Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes

Coppieters, Frauke; Casteels, Ingele; Meire, Françoise; Jaegere, Sarah De; Hooghe, Sally; Regemorter, N. Van; Esch, Hilde Van; Matulevičienė, Aušra; Nunes, Luís; Meersschaut, Valerie; Walraedt, Sophie; Standaert, Lieve; Coucke, Paul; Hoeben, Heidi; Kroes, Hester Y.; Walle, Johan Vande; Ravel, Thomy de; Leroy, Bart P.; Baere, Elfride De

doi:10.1002/humu.21336

Cited by 129 publications

(144 citation statements)

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“…The first part of this study was mainly aimed at validation of the enrichment protocol (proof of concept, patients 1-10), whereas the second part of this study consisted of a blind screening of 12 prescreened mutation-negative patients with LCA (patients [11][12][13][14][15][16][17][18][19][20][21][22]. enrichment of LcA disease genes qPCR was used to target all exons from 16 LCA disease genes.…”

Section: Resultsmentioning

confidence: 99%

“…In the positive control patients, Sanger sequencing was performed of CEP290, CRB1, RPE65, GUCY2D, AIPL1, and CRX. 16 In addition, patients 4 and 5, originating from a consanguineous marriage, were sequenced for IQCB1 and RDH12, respectively, following identification of these genes in homozygous regions (Affymetrix GeneChip Human Mapping 250K arrays; Affymetrix, Santa Clara, CA).…”

Section: Patientsmentioning

confidence: 99%

“…16 More than 160 unrelated healthy individuals were used as a control panel. Genomic DNA was extracted from leukocytes using the Puregene DNA isolation kit (Gentra, Minneapolis, MN).…”

Section: Patientsmentioning

confidence: 99%

“…For the second lane, libraries were prepared from a 200-300-bp size-selected fraction, and library quantification was performed using qPCR following manufacturer's protocols (lane 2, patients [11][12][13][14][15][16][17][18][19][20][21][22]. In total, 120 µl of a pool of the 12 normalized libraries (concentration of 10 pmolar) was subjected to paired-end sequencing of 2 × 45 cycles.…”

Section: Sequencing On the Illumina Genome Analyzer Iixmentioning

confidence: 99%

“…[13][14][15] Secondary genetic tests comprise denaturing high-performance liquid chromatography and Sanger sequencing, mostly of a subset of genes because of excessive costs and workload. 1,16,17 Hence, an urgent need exists for an effective approach able to identify mutations in all currently known LCA genes.…”

mentioning

confidence: 99%

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Massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis

Coppieters

Wilde

Lefever

et al. 2012

Genetics in Medicine

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Purpose: Leber congenital amaurosis (LCA) is a rare congenital retinal dystrophy associated with 16 genes. Recent breakthroughs in LCA gene therapy offer the first prospect of treating inherited blindness, which requires an unequivocal and early molecular diagnosis. While present genetic tests do not address this due to a tremendous genetic heterogeneity, massively parallel sequencing (MPS) strategies might bring a solution. Here, we developed a comprehensive molecular test for LCA based on targeted MPS of all exons of 16 known LCA genes. methods:We designed a unique and flexible workflow for targeted resequencing of all 236 exons from 16 LCA genes based on quantitative PCR (qPCR) amplicon ligation, shearing, and parallel sequencing of multiple patients on a single lane of a short-read sequencer. Twenty-two prescreened LCA patients were included, five of whom had a known molecular cause.Results: Validation of 107 variations was performed as proof of concept. In addition, the causal genetic defect and a single heterozygous mutation were identified in 3 and 5, respectively, of 17 patients without previously identified mutations. conclusion:We propose a novel targeted MPS-based approach that is suitable for accurate, fast, and cost-effective early molecular testing in LCA, and easily applicable in other genetic disorders.Genet Med 2012:14(6):576-585

