Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics

Khan, Mubeen; Cornelis, Stéphanie S.; Pozo-Valero, Marta l De; Whelan, Laura; Runhart, Esmee H.; Mishra, Ketan; Bults, Femke; AlSwaiti, Yahya; AlTalbishi, Alaa; Baere, Elfride De; Banfi, Sandro; Banin, Eyal; Bauwens, Miriam; Ben-Yosef, Tamar; Boon, Camiel J F; Born, L. Ingeborgh van den; Defoort, S.; Devos, Aurore; Dockery, Adrian; Ďuďáková, Ľubica; Fakin, Ana; Farrar, G. Jane; Sallum, Juliana Maria Ferraz; Fujinami, Kaoru; Gilissen, Christian; Glavač, Damjan; Gorin, Michael B.; Greenberg, Jacquie; Hayashi, Takaaki; Hettinga, Ymkje M.; Hoischen, Alexander; Hoyng, Carel B.; Hufendiek, Karsten; Jägle, Herbert; Kamakari, Smaragda; Karali, Marianthi; Kellner, Ulrich; Klaver, Caroline C W; Kousal, Bohdan; Lamey, Tina M.; MacDonald, Ian M.; Matynia, Anna; McLaren, Terri L.; Mena, Marcela; Meunier, Isabelle; Miller, Rianne; Newman, Hadas; Ntozini, Buhle; Ołdak, Monika; Pieterse, Marc; Podhajcer, Osvaldo L.; Puech, Bernard; Ramesar, Raj; Rüther, Klaus; Salameh, Manar; Salles, Mariana Vallim; Sharon, Dror; Simonelli, Francesca; Spital, Georg; Steehouwer, Marloes; Szaflik, Jacek P.; Thompson, Jennifer A.; Thuillier, C.; Tracewska, Anna M; Zweeden, Martine van; Vincent, Andrea L.; Zanlonghi, Xavier; Lišková, Petra; Stöhr, Heidi; Roach, John N. De; Ayuso, Carmen; Roberts, Lisa; Weber, Bernhard H. F.; Dhaenens, Claire‐Marie; Cremers, Frans P.M.

doi:10.1038/s41436-020-0787-4

Cited by 94 publications

(138 citation statements)

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“…In addition, to complete the genotype data for 34 cases, the entire ABCA4 gene was sequenced using single-molecule molecular inversion probe-based technology. 23 The pathogenicity of ABCA4 variants was established according to their allele frequency appearing in gnomAD (http://gnomad.broadinstitute.org/); in silico prediction tools were used to classify new splice and missense variants, including SIFT, 24 PolyPhen, 25 CADD, 26 and M-CAP. 27 In addition, we conducted cosegregation studies in family members when other relatives were available for study.…”

Section: Subjects and Samplesmentioning

confidence: 99%

“…29 Stop, frameshift, and splice variants were considered as truncating variants because of their presumable effect on the protein, including unreported noncanonical splice site variants. 23 Complex alleles are defined when 2 ABCA4 variants were present on the same allele. Complex alleles carrying a truncating variant were considered truncating alleles.…”

Section: Subjects and Samplesmentioning

confidence: 99%

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Genotype–Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants

Pozo‐Valero

Riveiro-Álvarez

Blanco‐Kelly

et al. 2020

American Journal of Ophthalmology

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To define genotype-phenotype correlations in the largest cohort study worldwide of patients with biallelic ABCA4 variants, including 434 patients with Stargardt disease (STGD1) and 72 with cone-rod dystrophy (CRD). DESIGN: Cohort study. METHODS: We characterized 506 patients with ABCA4 variants using conventional genetic tools and next-generation sequencing technologies. Medical history and ophthalmologic data were obtained from 372 patients. Genotype-phenotype correlation studies were carried out for the following variables: variant type, age at symptom onset (AO), and clinical phenotype. RESULTS: A total of 228 different pathogenic variants were identified in 506 ABCA4 patients, 50 of which were novel. Genotype-phenotype correlations showed that most of the patients with biallelic truncating variants presented with CRD and that these cases had a significantly earlier AO than patients with STGD1. Three missense variants are associated with CRD for the first time (c.1804C>T; p.[Arg602Trp], c.3056C>T; p.[Thr1019Met], and c.6320G>C; p.[Arg2107Pro]).

