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Keratoconus is a common corneal defect with a complex genetic basis. By whole exome sequencing of affected members from 11 multiplex families of European ancestry, we identified 23 rare, heterozygous, potentially pathogenic variants in 8 genes. These include nonsynonymous single amino acid substitutions in  HSPG2 ,  EML6  and  CENPF  in two families each, and in  NBEAL2 ,  LRP1B ,  PIK3CG  and  MRGPRD  in three families each;  ITGAX  had nonsynonymous single amino acid substitutions in two families and an indel with a base substitution producing a nonsense allele in the third family. Only  HSPG2 ,  EML6  and  CENPF  have been associated with ocular phenotypes previously. With the exception of  MRGPRD  and  ITGAX , we detected the transcript and encoded protein of the remaining genes in the cornea and corneal cell cultures. Cultured stromal cells showed cytoplasmic punctate staining of NBEAL2, staining of the fibrillar cytoskeletal network by EML6, while CENPF localized to the basal body of primary cilia. We inhibited the expression of  HSPG2 ,  EML6 ,  NBEAL2  and  CENPF  in stromal cell cultures and assayed for the expression of  COL1A1  as a readout of corneal matrix production. An upregulation in  COL1A1  after siRNA inhibition indicated their functional link to stromal cell biology. For  ITGAX , encoding a leukocyte integrin, we assayed its level in the sera of 3 affected families compared with 10 unrelated controls to detect an increase in all affecteds. Our study identified genes that regulate the cytoskeleton, protein trafficking and secretion, barrier tissue function and response to injury and inflammation, as being relevant to keratoconus.

Pathogenic alleles in microtubule, secretory granule and extracellular matrix-related genes in familial keratoconus