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

Anna M. Siemiatkowska, PhD1,2; Janneke H. M. Schuurs-Hoeijmakers, MD, PhD1,2; Danielle G. M. Bosch, MD1,3; F. Nienke Boonstra, MD, PhD3,4; Frans C. C. Riemslag, MD, PhD3,5; Mariken Ruiter, MD1; Bert B. A. de Vries, MD, PhD1,2,4; Anneke I. den Hollander, PhD1,2,6; Rob W. J. Collin, PhD1,2; Frans P. M. Cremers, PhD1,2
[+] Author Affiliations
1Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
2Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
3Bartimeus Institute for the Visually Impaired, Zeist, the Netherlands
4Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands
5The Rotterdam Eye Hospital, Rotterdam, the Netherlands
6Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands
JAMA Ophthalmol. 2014;132(8):1002-1004. doi:10.1001/jamaophthalmol.2014.983.
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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.

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Nonpenetrance of the NMNAT1 Variant p.Glu257Lys in a Family With Intellectual Disability

In patient II-4, exome sequencing had revealed a homozygous NMNAT1 variant (p.Glu257Lys), which did not fully segregate with the intellectual disability in this family. Individual II-1 also carries this variant in a homozygous state and on ophthalmologic examination (ie, electroretinography and optical coherence tomography) had no ocular abnormalities.

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