Genomic Landscape of Sporadic Retinitis Pigmentosa: Findings from 877 Spanish Cases

doi:10.1016/j.ophtha.2019.03.018

Ophthalmology

Volume 126, Issue 8, August 2019, Pages 1181-1188

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https://doi.org/10.1016/j.ophtha.2019.03.018 Get rights and content

Purpose

We aimed to unravel the molecular basis of sporadic retinitis pigmentosa (sRP) in the largest cohort reported to date.

Design

Case series.

Participants

A cohort of 877 unrelated Spanish sporadic cases with a clinical diagnosis of retinitis pigmentosa (RP) and negative family history.

Methods

The cohort was studied by classic genotyping or targeted next-generation sequencing (NGS). Multiplex ligation-dependent probe amplification (MLPA) and array-based comparative genomic hybridization were performed to confirm copy number variations detected by NGS. Quantitative fluorescent polymerase chain reaction was assessed in sRP cases carrying de novo variants to confirm paternity.

Main Outcome Measures

The study of the sRP cohort showed a high proportion of causal autosomal dominant (AD) and X-linked (XL) variants, most of them being de novo.

Results

Causative variants were identified in 38% of the patients studied, segregating recessively in 84.5% of the solved cases. Biallelic variants detected in only 6 different autosomal recessive genes explained 50% of the cases characterized. Causal AD and XL variants were found in 7.6% and 7.9% of cases, respectively. Remarkably, 20 de novo variants were confirmed after trio analysis, explaining 6% of the cases. In addition, 17% of the solved sRP cases were reclassified to a different retinopathy phenotype.

Conclusions

This study highlights the clinical utility of NGS testing for sRP cases, expands the mutational spectrum, and provides accurate prevalence of mutated genes. Our findings evidence the underestimated role of de novo variants in the etiology of RP, emphasizing the importance of segregation analysis as well as comprehensive screening of genes carrying XL and AD variants in sporadic cases. Such in-depth study is essential for accurate family counseling and future enrollment in gene therapy–based treatments.

Section snippets

Cohort Description

A cohort of 877 unrelated Spanish cases (475 female and 402 male participants) with no family history of retinal dystrophy was selected from the database at Fundación Jiménez Díaz University Hospital (FJD, Madrid, Spain). All patients had been referred to our unit for genetic testing because of clinical suspicion of RP. Specific exclusion criteria were as follows: (1) family pedigree compatible with AR, AD, or XL inheritance; (2) visual deficiency with onset before age 1 year and compatible

Mutation Detection Rate and Mutational Spectrum

A cohort of 877 sRP cases underwent comprehensive analysis of single nucleotide variants (SNVs) and CNVs, as detailed in the genetic algorithm in Figure 1. Likely disease-causing genotypes were identified in 330 patients, and thus the overall mutation-detection rate was 38%. A total of 304 different variants were found in 56 different genes, including 298 SNVs and 6 structural variants (SVs). Figure 2A shows the overall frequencies of disease-causing genotypes in the mutated genes. Of note, 6

Discussion

Most patients with IRD referred for routine genetic testing in Spain are sporadic cases of RP. The lack of a priori knowledge about the mode of inheritance, along with the intrinsically high clinical and genetic heterogeneity of IRD, hampers efforts to establish an accurate clinical diagnosis in these patients. In addition, doubts remain as to the likelihood that a sporadic case with an initial suspicion of IRD will have positive genetic test results. To shed light on this issue, we performed a

References (36)

X.F. Huang et al.
Genotype-phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing
Genet Med
(2015)
S.K. Verbakel et al.
Non-syndromic retinitis pigmentosa
Prog Retin Eye Res
(2018)
A. Avila-Fernandez et al.
Identification of an RP1 prevalent founder mutation and related phenotype in Spanish patients with early-onset autosomal recessive retinitis
Ophthalmology
(2012)
S. Richards et al.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
Genet Med
(2015)
L. Cavalier et al.
Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families
Am J Hum Genet
(1998)
K. Iwasa et al.
Retinitis pigmentosa and macular degeneration in a patient with ataxia with isolated vitamin E deficiency with a novel c.717 del C mutation in the TTPA gene
J Neurol Sci
(2014)
C. Rivolta et al.
Missense mutation in the USH2A gene: association with recessive retinitis pigmentosa without hearing loss
Am J Hum Genet
(2000)
T.L. McGee et al.
Evidence that the penetrance of mutations at the RP11 locus causing dominant retinitis pigmentosa is influenced by a gene linked to the homologous RP11 allele
Am J Hum Genet
(1997)
S. Ali et al.
Phenotypic variability associated with the D226N allele of IMPDH1
Ophthalmology
(2015)
G. Liew et al.
A comparison of the causes of blindness certifications in England and Wales in working age adults (16-64 years), 1999-2000 with 2009-2010
BMJ Open
(2014)

R.S. Ramrattan et al.

Prevalence and causes of visual field loss in the elderly and associations with impairment in daily functioning: the Rotterdam Study

Arch Ophthalmol

(2001)

A.I. den Hollander et al.

Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies

J Clin Invest

(2010)

C. Hamel

Retinitis pigmentosa

Orphanet J Rare Dis

(2006)

C. Ayuso et al.

Retinitis pigmentosa and allied conditions today: a paradigm of translational research

Genome Med

(2010)

K.M. Nishiguchi et al.

