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

doi:10.1001/jamaophthalmol.2014.983

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 journal › Article › Research › peer-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 language	English
Pages (from-to)	1002-4
Number of pages	3
Journal	JAMA Ophthalmology
Volume	132
Issue number	8
DOIs	https://doi.org/10.1001/jamaophthalmol.2014.983
Publication status	Published - Aug 2014

Keywords

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

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Siemiatkowska, A. M., Schuurs-Hoeijmakers, J. H. M., Bosch, D. G. M., Boonstra, F. N., Riemslag, F. C. C., Ruiter, M., de Vries, B. B. A., den Hollander, A. I., Collin, R. W. J., & Cremers, F. P. M. (2014). Nonpenetrance of the most frequent autosomal recessive leber congenital amaurosis mutation in NMNAT1. JAMA Ophthalmology, 132(8), 1002-4. https://doi.org/10.1001/jamaophthalmol.2014.983

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title = "Nonpenetrance of the most frequent autosomal recessive leber congenital amaurosis mutation in NMNAT1",

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.",

keywords = "Humans, Leber Congenital Amaurosis/genetics, Mutation, Nicotinamide-Nucleotide Adenylyltransferase/genetics",

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

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doi = "10.1001/jamaophthalmol.2014.983",

language = "English",

volume = "132",

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T1 - Nonpenetrance of the most frequent autosomal recessive leber congenital amaurosis mutation in NMNAT1

AU - Siemiatkowska, Anna M

AU - Schuurs-Hoeijmakers, Janneke H M

AU - Bosch, Danielle G M

AU - Boonstra, F Nienke

AU - Riemslag, Frans C C

AU - Ruiter, Mariken

AU - de Vries, Bert B A

AU - den Hollander, Anneke I

AU - Collin, Rob W J

AU - Cremers, Frans P M

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N2 - 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.

AB - 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.

KW - Humans

KW - Leber Congenital Amaurosis/genetics

KW - Mutation

KW - Nicotinamide-Nucleotide Adenylyltransferase/genetics

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SP - 1002

EP - 1004

JO - JAMA Ophthalmology

JF - JAMA Ophthalmology

IS - 8

ER -

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

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Keywords

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