Spectrum of Germline and Somatic Mitochondrial DNA Variants in Tuberous Sclerosis Complex

Hilaire Lam, PhD
Department of Medicine
Division of Pulmonary and Critical Care Medicine
Poster Overview

Tuberous Sclerosis Complex (TSC) is a rare genetic disorder which is characterized by neurological symptoms and benign tumors in different organs with high clinical heterogeneity among affected individuals. We have learned a lot about both the molecular basis and clinical aspects of this disease. However, the role of other genetic driver events beyond alterations in TSC2 and TSC1 gene in TSC pathogenesis are unknown. Currently, there is no previous knowledge regarding the role of mtDNA genome in TSC pathogenesis. We first applied high throughput approaches to study the entire mtDNA of 189 different tissues from 148 TSC patients, including buccal swaps and tumors in kidney, brain and skin with corresponding normal, through deep coverage sequencing. We observed variability in the number of mutant mitochondrial genes and mtDNA alterations across different TSC samples. Buccal swabs present higher mtDNA variant rate compared to tumor samples. We found one pathogenic mtDNA variant in one TSC patient. Analyses did not reveal any difference regarding the number and type of clinical features with the mtDNA variants. Our data demonstrate stability of the mitochondrial genome in TSC and our experimental strategy may be applied for the study of mtDNA in other related genetic disorders.

Scientific Abstract

Background: Tuberous Sclerosis Complex (TSC) is caused by mutations in TSC1 or TSC2. There is limited knowledge regarding the role of mitochondrial DNA (mtDNA) in TSC pathogenesis.

Aim: To examine the prevalence and spectrum of mtDNA variants in TSC patients and correlate them with disease severity.

Methods: We analyzed mtDNA of 189 different tissues from 148 TSC patients, including buccal swabs, brain, skin and kidney lesions. mtDNA variants were identified by either deep coverage amplicon massively parallel sequencing or extraction from exome data. Alterations in mitochondrial copy number were determined by qPCR in tumor-normal samples.

Results: A median of 21 non-synonymous mtDNA SNP variants were identified in 102 buccal swabs, with high homoplasmy (median: 99.62%) mainly missense of unknown significance. A pathogenic variant (MT-TL1; m.3243A>G, heteroplasmy 12%) was identified in one TSC patient. Analysis of TSC tumors demonstrated similar spectrum of mtDNA variants as seen in buccal swabs. mtDNA variants did not correlate with any pathological TSC features. qPCR analysis did not reveal changes in mitochondrial content between tumors and normal tissue.

Conclusions: Our study provides insight into the mtDNA landscape in TSC for first time, demonstrating that mtDNA genome is stable within the tumors analyzed and across different tissues.

Clinical Implications
Our studies have deciphered for first time the spectrum of germline and somatic mtDNA variants in various tumors and neoplastic lesions from TSC patients. Our comprehensive exploratory methodologies may have broad applications for other tumor suppressor gene syndromes.
Research Areas
Krinio Giannikou, Sergey Naunmeko, Thomas R. Hougard, Yan Tang, David J. Kwiatkowski, Hilaire C. Lam
Principal Investigator
Hilaire C. Lam

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