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Section: Resultsmentioning

confidence: 99%

Section: Patientsmentioning

confidence: 99%

“…16 More than 160 unrelated healthy individuals were used as a control panel. Genomic DNA was extracted from leukocytes using the Puregene DNA isolation kit (Gentra, Minneapolis, MN).…”

Section: Patientsmentioning

confidence: 99%

Section: Sequencing On the Illumina Genome Analyzer Iixmentioning

confidence: 99%

mentioning

confidence: 99%

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Massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis

Coppieters

Wilde

Lefever

et al. 2012

Genetics in Medicine

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Co‐occurrence of distinct ciliopathy diseases in single families suggests genetic modifiers

Zaki

Sattar

Massoudi

et al. 2011

American J of Med Genetics Pt A

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Disorders within the “ciliopathy” spectrum include Joubert (JS), Bardet–Biedl syndromes (BBS), and nephronophthisis (NPHP). Although mutations in single ciliopathy genes can lead to these different syndromes between families, there have been no reports of phenotypic discordance within a single family. We report on two consanguineous families with discordant ciliopathies in sibling. In Ciliopathy-672, the older child displayed dialysis-dependent NPHP whereas the younger displayed the pathognomonic molar tooth MRI sign (MTS) of JS. A second branch displayed two additional children with NPHP. In Ciliopathy-1491, the oldest child displayed classical features of BBS whereas the two younger children displayed the MTS. Importantly, the children with BBS and NPHP lacked MTS, whereas children with JS lacked obesity or NPHP, and the child with BBS lacked MTS and NPHP. Features common to all three disorders included intellectual disability, postaxial polydactyly, and visual reduction. The variable phenotypic expressivity in this family suggests that genetic modifiers may determine specific clinical features within the ciliopathy spectrum. © 2011 Wiley Periodicals, Inc.

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Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients

Sallum

Motta

Arno

et al. 2020

American J of Med Genetics Pt C

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Leber congenital amaurosis (LCA) and early-onset retinal dystrophy (EORD) are severe inherited retinal dystrophy that can cause deep blindness childhood. They represent 5% of all retinal dystrophies in the world population and about 10% in Brazil. Clinical findings and molecular basis of syndromic and nonsyndromic LCA/EORD in a Brazilian sample (152 patients/137 families) were studied. In this population, 15 genes were found to be related to the phenotype, 38 new variants were detected and four new complex alleles were discovered. Among 123 variants found, the most common were CEP290: c.2991+1655A>G, CRB1: p.Cys948Tyr, and RPGRIP1: exon10-18 deletion. K E Y W O R D S causal genes, childhood blindness, early-onset retinal dystrophy (EORD), genotypephenotype, Leber congenital amaurosis (LCA), pathogenic variants 1 | INTRODUCTION Leber congenital amaurosis (LCA) is the most severe and earliest onset inherited retinal dystrophy. Affected individuals usually present, in the first year of life with severe visual impairment, nystagmus and occasionally a systemic manifestation (Francis, 2006). Phenotypic variability in fundus abnormality, refractive errors, photophobia or lightseeking behavior, nyctalopia, nystagmus, low visual acuity, and Franceschetti's oculo-digital sign, are also commonly observed in these patients (Chung & Traboulsi, 2009; den Hollander, Roepman, Koenekoop, & Cremers, 2008). Early-onset retinal dystrophy (EORD) can be considered as belonging to the same LCA spectrum but a milder form, where signs and symptoms appear after the first year of life up to 5-7 years-old (Weleber, Francis, Trzupek, & Beattie, 2004), but still a disease that severely compromises vision. Clinically, LCA and EORD are similar and may represent a continuum; the distinction between them is an extinguished or markedly diminished ERG response before the first year of life for individuals with

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Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes

Cited by 129 publications

References 72 publications

Massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis

Massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis

Co‐occurrence of distinct ciliopathy diseases in single families suggests genetic modifiers

Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients

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