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


METHODS
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
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.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands2Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Anna M
AM
Siemiatkowska
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands2Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Janneke H M
JH
Schuurs-Hoeijmakers
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands3Bartimeus Institute for the Visually Impaired, Zeist, the Netherlands.
Danielle G M
DG
Bosch
Bartimeus Institute for the Visually Impaired, Zeist, the Netherlands4Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
F Nienke
FN
Boonstra
Bartimeus Institute for the Visually Impaired, Zeist, the Netherlands5The Rotterdam Eye Hospital, Rotterdam, the Netherlands.
Frans C C
FC
Riemslag
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
Mariken
M
Ruiter
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands2Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands4Donders Institute for Brain, Cognition and Behavior, Rad.
Bert B A
BB
de Vries
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands2Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands6Department of Ophthalmology, Radboud University Medical.
Anneke I
AI
den Hollander
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands2Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Rob W J
RW
Collin
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands2Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Frans P M
FP
Cremers
D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics*; D009154:Mutation; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics*
C484007:NMNAT1 protein, human; D009612:Nicotinamide-Nucleotide Adenylyltransferase