Nonpenetrance of the most frequent autosomal recessive leber congenital amaurosis mutation in NMNAT1

Anna M Siemiatkowska, Janneke H M Schuurs-Hoeijmakers, Danielle G M Bosch, F Nienke Boonstra, Frans C C Riemslag, Mariken Ruiter, Bert B A de Vries, Anneke I den Hollander, Rob W J Collin, Frans P M Cremers

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    IMPORTANCE: The NMNAT1 gene was recently found to be mutated in a subset of patients with Leber congenital amaurosis and macular atrophy. The most prevalent NMNAT1 variant was p.Glu257Lys, 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 ocular abnormalities.

    CONCLUSIONS AND RELEVANCE: On the basis of these results, the p.Glu257Lys variant is considered not fully penetrant. Homozygotes of the p.Glu257Lys variant in most persons are therefore not associated with ocular disease. Consequently, genetic counselors should exercise great caution in the interpretation of this variant.

    Original languageEnglish
    Pages (from-to)1002-4
    Number of pages3
    JournalJAMA Ophthalmology
    Volume132
    Issue number8
    DOIs
    Publication statusPublished - Aug 2014

    Keywords

    • Humans
    • Leber Congenital Amaurosis/genetics
    • Mutation
    • Nicotinamide-Nucleotide Adenylyltransferase/genetics

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