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

PURPOSE: The ClinGen 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. This work summarizes the findings of the Cranio GCEP during its first round of curation, aiming to provide expert guidance for clinical validity of gene-disease relationships in the context of craniofacial malformations. METHODS: The curation scope of the GCEP was separated into multiple rounds based on frequency of occurrence and uniqueness of associated features. Twelve genes (EFNB1, ERF, FGFR1, FGFR2, FGFR3, MEGF8, MSX2, POR, RAB23, SKI, TCF12, and TWIST1) were selected, based on review of literature, multi-gene sequencing panels from the Genetic Testing Registry (GTR), and expert input. RESULTS: On average, there were two disease relationships per gene, ranging from one to six. In total, the Cranio GCEP curated 23 gene-disease pairs. Of these curations, 17 (74%) classifications reached Definitive, 3 (13%) Moderate, and 3 (13%) Limited. CONCLUSIONS: 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, new collaboration, and encourages publication of clinical cases in previously discovered genes in order to reflect the broadening spectrum of gene-disease relationships in the craniofacial malformation and craniosynostosis literature.