Date of Award

January 2022

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Michael Alperovich

Abstract

Background: Non-syndromic craniosynostosis (NSC) is one of the most common anomalies treated by craniofacial surgeons. Despite optimal surgical management, nearly half of children with NSC have subtle neurocognitive deficits. Whereas the impact of timing and type of surgical intervention on neurodevelopment in NSC has been studied, the possibility of genetic influence on neurodevelopment remains unexplored. The purpose of this study is to establish and quantify the association between de novo and transmitted damaging mutations in genes under high evolutionary constraint (high pLI) with neurodevelopmental delays in non-syndromic craniosynostosis (NSC).

Methods: Parents of children with NSC who had previously undergone genetic testing were surveyed to determine the prevalence of various types of neurodevelopmental delay. Patients with and without each mutation class were analyzed by the presence or absence of various types of neurodevelopmental delay, including motor delays, speech/language delays, and intellectual disability using Fischer’s Exact tests. In addition, neurocognitive tests were administered to patients with sagittal NSC who were greater than 6 years of age. 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.

Results: Compared to those without mutations, children with mutations in high pLI genes had about a 2 times higher incidence of neurodevelopmental delay (P=0.001), greater than 20 times higher incidence of intellectual disability (P=7.2x10-7), and were 3.6 times more likely to have delays that persisted beyond age 5 (P=4.4x10-4). Among the 56 patients who completed neurocognitive testing, patients with high-risk mutations had poorer performance compared to patients without high-risk mutations in every testing category, with significant differences in full-scale IQ (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.

Conclusions: Even after controlling for exogenous factors, the presence of mutations in high-risk genes led to poorer neurocognitive outcomes. High risk genotypes likely predispose individuals with NSC to cognitive deficits.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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