Mutations in multidomain protein MEGF8 identify a carpenter syndrome subtype associated with defective lateralization

Stephen R F Twigg, Deborah Lloyd, Dagan Jenkins, Nursel E. Elçioglu, Christopher D O Cooper, Nouriya Al-Sannaa, Ali Annagür, Gabriele Gillessen-Kaesbach, Irina Hüning, Samantha J L Knight, Judith A. Goodship, Bernard D. Keavney, Philip L. Beales, Opher Gileadi, Simon J. McGowan, Andrew O M Wilkie

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64 Citations (SciVal)


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.

Original languageEnglish
Pages (from-to)897-905
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number5
Publication statusPublished - 2 Nov 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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