Background: Previous work has identified an association between de novo and transmitted loss-of-function mutations in genes under high evolutionary constraint with neurodevelopmental delays in nonsyndromic craniosynostosis (NSC). The authors sought to quantify the neurocognitive effect of these genetic lesions.
Methods: 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 genes with a high probability of loss of function intolerance 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.
Results: Fifty-six 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 with patients without high-risk mutations in every testing category, with significant differences in FSIQ (102.9 ± 11.4 versus 110.1 ± 11.3; P = 0.033) and visuomotor integration (100.0 ± 11.9 versus 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.
Conclusions: 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 FSIQ and visuomotor integration.
Clinical question/level of evidence: Risk, II.
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