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The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients

Lookup NU author(s): Dr Marta Bertoli, Jessica Zambonin

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© The Author(s) 2024. 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.

Publication metadata

Author(s): Watts LM, Bertoli M, Attie-Bitach T, Roux N, Rausell A, Paschal CR, Zambonin JL, Curry CJ, Martin B, Tooze RS, Hawkes L, Kini U, Twigg SRF, Wilkie AOM

Publication type: Article

Publication status: Published

Journal: European Journal of Human Genetics

Year: 2024

Pages: ePub ahead of Print

Online publication date: 17/05/2024

Acceptance date: 25/04/2024

Date deposited: 29/05/2024

ISSN (print): 1018-4813

ISSN (electronic): 1476-5438

Publisher: Springer Nature

URL: https://doi.org/10.1038/s41431-024-01624-9

DOI: 10.1038/s41431-024-01624-9

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