Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States

Abstract

Tuberous sclerosis complex is an autosomal dominant neurocutaneous disorder marked by hamartoma growth in multiple organ systems. We performed mutational analyses on 325 individuals with definite tuberous sclerosis complex diagnostic status. We identified mutations in 72% (199/257) of de novo and 77% (53/68) of familial cases, with 17% of mutations in the TSC1 gene and 50% in the TSC2 gene. There were 4% unclassified variants and 29% with no mutation identified. Genotype/phenotype analyses of all observed tuberous sclerosis complex findings in probands were performed, including several clinical features not analyzed in two previous large studies. We showed that patients with TSC2 mutations have significantly more hypomelanotic macules and learning disability in contrast to those with TSC1 mutations, findings not noted in previous studies. We also observed results consistent with two similar studies suggesting that individuals with mutations in TSC2 have more severe symptoms. On performing meta-analyses of our data and the other two largest studies in the literature, we found significant correlations for several features that It has alternative splice sites at two exons (25 and 31) to create isoforms. 4,5 Tuberin has a calculated molecular weight of approximately 200 kD coding from a transcript of approximately 5.5 kb. The TSC1 gene was discovered a decade after the initial report of linkage (Online Mendelian Inheritance in Man 191100). 6 In contrast with the TSC2 gene, the TSC1 gene has 23 exons extending over approximately 55 kb of genomic DNA on chromosome 9q34.3. The TSC1 gene product is coded from exons 3 to 23. Noncoding sequences include exons 1 and 2, and a 4.5-kb 3= untranslated region. The protein product of the TSC1 gene (hamartin) has an estimated molecular weight of 130 kD coding from an 8.6-kb mRNA transcript. To date, more than 680 disease-causing mutations have been identified in either the TSC1 or TSC2 genes. 7 Approximately 70% to 80% of individuals who meet definite diagnostic criteria have a small identifiable TSC1 or TSC2 gene mutation. The remaining individuals probably have large gene deletions, somatic mosaic mutations, and mutations in unanalyzed gene noncoding regions, rather than an additional TSC gene locus.Of interest is whether the phenotypic presentation of TSC differs by whether the disease results from mutations in TSC1 or TSC2. Early studies reporting genotype/phenotype correlations did not find evidence for phenotypic differences between patients with TSC1 mutations and patients with no mutation identified

Genotype and cognitive phenotype of patients with tuberous sclerosis complex

“…19,39,40 However, the nearly identical IQ/DQs in men and women in our large TSC1 and TSC2 cohorts are more consistent with previous data on the prevalence of autism, ADHD and other neuropsychiatric disorders in the TSC population, 41,42 suggesting that genetic effects override gender effects.…”

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

“…Although TSC affects different organ systems, central nervous system involvement is common, resulting in developmental delay, neurobehavioral disability (such as autism), and often severe epilepsy [117,180,181]. Genotypephenotype correlation studies suggest that patients with TSC2 mutations may have a more severe neurologic phenotype [182][183][184][185].…”

An Overview of Autosomal Dominant Tumour Syndromes with Prominent Features in the Oral and Maxillofacial Region

“…The most frequent mutations are in the TSC2 (Tuberous sclerosis-2) gene with a smaller proportion of cases showing mutations in TSC1 [14][15][16]. Inheritance is in an autosomal dominant manner, however, in 60% of cases there is no history of the condition in either parent [12].…”

“…The variability of tuberous sclerosis complex reflects the differing effects of TSC1 and TSC2 mutations, variable expressivity and somatic mosaicism [12,16,17].…”

“…Multiple facial angiofibromas occur in the most cases particularly around the nose, appearing as firm skin coloured 2-3 mm telangiectatic papules [4,16]. Facial angiofibromas are also described in multiple endocrine neoplasia 1 and Birt-Hogg-Dubé syndrome but are less prominent features.…”