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A novel deletion mutation in GUCY2D gene may be responsible for Leber congenital amaurosis-1 disease: A case report.

ABSTRACT: Purpose:To investigate genetic mutation(s) underlying retinal degeneration in a male patient. Methods:A seven-year-old male patient was referred to receive genetic counseling and molecular testing. Clinical examination was performed by slit-lamp examination and electroretinography (ERG). Molecular testing was undertaken through arrayed-primer extension (APEX) and Sanger sequencing. Results:Slit-lamp examination and flat ERG were in favor of Leber congenital amaurosis (LCA) disease as well as fundus findings. The genetic screening revealed two novel homozygote deletion and duplication variants in intron 15 and exon 16 of the GUCY2D gene. Segregation analysis in the family supports the probable contribution of these two novel mutations in clinical representations of the patient. Conclusions:This report provides more information about LCA disease and its relevant mutations in Iran. Considering the overlapping phenotypes observed in retinal degenerative disorders, comprehensive molecular testing is needed for precise diagnosis.

SUBMITTER: Salehi Chaleshtori AR

PROVIDER: S-EPMC6896468 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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A novel deletion mutation in GUCY2D gene may be responsible for Leber congenital amaurosis-1 disease: A case report.

Salehi Chaleshtori Ahmad Reza AR Garshasbi Masoud M Salehi Ali A

Journal of current ophthalmology 20190727 4

<h4>Purpose</h4>To investigate genetic mutation(s) underlying retinal degeneration in a male patient.<h4>Methods</h4>A seven-year-old male patient was referred to receive genetic counseling and molecular testing. Clinical examination was performed by slit-lamp examination and electroretinography (ERG). Molecular testing was undertaken through arrayed-primer extension (APEX) and Sanger sequencing.<h4>Results</h4>Slit-lamp examination and flat ERG were in favor of Leber congenital amaurosis (LCA) ...[more]

PMID: 31844802

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Project description:PurposeTo describe the natural history of Leber congenital amaurosis (LCA) associated with GUCY2D variants (GUCY2D-LCA) in a cohort of children and adults, in preparation for trials of novel therapies.DesignRetrospective case series.MethodsParticipants: Patients with GUCY2D-LCA at a single referral center.ProceduresReview of clinical notes, retinal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT), electroretinography (ERG), and molecular genetic testing.Main outcome measuresDemographic data, symptoms at presentation, visual acuity, evidence of progression, OCT and FAF findings, ERG assessment, and molecular genetics.ResultsTwenty-one subjects with GUCY2D-LCA were included, with a mean follow-up ± standard deviation (SD) of 10 ± 11.85 years. Marked reduction in visual acuity (VA) and nystagmus was documented in all patients within the first 3 years of life. Fifty-seven percent (n = 12) exhibited photophobia and 38% (n = 8) had nyctalopia. VA was worse than hand motion in 71% of the patients (n = 15). Longitudinal assessment of VA showed stability in all patients, except 1 patient who experienced deterioration over a follow-up of 44 years. Hyperopia was reported in 13 of the 17 subjects (71%) with available refraction data. Eighteen subjects had either normal fundus appearance (n = 14) or a blond fundus (n = 3), while only 4 of the eldest subjects had mild retinal pigment epithelium (RPE) atrophy (mean, 49 years; range 40-54 years). OCT data were available for 11 subjects and 4 different grades of ellipsoid zone (EZ) integrity were identified: (1) continuous/intact EZ (n = 6), (2) focally disrupted EZ (n = 2), (3) focally disrupted with RPE changes (n = 2), and (4) diffuse EZ disruption with RPE changes (n = 1). All examined subjects had stable OCT findings over the long follow-up period. Full-field ERGs showed evidence of a severe cone-rod dystrophy in 5 of 6 patients and undetectable ERGs in 1 subject. Novel genotype-phenotype correlations are also reported.ConclusionGUCY2D-LCA is a severe early-onset retinal dystrophy associated with very poor VA from birth. Despite the severely affected photoreceptor function, the relatively preserved photoreceptor structure based on EZ integrity until late in the disease in the majority of subjects suggests a wide therapeutic window for gene therapy trials.

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.

Project description:PurposeLeber congenital amaurosis (LCA) is one of the most common causes of hereditary blindness in infants. To date, mutations in 13 known genes and at two other loci have been implicated in LCA causation. An examination of the known genes highlights several processes which, when defective, cause LCA, including photoreceptor development and maintenance, phototransduction, vitamin A metabolism, and protein trafficking. In addition, it has been known for some time that defects in sensory cilia can cause syndromes involving hereditary blindness. More recently evidence has come to light that non-syndromic LCA can also be a "ciliopathy."MethodsHere we present a homozygosity mapping analysis in a consanguineous sibship that led to the identification of a mutation in the recently discovered LCA5 gene. Homozygosity mapping was done using Affymetrix 10K Xba I Gene Chip and a 24.5cM region on chromosome 6 (6q12- q16.3) was identified to be significantly homozygous. The LCA5 gene on this region was sequenced and cDNA sequencing also done to characterize the mutation.ResultsA c.955G>A missense mutation in the last base of exon 6 causing disruption of the splice donor site was identified in both the affected sibs. Since there is a second consensus splice donor sequence 5 bp into the adjacent intron, this mutation results in a transcript with a 5 bp insertion of intronic sequence, leading to a frameshift and premature truncation.ConclusionsWe report a missense mutation functionally altering the splice donor site and leading to a truncated protein. This is the second report of LCA5 mutations causing LCA. It may also be significant that one affected child died at eleven months of age due to asphyxia during sleep. To date the only phenotype unambiguously associated with mutations in this gene is LCA. However the LCA5 gene is known to be expressed in nasopharynx, trachea and lungs and was originally identified in the proteome of bronchial epithelium ciliary axonemes. The cause of death in this child may therefore imply that LCA5 mutations can in fact cause a wider spectrum of phenotypes including respiratory disease.

Dataset Information

A novel deletion mutation in GUCY2D gene may be responsible for Leber congenital amaurosis-1 disease: A case report.

Publications

A novel deletion mutation in GUCY2D gene may be responsible for Leber congenital amaurosis-1 disease: A case report.

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