Laura S Farach1, Deborah A Pearson2, John P Woodhouse3, Jeremy M Schraw4, Mustafa Sahin5, Darcy A Krueger6, Joyce Y Wu7, Elizabeth M Bebin8, Philip J Lupo3, Kit Sing Au9, Hope Northrup9. 1. Department of Pediatrics, Division of Medical Genetics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas. Electronic address: Laura.S.Farach@uth.tmc.edu. 2. Department of Psychiatry, Division of Child and Adolescent Psychiatry, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas. 3. Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Texas. 4. Department of Medicine, Section of Epidemiology and Population Sciences, Baylor College of Medicine, Houston, Texas. 5. Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. 6. Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 7. Division of Pediatric Neurology, UCLA Mattel Children's Hospital and David Geffen School of Medicine, Los Angeles, California. 8. University of Alabama at Birmingham, Birmingham, Alabama. 9. Department of Pediatrics, Division of Medical Genetics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas.
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.
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.
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