Nonpenetrance of the Most Frequent Autosomal Recessive Leber Congenital Amaurosis Mutation in NMNAT1

IMPORTANCE The NMNAT1 gene was recently found to be mutated in a subset of patients with Leber congenitalamaurosis and macular atrophy. The most prevalent NMNAT1 variant was p.G1u257Lys, which was observed in 38 of 106 alleles (35.8%). On the basis of functional assays, it Was deemed a severe variant. OBSERVATIONS The p.Glu257Lys variant was 80-fold less frequent in a homozygous state in patients with Leber congenital amaurosis than predicted based on its heterozygosity frequency in the European American population. Moreover, we identified this variant in a homozygous state in a patient with no ocularabnormalities. CONCLUSIONS AND RELEVANCE On the basis of these results, the p.Glu257Lys variant is considered not fully penetrant. Homo zygotes of the p Glu257Lys variant in most persons are therefore not associated with ocular disease. Consequently, genetic counselors should exerdse great caution in the interpretation of this variant.