PhD student Erasmus Medical center Rotterdam, Zuid-Holland, Netherlands
Background: Craniosynostosis is a rare congenital anomaly which requires major cranial vault surgery in the first year of life. It may present in isolation as ‘non-syndromic craniosynostosis’, or with additional congenital anomalies and/or neurodevelopmental disorders, i.e. ‘syndromic craniosynostosis’. Clinical focus has shifted from identifying classical syndromic cases to offering genetic diagnostic testing to all craniosynostosis patients over the last decade. Objective: We aimed to establish the diagnostic yield of genetic diagnostics by investigating the prevalence of chromosomal and monogenic (likely) pathogenic variants in an 11-year birth cohort of 1020 children with craniosynostosis. Design/Methods: We conducted a retrospective study in the Erasmus Medical Center, Rotterdam, The Netherlands. We included all children born between January 1st 2010- January 1st 2021 with radiologically confirmed craniosynostosis. We collected information on genetic diagnostics, diagnosis, affected suture(s ), relevant gestational factors, family history and consanguinity. Results: Genetic diagnostics were performed in 502 children. A pathogenic variant was identified in 179 patients (36%). We found significantly higher diagnostic yield in patients with syndromic craniosynostosis (63%) as compared to patients with non-syndromic craniosynostosis (6%). Initially, targeted single-gene testing was performed on indication. Diagnostic yield was highest for FGFR2 (21%), FGFR3(13%), EFNB1(50%) and IL11RA(14%).Diagnostic yield for microarray and Next Generation Sequencing (NGS) craniosynostosis panel were 8% and 10%, respectively. On indication additional NGS analyses were performed. Diagnostic yield was highest for NGS open exome (29%), followed by the Multiple congenital anomaly (15%) and Intellectual Disability panels(11%).
Conclusion(s): Array analysis and NGS craniosynostosis panels are key to identify pathogenic variants in children with craniosynostosis. If no diagnosis is obtained through these analyses, open exome sequencing is recommended after adequate genetic counseling regarding incidental findings. If parents reject or do not feel comfortable with open exome sequencing, multiple congenital anomaly or intellectual disability NGS panels may be considered. Although current genetic analyses do not have a 100% diagnostic yield, they are important as a genetic diagnosis can be a strong predictor for clinical outcome, may warrant screening for additional congenital anomalies, and is key for counseling (future) parents on recurrence risk and prognosis of the affected child.
