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Carpenter syndrome (CRPTS) is a rare autosomal recessive condition caused by biallelic variants in genes that encode negative regulators of hedgehog signalling (RAB23 [CRPT1] or, more rarely, MEGF8 [CRPT2]), and is characterised by craniosynostosis, polysyndactyly, and other congenital abnormalities. We describe a further six families comprising eight individuals with MEGF8-associated CRPT2, increasing the total number of reported cases to fifteen, and refine the phenotype of CRPT2 compared to CRPT1. The core features of craniosynostosis, polysyndactyly and (in males) cryptorchidism are almost universal in both CRPT1 and CRPT2. However, laterality defects are present in nearly half of those with MEGF8-associated CRPT2, but are rare in RAB23-associated CRPT1. Craniosynostosis in CRPT2 commonly involves a single midline suture in comparison to the multi-suture craniosynostosis characteristic of CRPT1. No patient to date has carried two MEGF8 gene alterations that are both predicted to lead to complete loss-of-function, suggesting that a variable degree of residual MEGF8 activity may be essential for viability and potentially contributing to variable phenotypic severity. These data refine the phenotypic spectrum of CRPT2 in comparison to CRPT1 and more than double the number of likely pathogenic MEGF8 variants in this rare disorder., (© 2024. The Author(s).)

Genomic medicine, an emerging medical discipline, applies the principles of evolution, developmental biology, functional genomics, and structural genomics within clinical care. Enabling widespread adoption and integration of genomic medicine into clinical practice is key to achieving precision medicine. We delineate a biological framework defining diagnostic utility of genomic testing and map the process of genomic medicine to inform integration into clinical practice. This process leverages collaboration and collective cognition of patients, principal care providers, clinical genomic specialists, laboratory geneticists, and payers. We detail considerations for referral, triage, patient intake, phenotyping, testing eligibility, variant analysis and interpretation, counseling, and management within the utilitarian limitations of health care systems. To reduce barriers for clinician engagement in genomic medicine, we provide several decision-making frameworks and tools and describe the implementation of the proposed workflow in a prototyped electronic platform that facilitates genomic care. Finally, we discuss a vision for the future of genomic medicine and comment on areas for continued efforts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Handra, Elbert, Gazzaz, Moller-Hansen, Hyunh, Lee, Boerkoel, Alderman, Anderson, Clarke, Hamilton, Hamman, Hughes, Ip, Langlois, Lee, Li, Mackenzie, Patel, Prentice, Sangha, Sato, Seath, Seppelt, Swenerton, Warnock, Zambonin, Boerkoel, Chin and Armstrong.)