Objective To determine the genotype underlying suspected X-linked infantile nystagmus in a family and to correlate genotype with clinical examination in potential female carriers.
Methods Ophthalmic examination (ophthalmic, orthoptic, optokinetic [OKN] drum, and electrophysiologic when possible) and candidate gene analysis.
Results Two affected brothers had infantile nystagmus with no evidence of associated visual or neurological disease. The symptomatic maternal aunt had infantile nystagmus in addition to congenital fibrosis of the extraocular muscles (CFEOM) (bilateral hypotropia, exotropia, ptosis, almost complete ophthalmoplegia, and poorly reactive pupils). A sister, the mother, and the maternal grandmother—all 3 of whom were asymptomatic—had delayed corrective saccades (prolonged pursuit) during OKN drum testing. A brother and the father—both of whom were asymptomatic—had unremarkable examination findings. A FRMD7 splice variant (c.1050 + 5 G>A) was identified in the 2 affected brothers and in the 3 asymptomatic women only. Allele sharing analysis further confirmed that the aunt's phenotype was not related to the FRMD7 variant, which was absent in 246 ethnic controls. Her phenotype was also not related to mutation in known CFEOM genes (KIF21A, PHOX2A, TUBB3).
Conclusions Prolonged pursuit responses during OKN drum testing in asymptomatic female carriers is consistent with the concept of infantile nystagmus being an abnormally increased pursuit oscillation. Further studies are required to determine the reproducibility of this potential female carrier sign. Rather than being FRMD7 related, nystagmus in the maternal aunt represented a second disease in this family, likely related to CFEOM.
Clinical Relevance Clinicians can use the OKN drum to assess obligate female carriers in a family suspected of having X-linked nystagmus.