42. Laboratory and clinician collaboration yields results: Development of a comprehensive craniosynostosis genetic testing panel with a high diagnostic rate

Abstract

Craniosynostosis is the premature fusion of one or more of the cranial sutures. The etiology of craniosynostosis is complex, with both environmental and genetic risk factors. With input from multiple stakeholders, including clinical geneticists and craniofacial pediatricians, our laboratory recently launched a comprehensive genetic testing panel for craniosynostosis using targeted next generation sequencing and copy number analysis via exon-level microarray. Testing options include single gene analysis or a focused panel, which includes seven genes (EFNB1, ERF, FGFR1, FGFR2, FGFR3, TCF12, TWIST1). Pathogenic variants in these seven genes account for approximately 75% of individuals with syndromic craniosynostosis. An expanded panel is also available that includes 42 additional genes that have been linked to craniosynostosis in at least two published reports. To date, ten clinical samples have been tested in our lab, with variants reported in seven (four pathogenic, one likely pathogenic, and two variants of uncertain significance). A pathogenic TCF12 nonsense variant was detected in a 14 year old female with bicoronal craniosynostosis and a shortened right forefoot. A ∼1 kb deletion encompassing exon 4 within GLI3 was detected in an 8 month old male with sagittal craniosynostosis and preaxial polydactyly of the right foot, consistent with a diagnosis of Greig cephalopolysyndactyly syndrome. Sequencing was performed for a 4 month old female with coronal craniosynostosis and polysyndactyly of the left foot and a known diagnosis of 22q11.2 deletion syndrome. A rare missense variant was detected in CDC45, which lies within the 22q11.2 critical region. Involving our institution's clinicians in test development enabled development of panels most appropriate for our patient population, with high detection rates. Future goals for the panel include streamlining the laboratory workflow by detection of copy number variants via NGS data and regular updates to panel content to include genes recently implicated in craniosynostosis.