Twigg, SR; Lloyd, D; Jenkins, D; Elçioglu, NE; Cooper, CD; Al-Sannaa, N; Annagür, A; + view all Twigg, SR; Lloyd, D; Jenkins, D; Elçioglu, NE; Cooper, CD; Al-Sannaa, N; Annagür, A; Gillessen-Kaesbach, G; Hüning, I; Knight, SJ; Goodship, JA; Keavney, BD; Beales, PL; Gileadi, O; McGowan, SJ; Wilkie, AO; - view fewer (2012) Mutations in multidomain protein MEGF8 identify a Carpenter syndrome subtype associated with defective lateralization.

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	Excel Spreadsheet ( Table 1. Clinical Features of Subjects with Mutations in MEGF8) table1.csv Download (3kB)
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Abstract

Carpenter syndrome is an autosomal-recessive multiple-congenital-malformation disorder characterized by multisuture craniosynostosis and polysyndactyly of the hands and feet; many other clinical features occur, and the most frequent include obesity, umbilical hernia, cryptorchidism, and congenital heart disease. Mutations of RAB23, encoding a small GTPase that regulates vesicular transport, are present in the majority of cases. Here, we describe a disorder caused by mutations in multiple epidermal-growth-factor-like-domains 8 (MEGF8), which exhibits substantial clinical overlap with Carpenter syndrome but is frequently associated with abnormal left-right patterning. We describe five affected individuals with similar dysmorphic facies, and three of them had either complete situs inversus, dextrocardia, or transposition of the great arteries; similar cardiac abnormalities were previously identified in a mouse mutant for the orthologous Megf8. The mutant alleles comprise one nonsense, three missense, and two splice-site mutations; we demonstrate in zebrafish that, in contrast to the wild-type protein, the proteins containing all three missense alterations provide only weak rescue of an early gastrulation phenotype induced by Megf8 knockdown. We conclude that mutations in MEGF8 cause a Carpenter syndrome subtype frequently associated with defective left-right patterning, probably through perturbation of signaling by hedgehog and nodal family members. We did not observe any subject with biallelic loss-of function mutations, suggesting that some residual MEGF8 function might be necessary for survival and might influence the phenotypes observed.

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