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.
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© 2021 Published by Elsevier Inc.