A new approach based on targeted pooled DNA sequencing identifies novel mutations in patients with Inherited Retinal Dystrophies

Ezquerra-Inchausti, Maitane; Anasagasti, Ander; Barandika, Olatz; Garay‐Aramburu, Gonzaga; Galdós, Marta Barandiarán; Munáin, Adolfo López de; Irigoyen, Cristina; Ruiz-Ederra, Javier

doi:10.1038/s41598-018-33810-3

Cited by 17 publications

(9 citation statements)

References 87 publications

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“…In our study, ABCA4 and USH2A are the most frequent mutated-genes, similar to other studies ( Bernardis et al, 2016 ; Ezquerra-Inchausti et al, 2018 ; Jespersgaard et al, 2019 ). In ABCA4 , 10% of alleles are reported to be complex ( Shroyer et al, 2001 ; Zhang et al, 2015 ), a value that increased to 25% in our results.…”

Section: Discussionsupporting

confidence: 92%

Updating the Genetic Landscape of Inherited Retinal Dystrophies

Bohórquez

Aller²,

Muñoz³

et al. 2021

Front. Cell Dev. Biol.

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Inherited retinal dystrophies (IRD) are a group of diseases characterized by the loss or dysfunction of photoreceptors and a high genetic and clinical heterogeneity. Currently, over 270 genes have been associated with IRD which makes genetic diagnosis very difficult. The recent advent of next generation sequencing has greatly facilitated the diagnostic process, enabling to provide the patients with accurate genetic counseling in some cases. We studied 92 patients who were clinically diagnosed with IRD with two different custom panels. In total, we resolved 53 patients (57.6%); in 12 patients (13%), we found only one mutation in a gene with a known autosomal recessive pattern of inheritance; and 27 patients (29.3%) remained unsolved. We identified 120 pathogenic or likely pathogenic variants; 30 of them were novel. Among the cone-rod dystrophy patients, ABCA4 was the most common mutated gene, meanwhile, USH2A was the most prevalent among the retinitis pigmentosa patients. Interestingly, 10 families carried pathogenic variants in more than one IRD gene, and we identified two deep-intronic variants previously described as pathogenic in ABCA4 and CEP290. In conclusion, the IRD study through custom panel sequencing demonstrates its efficacy for genetic diagnosis, as well as the importance of including deep-intronic regions in their design. This genetic diagnosis will allow patients to make accurate reproductive decisions, enroll in gene-based clinical trials, and benefit from future gene-based treatments.

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Section: Discussionsupporting

confidence: 92%

Updating the Genetic Landscape of Inherited Retinal Dystrophies

Bohórquez

Aller²,

Muñoz³

et al. 2021

Front. Cell Dev. Biol.

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“…As compared with other reported cases, all patients shared a common phenotype characterized by early-onset RP with secondary macular involvement, even with different ArRP mutations in the RP1 gene 3,4 . Our clinical study showed that all of the affected patients had severe RP with decreased visual acuity, bilateral macular involvement Avila-Fernandez et al 4 Wang et al 17 El Shamieh et al 3 Ezquerra-Inchausti et al 18 Pérez-Carro et al 19 5 with an abnormal foveal reflex, dark perifoveal area and macular atrophy. While patient 2 and 7 had few pigment deposits, patient 6 had widespread bone spicules.…”

