Abstract
PurposeNeurofibromatosis type 1 (NF1) is an autosomal dominant disorder associated with cognitive deficits. The NF1 cognitive phenotype is generally considered to be highly variable, possibly due to the observed T2-weighted hyperintensities, loss of heterozygosity, NF1-specific genetic modifiers, or allelic imbalance. MethodsWe investigated cognitive variability and assessed the contribution of genetic factors by performing a retrospective cohort study and a monozygotic twin case series. We included data of 497 children with genetically confirmed NF1 and an IQ assessment, including 12 monozygotic twin and 17 sibling sets. ResultsIndividuals carrying an NF1 chromosomal microdeletion showed significant lower full-scale IQ (FSIQ) scores than individuals carrying intragenic pathogenic NF1 variants. For the intragenic subgroup, the variability in cognitive ability and the correlation of IQ between monozygotic NF1 twin pairs or between NF1 siblings is similar to the general population. ConclusionsThe variance and heritability of IQ in individuals with NF1 are similar to that of the general population, and hence mostly driven by genetic background differences. The only factor that significantly attenuates IQ in NF1 individuals is the NF1 chromosomal microdeletion genotype. Implications for clinical management are that individuals with intragenic NF1 variants that score <1.5–2 SD below the mean of the NF1 population should be screened for additional causes of cognitive disability.
Highlights
Neurofibromatosis type 1 (NF1, OMIM 162200) is a genetic disorder1 caused by heterozygous loss-of-function variants in NF1 (OMIM 613113)
Subsequent post hoc testing for full-scale IQ (FSIQ) revealed that the group effect was driven by the CMD group, which had significantly lower IQ scores compared with the other groups (Fig. 1 and Table S1)
To assess whether specific intragenic NF1 variants increase the variability of cognitive ability relative to the general population, we characterized the variability for all children in the combined cohort with an intragenic genotype, excluding those with a CMD genotype
Summary
Neurofibromatosis type 1 (NF1, OMIM 162200) is a genetic disorder (birth prevalence ~1:2000) caused by heterozygous loss-of-function variants in NF1 (OMIM 613113). NF1 encodes the protein neurofibromin, which is a negative regulator of the RAS signaling pathway. Hallmark NF1 features are café-au-lait spots, inguinal freckling, (sub) cutaneous neurofibromas, plexiform neurofibromas, hamartomas of the iris, optic pathway gliomas, and bone dysplasia.. Hallmark NF1 features are café-au-lait spots, inguinal freckling, (sub) cutaneous neurofibromas, plexiform neurofibromas, hamartomas of the iris, optic pathway gliomas, and bone dysplasia.2 In addition to these somatic features, NF1 individuals have cognitive deficits, behavioral problems, and motor difficulties.. The cognitive deficits significantly impact the daily lives of NF1 individuals, as cognitive deficits are rated the highest disease burden in childhood.. The prevalence of attention deficit–hyperactivity disorder and autism spectrum disorder is increased tenfold in the NF1 population. Hallmark NF1 features are café-au-lait spots, inguinal freckling, (sub) cutaneous neurofibromas, plexiform neurofibromas, hamartomas of the iris, optic pathway gliomas, and bone dysplasia. In addition to these somatic features, NF1 individuals have cognitive deficits, behavioral problems, and motor difficulties. The cognitive deficits significantly impact the daily lives of NF1 individuals, as cognitive deficits are rated the highest disease burden in childhood. the prevalence of attention deficit–hyperactivity disorder and autism spectrum disorder is increased tenfold in the NF1 population.
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