Abstracts

Rationale: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by hamartomas and hamartias in multiple organs, and is often associated with epilepsy. TSC is caused by a wide spectrum of mutations within the TSC1 and TSC2 genes, mostly point mutations and small indels. Large deletion/duplication mutations are much less frequent and mostly identified in the TSC2 gene. We report the clinical and molecular data of a patient with TSC due to a single copy loss of TSC2. Methods: We performed a study of the TSC phenotype and genotype in a patient with a clinical diagnosis of TSC. TSC1 and TSC2 DNA sequencing, as well as TSC2 DNA deletion test were performed, followed by an oligonucleotide microarray using 1543 loci. Results: A 28-year-old man had focal seizure onset at 1 year of age well controlled by phenobarbital. TSC was diagnosed at age 5 years. He attended regular school until age 17 years, but had learning difficulties. An intraventricular tumor was found and remained stable during several years. At age 22 years, he developed cognitive deterioration and ataxia, repeat CT scan showed an increased volume of the intraventricular lesion and hydrocephalus. A right frontal subependymal giant cell astrocytoma (SEGA) was resected and seizures recurred. At the age of 26, CT scan and sonography of the abdomen showed angiomyolipomas of the liver, and multiple small angiolipomas as well as several cysts of both kidneys. Two years later, seizures increased and an MRI showed a residual right intraventricular SEGA with an increased cystic component and hydrocephalus, as well as multiple cortical and subcortical tubers. He was treated by endoscopic fenestration of the intraventricular cyst and eight months later had resection of the glial scar and right residual intraventricular SEGA. He developed a sudden left hemiparesis due to an epidural hematoma which was subsequently drained. DNA studies revealed deletion of all exons (1-41) of the TSC2 gene. Microarray analysis detected a single copy loss of 25 oligonucleotide probes from the short arm of chromosome 16 at 16p13.3. This was estimated to be approximately 194.3 Kb in size; it overlapped the TSC2 locus and contained at least 10 other genes. There was no evidence for TSC in available family members. Quantitative dosage analysis of genomic DNA in the mother and brother did not show any TSC2 deletion nor abnormal DNA sequence variants; the father was not available for genetic testing. Conclusions: To our knowledge, the variant detected here has not been previously reported. It appears to be associated with a severe TSC phenotype.