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SMAD6 Allele Predicts Neurodevelopment in Non-syndromic Craniosynostosis
Robin T. Wu, BS, Andrew T. Timberlake, MD PhD, Paul F. Abraham, BS, Kyle S. Gabrick, MD, Xiaona Lu, MD, Connor J. Peck, BS, Rajendra F. Sawh-Martinez, MD MHS, Derek M. Steinbacher, MD DMD, Michael A. Alperovich, MD MSc, John A. Persing, MD.
Yale University School of Medicine, New Haven, CT, USA.

Background: De-novo or rare transmitted mutations in the SMAD6 gene, an inhibitor of BMP, have significant genetic interactions with common BMP2 variants to affect 7% of non-syndromic midline synostosis (NSC). In addition to cranial abnormalities and brain deformation, neurodevelopmental outcomes of non-syndromic synostosis may be influenced by genetics. This study aimed to determine the neurocognitive sequelae of SMAD6 NSC in relation to non-SMAD6 NSC. Methods: Midline NSC patients >6 years of age, with SMAD6 mutations (identified in a national genetic study) and age/race/gender/synostosis type/operation matched non-SMAD6 NSC controls were recruited. All patients completed a double-blinded neurodevelopmental battery (Wechsler Fundamentals, Wechsler Abbreviated Scale of Intelligence, Beery-Buktenica Developmental Test) and parents/guardians completed behavioral surveys (Behavior Rating Inventory of Executive Function and Behavior Rating System for Children). Twenty demographic/patient factors, known to influence cognition, were collected. Statistical analyses involved Student's t-tests, z-scores, correlations, and multiple regressions. Results: All ten known SMAD6 patients nationwide (average age at testing 10.1 years; 1 female; 8 metopic, 2 sagittal; 9 treated with CVR, 1 strip) and ten matched controls (average age 9.8 years; 1 female; 8 metopic, 2 sagittal; 9 treated with CVR, 1 strip) participated in this study. There was no significant difference between all 18 demographic factors collected. In head to head comparison, SMAD6 cases scored significantly worse on numerical operations(p=0.012), performance IQ(p=0.004), full IQ(p=0.007), and motor coordination(p=0.007). Individual correlations between scores and demographic variables revealed 4 variables (age at testing, age at surgery, parental education, and household income) significantly correlated with cognition. Multiple regressions were performed to control for these 4 variables. SMAD6 patients, despite these factors, still performed worse on numerical operations(p=0.046), performance IQ(p=0.018), full IQ(p=0.010), motor coordination(p=0.043). On behavioral surveys, SMAD6 scored worse on inhibition(p=0.003), behavior regulation(p=0.032), hyperactivity(p=0.007), aggression(p=0.008), conduct(p=0.029), social skills (p=0.039), and communication(p=0.018). Post-hoc power analysis yielded power between 84.4% and 92.4% for all significant tests. Conclusion: This prospective double blinded control trial revealed that genetic influences of non-syndromic craniosynostosis may play a large role in functional neuropsychiatric development. Midline synostosis caused by SMAD6 mutations led to poorer head-to-head performance on mathematics, performance IQ, full IQ and motor coordination compared to non-SMAD6 craniosynostosis patients, even after controlling for factors that influence cognition. SMAD6 patients had additional behavioral deficits in inhibition, behavior regulation, hyperactivity, aggression, conduct, social skills, and communication. Moving forward, genetic testing may serve as a critical advocate for early adjunctive neuropsychiatric therapy in patients with non-syndromic craniosynostosis. <!--EndFragment-->


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