Personalized genetic counseling for Stargardt disease: Offspring risk estimates based on variant severity

Cornelis, Stéphanie S.; Runhart, Esmee H.; Bauwens, Miriam; Corradi, Zelia; Baere, Elfride De; Roosing, Susanne; Haer‐Wigman, Lonneke; Dhaenens, Claire‐Marie; Silfhout, Anneke T. Vulto-van; Cremers, Frans P.M.

doi:10.1016/j.ajhg.2022.01.008

Cited by 34 publications

(63 citation statements)

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“…Even though the clinical features associated with STGD1 reveal a wide range of heterogeneity, the severity of ABCA4 variants is directly correlated with the onset of the disease (Fakin et al 2016). The -10T>C variant is more often found in combination with one other moderate or mild variant in ABCA4 than in a homozygous state (Cornelis et al 2022; Maugeri et al 1999). Considering that severe mutations lead to the early STGD1 onset where the progress of the disease is faster, and milder mutations are associated with slower development of STGD1 hallmarks (Fujinami et al 2015) (Cremers et al 2020), the advanced stage of STGD1 could be significantly postponed or even completely repressed by correcting the aberrant splicing due to c.5461-10T>C. In the case of two deleterious ABCA4 alleles, the disease-associated changes characteristic of the early stage are observed in the region limited to the macula.…”

Section: Discussionmentioning

confidence: 97%

“…Although STGD1 is the most common form of inherited macular dystrophy, no treatment options are available, highlighting the importance of the development of therapeutic strategies. Studies on large cohorts of STGD1 patients have identified more than 2,200 disease-associated variants in ABCA4 (Cornelis et al 2022), the majority of which are missense variants, followed by mutations that alter pre-mRNA splicing (Cornelis et al 2017; Paloma et al 2001; Jonsson et al 2013; Klevering et al 2004).…”

Section: Introductionmentioning

confidence: 99%

“…ABCA4 c.5461-10T>C p.[Thr1821Aspfs*6,Thr1821Valfs*13] is a non-canonical splice site variant that causes the skipping of either exon 39 or exons 39 and 40 together, resulting in the production of out-of-frame ABCA4 isoforms (Aukrust et al 2017; Maugeri et al 1999; Sangermano et al 2016). It is the most common severe STGD1-causing variant (Cornelis et al 2022; Kitiratschky et al 2008; Miraldi Utz et al 2014; Runhart et al 2021). The onset of the first symptoms of STGD1 disease in individuals homozygous for the ABCA4 c.5461-10T>C variant is often in the first decade of life, after which the progress of the disease can sharply accelerate and lead to the state of legal blindness between the age of 20 and 30 (Cideciyan et al 2009; Sangermano et al 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Studies on large cohorts of STGD1 patients have identified more than 2,200 disease-associated variants in ABCA4 (Cornelis et al 2022), the majority of which are missense variants, followed by mutations that alter pre-mRNA splicing (Cornelis et al 2017;Paloma et al 2001;Jonsson et al 2013;Klevering et al 2004) . ABCA4 c.5461-10T>C p.[Thr1821Aspfs*6,Thr1821Valfs*13] is a non-canonical splice site variant that causes the skipping of either exon 39 or exons 39 and 40 together, resulting in the production of outof-frame ABCA4 isoforms (Aukrust et al 2017;Maugeri et al 1999;Sangermano et al 2016).…”

Section: Introductionmentioning

confidence: 99%

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Antisense oligonucleotide therapy for the common Stargardt disease type 1-causing variant in ABCA4

Kaltak

Bruijn

Piccolo³

et al. 2022

Preprint

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The c.5461-10T>C p.[Thr1821Aspfs*6,Thr1821Valfs*13] variant has been identified as the most common severe Stargardt disease type 1 (STGD1)-associated variant in ABCA4. STGD1 is the most recurrent hereditary form of maculopathy and so far, no treatment is available for STGD1. In STGD1 patients homozygous for this variant, the onset of the disease typically is in childhood and patients are legally blind by early adulthood. The variant leads to exon skipping and generates out-of-frame ABCA4 transcripts that prevent the translation of functional ABCA4 protein. We applied antisense oligonucleotides (AONs) to restore the wild-type RNA splicing in ABCA4 c.5461-10T>C. The effect of AONs was investigated in vitro using an ABCA4 midigene model and 3D human retinal organoids (ROs) homozygous for the ABCA4 c.5461-10T>C variant. The mRNA in untreated ROs contained only disease-associated isoforms, whereas the organoids treated with the lead AON sequence showed 53% splicing correction and restoration of ABCA4 protein. Collectively, these data identified the lead candidate QR-1011 as a potent splice-correcting AON to be further developed as therapeutic intervention for patients harboring the severe ABCA4 c.5461-10T>C variant.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Antisense oligonucleotide therapy for the common Stargardt disease type 1-causing variant in ABCA4

Kaltak

Bruijn

Piccolo³

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Despite the variant being present in previous ABCA4 -smMIPs sequencing data of the same proband, at the time of study, c.2813T>C was assigned a class 3 ACMG classification (VUS) [29]. More recently, when categorized by severity based on statistical comparisons of allele frequencies across patient and general populations, c.2813T>C is classed as a mild or moderate variant [51]. Further functional studies are required to determine whether this variant alone can lead to STGD1 in a homozygous state.…”

