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Isolated strabismus affects 1–5% of the general population 1 . Most forms of strabismus are multifactorial in origin; although there is probably an inherited component, the genetics of these disorders remain unclear. The congenital fibrosis syndromes (CFS) represent a subset of monogenic isolated strabismic disorders that are characterized by restrictive ophthalmoplegia, and include congenital fibrosis of the extraocular muscles (CFEOM) and Duane syndrome (DURS) 2 . Neuropathologic studies indicate that these disorders may result from the maldevelopment of the oculomotor (nIII), trochlear (nIV) and abducens (nVI) cranial nerve nuclei 3 , 4 , 5 . To date, five CFS loci have been mapped ( FEOM1, FEOM2, FEOM3 , DURS1 and DURS2 ) 6 , 7 , 8 , 9 , 10 , but no genes have been identified. Here, we report three mutations in ARIX (also known as PHOX2A ) in four CFEOM2 pedigrees. ARIX encodes a homeodomain transcription factor protein previously shown to be required for nIII/nIV development in mouse and zebrafish 11 , 12 . Two of the mutations are predicted to disrupt splicing, whereas the third alters an amino acid within the conserved brachyury-like domain 13 , 14 . These findings confirm the hypothesis that CFEOM2 results from the abnormal development of nIII/nIV (ref. 7 ) and emphasize a critical role for ARIX in the development of these midbrain motor nuclei 13 , 14 , 15 , 16 , 17 , 18 , 19 .