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

Abstract

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.

Fig. 1. Clinical features of individuals with MEGF8 variants.

Hands (A, B; post-operative following multiple syndactyly releases) and feet (C, D) of subject 1 at the age of 37 years; facial features (E, F), hands (G, H) and feet (I) of subject 2.ii; facial features (J, K), hand (L) and foot (M) of subject 3; facial features (N, O), hands (P), feet (Q) and chest (R) of subject 6.1 at 11 months (N, Q) and 16 years (O, P, R); facial features (S), hands (T) and knee demonstrating broad patellae (U) of subject 6.ii at 10 years old.

Fig. 2. Structure of MEGF8 and CRPT2-associated gene alterations reported in this study (red) and previously published (black).

A Diagram of the 41 exons of MEGF8. The 2778 amino acid reference sequence (RefSeq accession NM_001410.3, Ensembl ENST00000334370.8) omits exon 12A, shown in red. Genetic variants are shown, previously described are shown in black, those identified in this work are shown in red. B Domain organisation of MEGF8 protein with previously described variants shown in black and those identified in this work shown in red.