Section: Discussionmentioning

confidence: 99%

Using single molecule Molecular Inversion Probes as a cost-effective, high-throughput sequencing approach to target all genes and loci associated with macular diseases

Hitti‐Malin

Dhaenens

Panneman

et al. 2022

Preprint

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BackgroundMacular diseases (MDs) are a subgroup of retinal disorders characterized by central vision loss that represent a major cause of vision impairment. Despite the identification of numerous genes associated with inherited MD (iMD) and risk factors associated with age-related MD (AMD), the extent of genetic and non-genetic factors that influence the expression of MD is still not fully explained. Single molecule Molecular Inversion Probes (smMIPs) have proven effective in sequencing the ABCA4 gene in patients with Stargardt disease in a cost-effective manner to identify associated coding and non-coding variation, however a large portion of patients with MDs still remain genetically unexplained.MethodsFor MD patients, we hypothesized that the missing heritability may be revealed by smMIPs-based sequencing of all MD-associated genes and risk factors. We used 17,394 smMIPs to sequence the coding regions of 105 genes and non-coding or regulatory loci associated with iMD and AMD, known pseudo-exons, and the mitochondrial genome in two test cohorts that had previously been screened for variants in the entire ABCA4 gene.ResultsSequencing of 379 probands achieved an average nucleotide coverage of 431× across all targets. Following detailed sequencing analysis of 110 probands, a diagnostic yield of 38% was observed. This established an ‘‘MD-smMIPs panel’’ that allows a genotype-first approach in a high-throughput and cost-effective manner, whilst achieving uniform and high coverage across targets.ConclusionsFurther analysis will identify known and novel variants in MD-associated genes to offer an accurate clinical diagnosis to patients and their families. Furthermore, this will reveal new genetic associations for MD and potential genetic overlaps between iMD and AMD.

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Association Between Genotype and Phenotype Severity in ABCA4-Associated Retinopathy

et al. 2023

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ImportanceABCA4-associated retinopathy is a common inherited retinal disease, and its phenotype spans from late-onset macular dystrophy to extensive cone-rod degeneration. Over 2000 disease-causing variants in the ABCA4 gene have been identified.ObjectiveTo investigate genotype-phenotype correlations in ABCA4-associated retinopathy.Design, Setting, and ParticipantsThis cohort study took place at a single referral center for inherited retinal diseases in Italy. Data were prospectively acquired from January 2015 to June 2022. Patients diagnosed with an inherited retinal disease related to biallelic ABCA4 variants were included for analysis.ExposureGenotype, classified into 4 groups according to the presence of the (1) p.Gly1961Glu allele, (2) a hypomorphic allele, (3) at least 1 moderate variant (moderate genotypes), or (4) 2 biallelic severe variants (severe genotypes).Main Outcomes and MeasuresTotal decreased autofluorescence (TDAF) and definitely decreased autofluorescence (DDAF) areas, inner and outer retinal volumes, and the respective progression rate.ResultsA total of 71 patients (median [IQR] age, 34 [22.4-47.2] years; 40 [56%] female) were included in the study, and 54 (76%) were followed up for a median (IQR) of 3.5 (1.6-4.7) years. Compared with moderate genotypes, those with the p.Gly1961Glu allele had smaller TDAF lesions by 61% (95% CI, −78% to −33%; P &lt; .001) and DDAF lesions by 77% (95% CI, −93% to −18%; P = .02), along with slower growth rates for both TDAF (0.05 mm/y; 95% CI, 0.01-0.07; P &lt; .001) and DDAF (0.06 mm/y; 95% CI, 0-0.12; P = .004). Hypomorphic alleles were associated with a thicker inner (+0.19 mm3; 95% CI, +0.02 to +0.36; P = .03) and outer retinal volume (+0.16 mm3; 95% CI, +0.03 to +0.28; P = .01) compared with moderate genotypes as well as a slower TDAF growth rate (0.05 mm/y; 95% CI, 0.01-0.08; P = .007). Severe genotypes had a 7-fold larger TDAF area (95% CI, 3.4-14.7; P &lt; .001) and 11-fold larger DDAF area (95% CI, 2.9-42.1; P &lt; .001) compared with moderate genotypes, along with faster growth rates estimated at 0.16 mm/y for TDAF (95% CI, 0.12-0.20; P &lt; .001) and 0.17 mm/y for DDAF (95% CI, 0.12-0.23; P &lt; .001).Conclusions and RelevanceIn this study of ABCA4-associated retinopathy, a 4-tier classification of genotypes was found to capture substantial variation in disease phenotype severity. These findings could prove beneficial for the prognostication of patients and warrant consideration of genotype in the design of future clinical trials.

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Personalized genetic counseling for Stargardt disease: Offspring risk estimates based on variant severity

Cited by 34 publications

References 45 publications

Antisense oligonucleotide therapy for the common Stargardt disease type 1-causing variant in ABCA4

Antisense oligonucleotide therapy for the common Stargardt disease type 1-causing variant in ABCA4

Using single molecule Molecular Inversion Probes as a cost-effective, high-throughput sequencing approach to target all genes and loci associated with macular diseases

Association Between Genotype and Phenotype Severity in ABCA4-Associated Retinopathy

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