Genotype and cognitive phenotype of patients with tuberous sclerosis complex

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder, which affects 1 in 6000 people. About half of these patients are affected by mental retardation, which has been associated with TSC2 mutations, epilepsy severity and tuber burden. The bimodal intelligence distribution in TSC populations suggests the existence of subgroups with distinct pathophysiologies, which remain to be identified. Furthermore, it is unknown if heterozygous germline mutations in TSC2 can produce the neurocognitive phenotype of TSC independent of epilepsy and tubers. Genotype-phenotype correlations may help to determine risk profiles and select patients for targeted treatments. A retrospective chart review was performed, including a large cohort of 137 TSC patients who received intelligence assessment and genetic mutation analysis. The distribution of intellectual outcomes was investigated for selected genotypes. Genotype-neurocognitive phenotype correlations were performed and associations between specific germline mutations and intellectual outcomes were compared. Results showed that TSC1 mutations in the tuberin interaction domain were significantly associated with lower intellectual outcomes (P<0.03), which was also the case for TSC2 protein-truncating and hamartin interaction domain mutations (both P<0.05). TSC2 missense mutations and small in-frame deletions were significantly associated with higher IQ/DQs (P<0.05). Effects related to the mutation location within the TSC2 gene were found. These findings suggest that TSC2 protein-truncating mutations and small in-frame mutations are associated with distinctly different intelligence profiles, providing further evidence that different types and locations of TSC germline mutations may be associated with distinct neurocognitive phenotypes.

Figure 1

TSC1 and TSC2 gene exon map, depicting mutation types of patients with and without MR. CaMD, calmodulin-binding domain; CCD, coil–coil domain; ERM, ezrin–radixin–moesin; GAP, GTPase-activating protein; LZD, leucine zipper domain; TAD, transcription-activating domain; TMD, transmembrane domain.

Figure 2

Histograms depicting intelligence distributions of selected TSC mutation groups. (a) Intelligence outcomes of the total TSC cohort, including the TSC1 (dark gray), TSC2 (shaded gray) and NMI (light gray) cohorts. (b) Intelligence outcomes of TSC2 mutation subgroups with missense mutations and small in-frame deletions (dark gray), proximal protein-truncating mutations (shaded gray) and distal protein-truncating mutations (light gray).

Figure 3

Boxplots depicting intelligence outcomes of selected TSC mutation cohorts. (a) Intelligence outcomes of TSC1, TSC2 and NMI mutation cohort, including the mean intelligence, SD and outliers. (b) Intelligence distributions for TSC2 subgroups with small in-frame deletions, proximal protein-truncating mutations, distal protein-truncating mutations. Small in-frame mutations included missense mutations and deletions <1 exon.

Figure 4

Boxplot depicting intelligence outcomes for all patients with TSC2 missense mutations, specified per location of the mutation on the TSC2 gene. The outlier in the middle group represents a female patient with a neurological history of refractory partial complex seizures and epilepsy surgery; genetic analysis revealed a P1497R mutation.