Quantifying the Impact of Genetics on Neurocognition in Non-Syndromic Sagittal Craniosynostosis.

Abstract

Previous work has identified an association between de novo and transmitted loss of function mutations in genes under high evolutionary constraint (high pLI) with neurodevelopmental delays in non-syndromic craniosynostosis (NSC). We sought to quantify the neurocognitive effect of these genetic lesions. In a prospective, double-blinded cohort study, demographic surveys and neurocognitive tests were administered to patients recruited from a national sample of children with sagittal NSC. Scores for academic achievement, full-scale intelligence quotient (FSIQ), and visuomotor skills were directly compared between patients with and without damaging mutations in high pLI genes using two-tailed t tests. Analysis of covariance was also used to compare test scores while controlling for surgery type, age at surgery, and sociodemographic risk. 56 patients completed neurocognitive testing, 18 of whom had a mutation in a highly constrained gene. There was no significant difference between groups in any sociodemographic factors. After controlling for patient factors, patients with high-risk mutations had poorer performance compared to patients without high-risk mutations in every testing category, with significant differences in FSIQ (102.9 ± 11.4 vs. 110.1 ± 11.3, P=0.033) and visuomotor integration (100.0 ± 11.9 vs. 105.2 ± 9.5, P=0.003). There were no significant differences in neurocognitive outcome when stratifying groups based on type of surgery or age at time of surgery. Even after controlling for exogenous factors, the presence of mutations in high-risk genes led to poorer neurocognitive outcomes. High risk genotypes may predispose individuals with NSC to deficits, particularly in full-scale IQ and visuomotor integration.