Tuberous Sclerosis Complex Genotypes and Developmental Phenotype

Abstract

Background: Children with tuberous sclerosis complex (TSC), caused by pathogenic variants in TSC1/TSC2, are at risk for intellectual disability. TSC2 pathogenic variants appear to increase the risk, compared with TSC1. However, the effect of TSC2 pathogenic variants on early and specific domains of development hasn't been studied. Using an extensively phenotyped group, we aimed to characterize differences in early intellectual development between genotypes.

Methods: The study group (n = 92) included participants with TSC enrolled in a multicenter study involving genetic testing and detailed prospective phenotyping including the Mullen Scales of Early Learning, a validated measure of cognition, language, and motor development in babies and preschool children. Mean T-scores at 24 months for each Mullen Scales of Early Learning domain were calculated for children with, versus without, a TSC2 pathogenic variant. Multivariable linear regression models were used to compare the groups, adjusting for seizures.

Results: T-scores on every Mullen Scales of Early Learning domain were significantly worse in the TSC2 group. Below average composite scores were present in three-fourths of the TSC2 group, compared with one-fourth of those without TSC2. Having a TSC2 pathogenic variant was associated with lower composite Mullen Scales of Early Learning scores, even when corrected for seizures.

Conclusions: In a well-characterized patient population with standardized assessment of multiple aspects of development, we found that having a TSC2 pathogenic variant was associated with significantly lower Mullen Scales of Early Learning scores at age 24 months, independent of seizures. These data suggest that a baby with a TSC2 pathogenic variant is at high risk for significant developmental delays by 24 months.

Keywords: Cognition; Developmental delay; Genotype; Genotype-phenotype correlation; Mullen scales of early learning (MSEL); Phenotype; Tuberous sclerosis complex (TSC).

FIGURE.

Trajectories of mean (±standard error) MSEL domain scores from nine to 36 months for participants with TSC1/NMI, TSC2, and TSC2 excluding those with pathogenic variants known to confer a mild phenotype. The composite scale (A) has a mean standard score of 100 with S.D. of 15. The other domains (B–F) have a mean T-score of 50 with S.D. of 10. Scores in the T5C2 group are consistently lower than those of TSC1/NMI group in all domains, with the lowest scores belonging to the TSC2 group, which excludes mild variants.