Dataset Information

Seven novel variants expand the spectrum of RPE65-related Leber congenital amaurosis in the Chinese population.

ABSTRACT: Purpose:To screen RPE65 in 187 families with Leber congenital amaurosis (LCA). Methods:Sanger sequencing and/or targeted exome sequencing was employed to identify mutations in the RPE65 gene, and intrafamilial cosegregation analysis if DNA was available. In silico analyses and splicing assay were used to evaluate the variants' pathogenicity. Results:Genetic analysis revealed 15 mutations in RPE65 in 14 pedigrees, including one splice-site mutation, one frameshift mutation, three nonsense mutations, and ten missense mutations. Of the mutations identified in RPE65, seven are novel associated with LCA, including five missense variants (c.124C>T, c.149T>C, c.340A>C, c.425A>G, and c.1399C>G) and two indel (insertions or deletions) variants (c.858+1delG and c.1181_1182insT). In vitro splicing assay was performed to evaluate the functional impact on RNA splicing of novel mutations if two of three in silico analyses were predicated to be non-pathogenic at the protein level. Among these 15 variants, 14 were classified as 'pathogenic variants,' and a variant (c.124C>T) was 'variants with uncertain significance' according to the standards and guidelines of the American College of Medical Genetics and Genomics. Conclusions:Mutations in RPE65 were responsible for 11 of the cohort of 187 Chinese families with LCA, which expands the spectrum of RPE65-related LCA in the Chinese population and potentially facilitates its clinical implementation.

SUBMITTER: Zhong Z

PROVIDER: S-EPMC6441358 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Seven novel variants expand the spectrum of <i>RPE65-</i>related Leber congenital amaurosis in the Chinese population.

Zhong Zilin Z Rong Feng F Dai Yinghui Y Yibulayin Alakezi A Zeng Lin L Liao Jian J Wang Liefeng L Huang Zhihua Z Zhou Zhenping Z Chen Jianjun J

Molecular vision 20190318

<h4>Purpose</h4>To screen <i>RPE65</i> in 187 families with Leber congenital amaurosis (LCA).<h4>Methods</h4>Sanger sequencing and/or targeted exome sequencing was employed to identify mutations in the <i>RPE65</i> gene, and intrafamilial cosegregation analysis if DNA was available. In silico analyses and splicing assay were used to evaluate the variants' pathogenicity.<h4>Results</h4>Genetic analysis revealed 15 mutations in <i>RPE65</i> in 14 pedigrees, including one splice-site mutation, one ...[more]

PMID: 30996589

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Project description:PurposeThe gene encoding nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) was recently found to be mutated in a subset of patients with Leber congenital amaurosis (LCA) with macular atrophy. The aim of this study was to determine the occurrence and frequency of NMNAT1 mutations and associated phenotypes in different types of inherited retinal dystrophies.MethodsDNA samples of 161 patients with LCA without genetic diagnosis were analyzed for variants in NMNAT1 using Sanger sequencing. Variants in exon 5 of NMNAT1, which harbors the majority of the previously identified mutations, were screened in 532 additional patients with retinal dystrophies. This cohort encompassed 108 persons with isolated or autosomal recessive cone-rod dystrophy (CRD), 271 with isolated or autosomal recessive retinitis pigmentosa (RP), and 49 with autosomal dominant RP, as well as 104 persons with LCA in whom the causative mutation was previously identified.ResultsCompound heterozygous alterations were found in six patients with LCA and in one person with early-onset RP. All except one carried the common p.E257K variant on one allele. Macular atrophy was absent in one patient, who carried this variant in combination with a truncating mutation on the other allele. The p.E257K alteration was also found in a heterozygous state in five individuals with LCA and one with RP while no mutation was detected on the other allele. Two individuals with LCA carried other NMNAT1 variants in a heterozygous state, whereas no NMNAT1 variants in exon 5 were identified in individuals with CRD. The p.E257K variant was found to be enriched in a heterozygous state in individuals with LCA (0.94%) compared to Caucasian controls (0.18%), although the difference was statistically insignificant (p=0.12).ConclusionsAlthough macular atrophy can occur in LCA and CRD, no NMNAT1 mutations were found in the latter cohort. NMNAT1 variants were also not found in a large group of patients with sporadic or autosomal recessive RP. The enrichment of p.E257K in a heterozygous state in patients with LCA versus controls suggests that this allele could act as a modifier in other genetic subtypes of LCA.

Dataset Information

Seven novel variants expand the spectrum of RPE65-related Leber congenital amaurosis in the Chinese population.

Publications

Seven novel variants expand the spectrum of <i>RPE65-</i>related Leber congenital amaurosis in the Chinese population.

Similar Datasets

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