Examination of the genetic factors underlying the cognitive variability associated with neurofibromatosis type 1

Abstract

Purpose: Neurofibromatosis 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. Methods: We 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. Results: Individuals 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. Conclusions: The 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.

Clinical characterization of children and adolescents with NF1 microdeletions

“…However, somatic mosaicism with normal cells not harbouring the NF1 microdeletion is very rare in patients with type-1 NF1 deletions [12,13]. Table 5 FSIQ in patients with NF1 microdeletions analysed by Descheemaeker et al [22], Mautner et al [18], Ottenhoff et al [23] and in the present study Descheemaeker et al [22] Mautner et al [18] Ottenhoff et al [23] This study [22]. Six patients included in our present study have been already analysed previously by Mautner et al [18].…”

“…However, variance and heritability of IQ in individuals with NF1 are similar to that of the general population and mostly driven by genetic background differences [23]. Patients with NF1 microdeletions exhibit significantly lower mean FSIQ scores than individuals carrying intragenic pathogenic NF1 mutations [18,22,23]. In the study presented here, we determined FSIQ scores in 24 children and adolescents with NF1 microdeletions investigated at the age of 6-18 years.…”

“…Only one of these five patients had an atypical 4.7-Mb spanning deletion, and the others exhibited the frequent type-1 NF1 microdeletions of 1.4 Mb. Previously performed studies indicated an FSIQ < 70 in 18%, 35% and 41% of NF1 microdeletions patients [18,22,23] (Table 5). Thus, intellectual disability is observed only in a subgroup of patients with NF1 microdeletions.…”

“…Thus, the mean FSIQ in children with NF1 is lower than that of children from the general population. However, variance and heritability of IQ in individuals with NF1 are similar to that of the general population and mostly driven by genetic background differences [23]. Patients with NF1 microdeletions exhibit significantly lower mean FSIQ scores than individuals carrying intragenic pathogenic NF1 mutations [18,22,23].…”

“…Since the first identification of patients with NF1 microdeletions, it became clear that these patients often present with a severe clinical phenotype and exhibit features which are not common in patients with intragenic NF1 mutations including facial dysmorphic features, severe learning disabilities, high numbers of neurofibromas, overgrowth/tallfor-age stature, large hands and feet with excessive soft tissue, hyperflexibility of joints and congenital cardiac anomalies [8,[15][16][17][18][19][20][21]. The average intelligence in the group of patients with NF1 microdeletions was found to be lower than in patients with intragenic NF1 mutations [18,22,23].…”