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Section: Subjects and Samplesmentioning

confidence: 99%

Section: Subjects and Samplesmentioning

confidence: 99%

Genotype–Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants

Pozo‐Valero

Riveiro-Álvarez

Blanco‐Kelly

et al. 2020

American Journal of Ophthalmology

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“…Variants at or near canonical spice sites are readily recognized as pathogenic 67 , and these can be identified predicted with high accuracy by algorithms such as SpliceAI. However, for exonic variants, particularly those farther from exon junctions, splicing defects may be more challenging to identify bioinformatically [68][69][70] . Efforts to interpret these variants will need to account for the functional impacts of changing the encoded protein sequence as well as its splicing.…”

Section: Discussionmentioning

confidence: 99%

High-throughput splicing assays identify missense and silent splice-disruptivePOU1F1variants underlying pituitary hormone deficiency

Gergics

Smith

Bando

et al. 2021

Preprint

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Pituitary hormone deficiency occurs in ~1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated hypopituitarism patients that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant negative loss of function. Using a high throughput splicing reporter assay, we tested 1,080 single nucleotide variants in POU1F1. We identified 113 splice disruptive variants, including 23 synonymous variants. We evaluated separate cohorts of hypopituitarism patients and found two different synonymous splice disruptive variants that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in the POU1F1 gene.

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“…At the moment, there are some ongoing clinical trials for inherited retinal dystrophies at UNIFESP clinic. Brazil also collaborates in many multinational initiatives, providing molecularly diagnosed, deep phenotyped patients (Khan et al, 2020) and contributed to the discovery of NMNAT1 as a causative gene for a subset of individuals with LCA (Chiang et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Also, few ophthalmologists are well trained to diagnose and manage ophthalmic genetics patients, and there are no guidelines to follow.A current PubMed query of "ophthalmic genetics Argentina" provides 18 results (https://pubmed.ncbi.nlm.nih.gov/?term=ophthalmic +genetics+Argentina, queried on June 2020). Eight of these are about retinoblastoma, two about infectious diseases, two about glaucoma, two about systemic conditions with ophthalmic manifestations, one about corneal dystrophy, one about age-related macular degeneration, one is preclinical, and one is part of a multinational approach of Stargardt disease, where Argentina contributed with 27 patients, and Brazil with 9(Khan et al, 2020). The only one report addressing IRD is possibly due to the difficulties ophthalmologists face diagnosing these conditions.…”

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confidence: 99%

Ophthalmic genetics in South America

Varela

Moya

Schlottmann³

et al. 2020

American J of Med Genetics Pt C

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South America comprises of heterogeneous topographies, populations, and health care systems. Therefore, it is not surprising to see differences among the countries regarding expertise, education, and practices of ophthalmic genetics for patients with rare eye diseases. Nevertheless, common challenges such as limited genetics training in medical schools and among ophthalmologists, scarcity of diagnostic tools for phenotyping, and expensive genetic testing not covered by the public healthcare systems, are seen in all of them. Here, we provide a detailed report of the current status of ophthalmic genetics, described by the personal views of local ophthalmologists from Brazil, Colombia, Argentina, and Chile. By reporting our strengths and weaknesses as a region, we intend to highlight the need for guidelines on how to manage these patients aligned with public health policies. Our region contributes to research worldwide, with thousands of well diagnosed patients from a number of unique and genetically diverse populations. The constant expansion of ophthalmic genetics and molecular diagnostics requires us to join forces to collaborate across South America and with other countries to improve access to next-generation diagnostics and ultimately improve patient care.

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Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics

Cited by 94 publications

References 47 publications

Genotype–Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants

Genotype–Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants

High-throughput splicing assays identify missense and silent splice-disruptivePOU1F1variants underlying pituitary hormone deficiency

Ophthalmic genetics in South America

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