TSC2 c.1864C>T variant associated with mild cases of tuberous sclerosis complex

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited disorder with variable expressivity associated with hamartomatous tumors, abnormalities of the skin, and neurologic problems including seizures, intellectual disability, and autism. TSC is caused by pathogenic variants in either TSC1 or TSC2. In general, TSC2 pathogenic variants are associated with a more severe phenotype than TSC1 pathogenic variants. Here, we report a pathogenic TSC2 variant, c.1864C>T, p.(Arg622Trp), associated with a mild phenotype, with most carriers meeting fewer than two major clinical diagnostic criteria for TSC. This finding has significant implications for counseling patients regarding prognosis. More patient data are required before changing the surveillance recommendations for patients with the reported variant. However, consideration should be given to tailoring surveillance recommendations for all pathogenic TSC1 and TSC2 variants with documented milder clinical sequelae. © 2017 Wiley Periodicals, Inc.

Tuberous Sclerosis Complex Genotypes and Developmental Phenotype

“…Our findings were also consistent with those of previous studies that determined Arg622Trp 24 and Arg1200Trp 23 TSC2 pathogenic missense variants to be associated with a milder phenotype. Although the sample size of three was too small for statistical analysis, two of the children (Arg622Trp and Arg1200Trp) had composite scores in the “average” range, whereas the third (Arg1200Trp) had a “very high” composite score.…”

“…TSC2 pathogenic variants included frameshift (28%), nonsense (23%), missense (23%), splice site (14%), and deletion (12%). Three of the patients had TSC2 missense variants (Arg622Trp and Arg1200Trp) that had been previously associated with a milder phenotype 23,24 and unless otherwise specified, were included in the TSC2 group in analyses. There were no significant differences in sex, ethnicity, gestational age, and paternal age between the three groups: TSC1, TSC2, and NMI (Table 1).…”

“…Additional comparisons were made excluding patients (N = 3) with TSC2 pathogenic variants known to convey a milder phenotype. 23,24 Chi-squared and Fisher's exact tests were used to describe differences in categorical variables, and the Kruskal-Wallis test was used to describe differences in the distributions of continuous variables. Multivariable linear regression models were used to assess the independent effects of TSC2 pathogenic variants and seizures on MSEL scores, adjusting for maternal age.…”

Genetics, genomics, and genotype–phenotype correlations of TSC: Insights for clinical practice

“…The pathogenic c.3106T>C (p.Ser1036Pro) variant in exon 26 of TSC2 has been found in a single family with mild phenotype (brain and skin findings, normal cognitive level) and recurrent seizures in some members (O'Connor, Kwiatkowski, Roberts, Wollmann, & Huttenlocher, 2003). Recently, Farach et al (2017) found that the c.1864C>T (p. which can be summarized as milder than those with TSC2 pathogenic variants and similar but more severe with respect to renal findings than those with a TSC1 pathogenic variant (Camposano, Greenberg, Kwiatkowski, & Thiele, 2009;Peron et al, 2018). The only caveat to this general statement is that some NMI individuals with a severe clinical presentation have been reported.…”

“…The pathogenic c.3106T>C (p.Ser1036Pro) variant in exon 26 of TSC2 has been found in a single family with mild phenotype (brain and skin findings, normal cognitive level) and recurrent seizures in some members (O'Connor, Kwiatkowski, Roberts, Wollmann, & Huttenlocher, 2003). Recently, Farach et al (2017) found that the c.1864C>T (p.…”