Nonpenetrance of the Most Frequent Autosomal Recessive Leber Congenital Amaurosis Mutation in<i>NMNAT1</i>

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

doi:10.1001/jamaophthalmol.2014.983

Cited by 29 publications

(23 citation statements)

References 12 publications

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“…Siemiatkowska et al. () deduced this as a hypomorphic variant almost always causing LCA in combination with more severe NMNAT1 variants, consistent with our findings.…”

Section: Resultssupporting

confidence: 92%

“…Using in vitro and in vivo functional assays, Koenekoop et al (2012) and Sasaki et al (2015) agree this mutation could render the enzyme susceptible to stress-induced changes in protein folding and enzyme activity. Siemiatkowska et al (2014a) deduced this as a hypomorphic variant almost always causing LCA in combination with more severe NMNAT1 variants, consistent with our findings.…”

Section: Cell-cell Interactionsupporting

confidence: 92%

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The genetic profile of Leber congenital amaurosis in an Australian cohort

Thompson

Roach

McLaren

et al. 2017

Molec Gen & Gen Med

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BackgroundLeber congenital amaurosis (LCA) is a severe visual impairment responsible for infantile blindness, representing ~5% of all inherited retinal dystrophies. LCA encompasses a group of heterogeneous disorders, with 24 genes currently implicated in pathogenesis. Such clinical and genetic heterogeneity poses great challenges for treatment, with personalized therapies anticipated to be the best treatment candidates. Unraveling the individual genetic etiology of disease is a prerequisite for personalized therapies, and could identify potential treatment candidates, inform patient management, and discriminate syndromic forms of disease.MethodsWe have genetically analyzed 45 affected and 82 unaffected individuals from 34 unrelated LCA pedigrees using predominantly next‐generation sequencing and Array CGH technology.ResultsWe present the molecular findings for an Australian LCA cohort, sourced from the Australian Inherited Retinal Disease Registry & DNA Bank. CEP290 and GUCY2D mutations, each represent 19% of unrelated LCA cases, followed by NMNAT1 (12%). Genetic subtypes were consistent with other reports, and were resolved in 90% of this cohort.ConclusionThe high resolution rate achieved, equivalent to recent findings using whole exome/genome sequencing, reflects the progression from hypothesis (LCA Panel) to non‐hypothesis (RD Panel) testing and, coupled with Array CGH analysis, is a highly effective first‐tier test for LCA.

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“…Siemiatkowska et al. () deduced this as a hypomorphic variant almost always causing LCA in combination with more severe NMNAT1 variants, consistent with our findings.…”

Section: Resultssupporting

confidence: 92%

Section: Cell-cell Interactionsupporting

confidence: 92%

The genetic profile of Leber congenital amaurosis in an Australian cohort

Thompson

Roach

McLaren

et al. 2017

Molec Gen & Gen Med

View full text Add to dashboard Cite

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“…However, these findings are not consistent with a recent report that did not identify disease-causing NMNAT1 mutations among 108 CRD patients [76]. Furthermore, the interpretation of the most frequent variant (c.769G>A p.(E257K)) should be interpreted with caution since it was recently found homozygous in a subject with no ocular abnormalities, suggesting that this variant may not be fully penetrant [77]. Siemiatkowska et al hypothesized that this hypomorphic variant causes LCA in combination with a more severe NMNAT1 variant.…”

Section: Discussioncontrasting

confidence: 75%

Next-generation sequencing applied to a large French cone and cone-rod dystrophy cohort: mutation spectrum and new genotype-phenotype correlation

Boulanger-Scemama

Shamieh

Démontant

et al. 2015

Orphanet J Rare Dis

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BackgroundCone and cone-rod dystrophies are clinically and genetically heterogeneous inherited retinal disorders with predominant cone impairment. They should be distinguished from the more common group of rod-cone dystrophies (retinitis pigmentosa) due to their more severe visual prognosis with early central vision loss. The purpose of our study was to document mutation spectrum of a large French cohort of cone and cone-rod dystrophies.MethodsWe applied Next-Generation Sequencing targeting a panel of 123 genes implicated in retinal diseases to 96 patients. A systematic filtering approach was used to identify likely disease causing variants, subsequently confirmed by Sanger sequencing and co-segregation analysis when possible.ResultsOverall, the likely causative mutations were detected in 62.1 % of cases, revealing 33 known and 35 novel mutations. This rate was higher for autosomal dominant (100 %) than autosomal recessive cases (53.8 %). Mutations in ABCA4 and GUCY2D were responsible for 19.2 % and 29.4 % of resolved cases with recessive and dominant inheritance, respectively. Furthermore, unexpected genotype-phenotype correlations were identified, confirming the complexity of inherited retinal disorders with phenotypic overlap between cone-rod dystrophies and other retinal diseases.ConclusionsIn summary, this time-efficient approach allowed mutation detection in the most important cohort of cone-rod dystrophies investigated so far covering the largest number of genes. Association of known gene defects with novel phenotypes and mode of inheritance were established.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0300-3) contains supplementary material, which is available to authorized users.

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“…2014; Siemiatkowska et al. 2014). Discordance between DAF and incidence rate may be caused by another infrequent mutation closely linked to these mutations.…”

Section: Discussionmentioning

confidence: 99%

“…There is often the case where the causative mutations are determined too easily without analyzing potential effect of mutations (Cooper et al 2013;van Rheenen et al 2014;Siemiatkowska et al 2014). Discordance between DAF and incidence rate may be caused by another infrequent mutation closely linked to these mutations.…”

Section: Discussionmentioning

confidence: 99%

Global epidemiology of Familial Mediterranean fever mutations using population exome sequences

Fujikura

2015

Molec Gen & Gen Med

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Familial Mediterranean fever (FMF) is an inherited disorder characterized by recurrent episodes of fever accompanied by sterile peritonitis, arthritis, and pleuritis. Many mutations in the MEFV gene have been identified as causing FMF. However, accompanying epidemiological information remains quite scarce except in some Mediterranean countries, and the degree of penetrance has been a subject of controversy. Here, I established a genetic epidemiology of full FMF mutations using two population exome studies. Of 57 mutations associated with FMF, 22 were detected in a total of 9007 individuals from two exome sequences. Exome-based epidemiology revealed the carrier rates of FMF in 28 populations in 19 countries by individual mutation and showed strong population specificity for the MEFV mutations. Unexpectedly high carrier rates suggested that some mutations are benign variants with no pathological significance and highlighted the need for caution in analyzing MEFV mutations. Similar approach could be used to uncover the incomplete or no penetrance of mutations in most inherited disorders.

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Nonpenetrance of the Most Frequent Autosomal Recessive Leber Congenital Amaurosis Mutation inNMNAT1

Cited by 29 publications

References 12 publications

The genetic profile of Leber congenital amaurosis in an Australian cohort

The genetic profile of Leber congenital amaurosis in an Australian cohort

Next-generation sequencing applied to a large French cone and cone-rod dystrophy cohort: mutation spectrum and new genotype-phenotype correlation

Global epidemiology of Familial Mediterranean fever mutations using population exome sequences

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