Evidence-based classification of genes implicated in craniosynostosis disorders using the ClinGen curation framework

The Clinical Genome Resource Craniofacial Malformations Gene Curation Expert Panel (Cranio GCEP) was formed in 2020 with an initial target of evaluating genes implicated in craniosynostosis and skull abnormalities. The current work summarizes the findings of the Cranio GCEP during its first round of curation and aims to provide expert guidance on the clinical validity of gene-disease relationships in the context of craniofacial malformations.

The curation scope of the GCEP was separated into multiple rounds based on the frequency of occurrence and the uniqueness of associated features. Twelve genes (EFNB1, ERF, FGFR1, FGFR2, FGFR3, MEGF8, MSX2, POR, RAB23, SKI, TCF12, and TWIST1) were selected based on literature review, multi-gene sequencing panels from the Genetic Testing Registry, and expert input.

On average, there were 2 disease relationships per gene, ranging from 1 to 6. In total, the Cranio GCEP curated 23 gene-disease pairs. Of these curations, 17 (74%) were classified as definitive, 3 (13%) as moderate, and 3 (13%) as limited.

The classification of gene-disease relationships in round one curation of the Cranio GCEP has contributed to systematically evaluating the validity of gene-disease relationships for craniofacial malformations, to establish accurate testing panels, and improve patient care. By bringing together content experts to focus on gene curation, the Cranio GCEP facilitates education, fosters new collaborations, and encourages the publication of clinical cases involving previously discovered genes, reflecting the broadening spectrum of gene-disease relationships in the craniofacial malformation and craniosynostosis literature.