Section: Discussionmentioning

confidence: 66%

Retinitis Pigmentosa Due to Rp1 Biallelic Variants

Silva¹,

Salles

Motta

et al. 2020

Sci Rep

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In the present study, we screened 529 Brazilian individuals affected by inherited retinal disorders. A total of seven unrelated and nonsyndromic patients with RP1 biallelic variants (OMIM # 180100) were diagnosed in our centre and included in the study. They had classic retinitis pigmentosa with diagnosis at the first decade of life. The visual acuities were severely affected at a young age. The fundus aspects were similar among all patients. An atrophic ring was present around the fovea in several cases. All patients had molecular diagnosis, with six different RP1 variants. This study reports two new pathogenic variants -two frameshift duplications (c.1234dupA p.Met412Asnfs*7 and c.1265dupC p.Ala423Cysfs*2) and reinforces other four known pathogenic variants -two frameshift deletions (c.469delG p.Val157Trpfs*16 and c.3843delT p.Pro1282Leufs*12) and two stop gain mutations (c.1186 C > T p.Arg396* and c.1625C > G p.Ser542*). These findings broaden the spectrum of RP1 variants. This study also reviewed the fundus characteristics that clinically could raise the hypothesis of a retinitis pigmentosa due to RP1 gene. It is worthwhile to try to identify the disease-causing variants in each patient since it can provide prognostic information and be useful in genetic consultation and diagnosis in the future.Retinitis pigmentosa (RP; Online Mendelian Inheritance in Man -OMIM #268000), refers to a clinically and genetically heterogeneous group of progressive inherited retinal disorders (IRD) that result in retinal degeneration, affecting 1 in 4000 people 1-3 . There is tremendous heterogeneity according to the age of onset, progression, retinal appearance and visual outcome 4,5 . The disease is characterized by nyctalopia and progressive visual field loss due to primary rod dysfunction. In most cases, it also courses with dyschromatopsia and progressive loss of central vision owing to secondary cone degeneration 1,3 . On examination, patients have a classic fundus appearance with 'bone spicules' -dark clumps of pigment in the midperiphery and perivenous areas -and attenuated retinal vessels, cystoid macular oedema and waxy optic disc pallor 4 .Most commonly, RP is inherited as a Mendelian trait but its genetics is more complex than once expected 3 . The disease can be divided into 3 patterns of inheritance: autosomal recessive (ArRP) (50-60%), autosomal dominant (AdRP) (30-40%), and X linked RP (xLRP) (5-15%) 3,6 , and up to 50% represent isolated cases due to the absence of family history, simplex RP (sRP) 4 . To date, 93 genes of RP were mapped and identified -29 AdRP, 61 ArRP and 3 xLRP, (until February 5, 2018, https://sph.uth.edu/retnet/sum-dis.htm#C-complex). Although most cases follow the most common forms of classical Mendelian inheritance patterns, these are not exclusive in this disease.RP1 (OMIM #180100) is one of many genes analysed in molecular diagnosis for IRD. Because of its response to in vivo retinal oxygen levels, this protein was initially named oxygen-regulated protein-1. Afterwards, it was found that m...

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“…However, the patient’s mother (Family 16-I:2 JU1475) was unaffected, consistent with AR inheritance. Furthermore, 10 missense variants, with 7 located within the DCX domain or BIF region, have also been associated with AR-RP [ 24 , 41 , 43 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. Surprisingly, even some missense variants (p.Leu172Arg, p.Asp202Glu, p.Gly203Arg, and p.Phe227Val) located within the DCX domain in homozygous states have been reported as causes of AR-RP [ 50 , 52 , 54 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

Genotype-Phenotype Correlations in RP1-Associated Retinal Dystrophies: A Multi-Center Cohort Study in JAPAN

Mizobuchi

Hayashi

Oishi

et al. 2021

JCM

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Background: Little is known about genotype–phenotype correlations of RP1-associated retinal dystrophies in the Japanese population. We aimed to investigate the genetic spectrum of RP1 variants and provide a detailed description of the clinical findings in Japanese patients. Methods: In total, 607 patients with inherited retinal diseases were examined using whole-exome/whole-genome sequencing (WES/WGS). PCR-based screening for an Alu element insertion (c.4052_4053ins328/p.Tyr1352AlafsTer9) was performed in 18 patients with autosomal-recessive (AR)-retinitis pigmentosa (RP) or AR-cone dystrophy (COD)/cone-rod dystrophy (CORD), including seven patients with heterozygous RP1 variants identified by WES/WGS analysis, and 11 early onset AR-RP patients, in whom no pathogenic variant was identified. We clinically examined 25 patients (23 families) with pathogenic RP1 variants, including five patients (five families) with autosomal-dominant (AD)-RP, 13 patients (11 families) with AR-RP, and seven patients (seven families) with AR-COD/CORD. Results: We identified 18 pathogenic RP1 variants, including seven novel variants. Interestingly, the Alu element insertion was the most frequent variant (32.0%, 16/50 alleles). The clinical findings revealed that the age at onset and disease progression occurred significantly earlier and faster in AR-RP patients compared to AD-RP or AR-COD/CORD patients. Conclusions: Our results suggest a genotype–phenotype correlation between variant types/locations and phenotypes (AD-RP, AR-RP, and AR-COD/CORD), and the Alu element insertion was the most major variant in Japanese patients with RP1-associated retinal dystrophies.

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A new approach based on targeted pooled DNA sequencing identifies novel mutations in patients with Inherited Retinal Dystrophies

Cited by 17 publications

References 87 publications

Updating the Genetic Landscape of Inherited Retinal Dystrophies

Updating the Genetic Landscape of Inherited Retinal Dystrophies

Retinitis Pigmentosa Due to Rp1 Biallelic Variants

Genotype-Phenotype Correlations in RP1-Associated Retinal Dystrophies: A Multi-Center Cohort Study in JAPAN

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