC1/TSC2 Genes in Patients with Clinical Suspicion of Tuberous Sclerosis Complex and Definition of 3 Novel Variants.

Similar Datasets

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