Genes associated with retinitis pigmentosa and allied diseases are frequently mutated in the general population

PLoS One

(2012)

R. Perez-Carro et al.

Unravelling the pathogenic role and genotype-phenotype correlation of the USH2A p.(Cys759Phe) variant among Spanish families

PLoS One

(2018)

R. Riveiro-Alvarez et al.

Frequency of ABCA4 mutations in 278 Spanish controls: an insight into the prevalence of autosomal recessive Stargardt disease

Br J Ophthalmol

(2009)

K. Neveling et al.

Identification and analysis of inherited retinal disease genes

Methods Mol Biol

(2013)

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In the later stage, the visual field is tubular and completely blind at middle or old age. RP is inherited in a complicated mode, encompassing autosomal dominant patterns (AD, about 20 %), autosomal recessive manners (AR, about 30 %) and X-linked inheritance (XL, about 10 %), occasionally digenic modes and mitochondrial inheritance also have been reported (Kajiwara et al., 1994; Beales et al., 2003; Hartong et al., 2006; Martin-Merida et al., 2019), which further indicates the typical genetic heterogeneity of RP. Meanwhile, those without a family history were referred to as sporadic cases, and the proportion of sporadic RP is approaching 40 % (Martin-Merida et al., 2019).
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: Supplemental material available at www.aaojournal.org.

: Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

: I.M.M. and O.Z..: Sponsored by the CIBERER.

: M.dP.: Supported by a PhD fellowship from the Conchita Rábago Foundation.

: M.C.: Supported by the Miguel Servet Program (CPII17_00006) from ISCIII.

: Supported by grants from the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Health, including the Center for Biomedical Research Network on Rare Diseases (CIBERER 06/07/0036), FIS (PI16/00425), and IIS-FJD Biobank PT13/0010/0012; and from Regional Government of Madrid (CAM, B2017/BMD37), all partially supported by FEDER (European Regional Development Fund). The Spanish National Organization for the Blind (ONCE), the Spanish Fighting Blindness Foundation (FUNDALUCE), University Chair UAM-IIS-FJD of Genomic Medicine, and the Ramon Areces Foundation supported our work.

: HUMAN SUBJECTS: Human subjects were included in this study. The human ethics committees at the IIS-Fundacion Jimenez Diaz University Hospital approved the study. All research adhered to the tenets of the Declaration of Helsinki. All participants provided informed consent.

: No animal subjects were used in this study.

: Author Contributions:

: Conception and design: Martin-Merida, Corton, Ayuso

: Analysis and interpretation: Martin-Merida, Avila-Fernandez, del Pozo-Valero, Zurita, Perez-Carro, Aguilera-Garcia, Riveiro-Alvarez, Ana Arteche, Trujillo-Tiebas, Lorda-Sanchez, Garcia-Sandoval, Corton, Ayuso

: Data collection: Martin-Merida, Avila-Fernandez, Blanco-Kelly, Zurita, Perez-Carro, Aguilera-Garcia, Riveiro-Alvarez, Ana Arteche, Trujillo-Tiebas, Tahsin-Swafiri, Rodriguez-Pinilla, Lorda-Sanchez, Garcia-Sandoval, Corton, Ayuso

: Obtained funding: Ayuso

: Overall responsibility: Martin-Merida, Avila-Fernandez, Del Pozo-Valero, Blanco-Kelly, Zurita, Perez-Carro, Aguilera-Garcia, Riveiro-Alvarez, Arteche, Trujillo-Tiebas, Tahsin-Swafiri, Rodriguez-Pinilla, Lorda-Sanchez, Garcia-Sandoval, Corton, Ayuso

^∗: M.C. and C.A. have contributed equally.

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Original ArticleGenomic Landscape of Sporadic Retinitis Pigmentosa: Findings from 877 Spanish Cases

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Section snippets

Cohort Description

Mutation Detection Rate and Mutational Spectrum

Discussion

Genet Med

Prog Retin Eye Res

Ophthalmology

Genet Med

Am J Hum Genet

J Neurol Sci

Am J Hum Genet

Am J Hum Genet

Ophthalmology

A comparison of the causes of blindness certifications in England and Wales in working age adults (16-64 years), 1999-2000 with 2009-2010

BMJ Open

Prevalence and causes of visual field loss in the elderly and associations with impairment in daily functioning: the Rotterdam Study

Arch Ophthalmol

Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies

J Clin Invest

Retinitis pigmentosa

Orphanet J Rare Dis

Retinitis pigmentosa and allied conditions today: a paradigm of translational research

Genome Med

Genes associated with retinitis pigmentosa and allied diseases are frequently mutated in the general population

PLoS One

Unravelling the pathogenic role and genotype-phenotype correlation of the USH2A p.(Cys759Phe) variant among Spanish families

PLoS One

Frequency of ABCA4 mutations in 278 Spanish controls: an insight into the prevalence of autosomal recessive Stargardt disease

Br J Ophthalmol

Identification and analysis of inherited retinal disease genes

Methods Mol Biol

Original Article
Genomic Landscape of Sporadic Retinitis Pigmentosa: Findings from 877 Spanish Cases