Genomic analysis of Meckel-Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

Eur J Hum Genet. 2013 Jul;21(7):762-8. doi: 10.1038/ejhg.2012.254. Epub 2012 Nov 21.


Meckel-Gruber syndrome (MKS, OMIM #249000) is a multiple congenital malformation syndrome that represents the severe end of the ciliopathy phenotypic spectrum. Despite the relatively common occurrence of this syndrome among Arabs, little is known about its genetic architecture in this population. This is a series of 18 Arab families with MKS, who were evaluated clinically and studied using autozygome-guided mutation analysis and exome sequencing. We show that autozygome-guided candidate gene analysis identified the underlying mutation in the majority (n=12, 71%). Exome sequencing revealed a likely pathogenic mutation in three novel candidate MKS disease genes. These include C5orf42, Ellis-van-Creveld disease gene EVC2 and SEC8 (also known as EXOC4), which encodes an exocyst protein with an established role in ciliogenesis. This is the largest and most comprehensive genomic study on MKS in Arabs and the results, in addition to revealing genetic and allelic heterogeneity, suggest that previously reported disease genes and the novel candidates uncovered by this study account for the overwhelming majority of MKS patients in our population.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arabs / genetics
  • Ciliary Motility Disorders / genetics*
  • Ciliary Motility Disorders / physiopathology
  • Encephalocele / genetics*
  • Encephalocele / physiopathology
  • Exome
  • Genetic Association Studies
  • Genetic Heterogeneity
  • Genome, Human
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins / genetics*
  • Mutation
  • Polycystic Kidney Diseases / genetics*
  • Polycystic Kidney Diseases / physiopathology
  • Proteins / genetics*
  • Retinitis Pigmentosa
  • Sequence Analysis, DNA
  • Vesicular Transport Proteins / genetics*


  • CPLANE1 protein, human
  • EVC2 protein, human
  • EXOC4 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Proteins
  • Vesicular Transport Proteins

Supplementary concepts

  • Meckel syndrome type 1