The genetic architecture of Stargardt macular dystrophy (STGD1): a longitudinal 40-year study in a genetic isolate

Green, Jane S.; O’Rielly, Darren D.; Pater, Justin A.; Houston, Jim; Rajabi, Hoda; Galutira, Dante; Benteau, Tammy; Sheaves, Amy; Abdelfatah, Nelly; Bautista, Donna; Whelan, Jim; Young, Terry‐Lynn

doi:10.1038/s41431-020-0581-4

Cited by 11 publications

(22 citation statements)

References 45 publications

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“…The variant frequency of c.5882G>A p.(Gly1961Glu) was 5.9% (5/85 individuals) in this cohort compared with 0.46% in the worldwide population (gnomAD). A further ABCA4 splice variant c.5714+5G>A was observed in a compound heterozygous state in three unrelated families (22, 26, and 28), this is considered a “mild” variant also found in those of European descent and whose frequency has increased in Newfoundland, Canada due to a founder effect (Green et al, 2020 ). A larger UAE molecularly confirmed cohort will further support the evidence for founder mutations, which may be abundant in this population due to the high consanguinity rate.…”

Section: Discussionmentioning

confidence: 99%

The genetic landscape of inherited eye disorders in 74 consecutive families from the United Arab Emirates

Méjécase

Kozak²,

Moosajee

2020

American J of Med Genetics Pt C

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Genetic eye diseases are phenotypically and genetically heterogeneous, affecting 1 in 1,000 people worldwide. This prevalence can increase in populations where endogamy is a social preference, such as in Arab populations. A retrospective consecutive cohort of 91 patients from 74 unrelated families affected with non-syndromic and syndromic inherited eye disease presenting to the ocular genetics service at Moorfields Eye Hospitals United Arab Emirates (UAE) between 2017 and 2019, underwent clinically accredited genetic testing using targeted gene panels. The mean ± SD age of probands was 27.4 ± 16.2 years, and 45% were female (41/91). The UAE has a diverse and dynamic population, and the main ethnicity of families in this cohort was 74% Arab (n = 55), 8% Indian (n = 6) and 7% Pakistani (n = 5). Fiftysix families (90.3%) were genetically solved, with 69 disease-causing variants in 40 genes. Fourteen novel variants were detected with large deletions in CDHR1 and TTLL5, a multiexon (1-8) duplication in TEAD1 and 11 single nucleotides variants in 9 further genes. ABCA4-retinopathy was the most frequent cause accounting for 21% of cases, with the confirmed UAE founder mutation c.5882G>A p.(Gly1961Glu)/ c.2570T>C p.(Leu857Pro) in 25%. High diagnostic yield for UAE patients can guide prognosis, family decision-making, access to clinical trials and approved treatments.

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Section: Discussionmentioning

confidence: 99%

The genetic landscape of inherited eye disorders in 74 consecutive families from the United Arab Emirates

Méjécase

Kozak²,

Moosajee

2020

American J of Med Genetics Pt C

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“…The retinoid substrates imported by ABCA4 from the extracellular or intradiscal (rod) membrane surfaces to the cytoplasmic membrane surface are reduced to vitamin A by trans -retinol dehydrogenase and then transferred to the RPE where it is converted to 11- cis -retinal in both rod and cone photoreceptor cells ( 56 ). Owing to its essential function in the visual cycle, mutations in ABCA4 are also associated with retinitis pigmentosa-19, cone-rod dystrophy type 3, early-onset severe retinal dystrophy, fundus flavimaculatus, and other macular degenerative diseases ( 46 , 51 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ).…”

mentioning

confidence: 99%

Very long chain fatty acid-containing lipids: a decade of novel insights from the study of ELOVL4

Yeboah

Lobanova

Brush

et al. 2021

Journal of Lipid Research

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…It has also been suggested that c.2588G>C p.(Gly863Ala) is a modifier that only causes disease when it is in cis with c.5603A>T p.(Asn1868Ile). The c.2588G>C p.(Gly863Ala) variant has also been detected in cis in 2/29 alleles with the c.5714+5G>A variant [115,143]. Moreover, the c.5714+5G>A variant was first suggested to have a moderately severe effect [144] and has been observed in mildly affected homozygous STGD1 patients [115].…”

Section: Hypomorphic Alleles and Modifiersmentioning

confidence: 98%

“…Moreover, founder variants are often found in isolated populations and those originating from settlers. In these populations, the founder variants can explain a significant proportion of STGD1 with a high molecular diagnosis rate despite a small number of variants being detected in the population [113][114][115]. Detection rates for the ABCA4 variants appear to be similar in populations (Table 2), although it is important to note that the detection rate is mostly influenced by the clinical expertise and how well defined the phenotype of the patient is.…”

Section: Variability In Variants Between Populationsmentioning

confidence: 99%

“…The c.5603A>T p.(Asn1868Ile) has been reported to form complex alleles with c.2588G>C p.(Gly863Ala) [85,127,140], c.5461-10T>C [127,141], c.4496G>A [142], c.2564G>A [115], and c.769-784C>T [133]. Zernant et al proposed that this complex allele has a variable phenotype depending on the severity of the variant in trans and that both variants in the complex allele could have a synergistic effect due to both variants being predicted to affect protein folding and exerting their effect on the ABCA4 protein on the same side of the photoreceptor outer segment [127].…”

Section: Hypomorphic Alleles and Modifiersmentioning

confidence: 99%

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An Overview of the Genetics of ABCA4 Retinopathies, an Evolving Story

Al‐Khuzaei

Broadgate

Foster

et al. 2021

Genes

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Stargardt disease (STGD1) and ABCA4 retinopathies (ABCA4R) are caused by pathogenic variants in the ABCA4 gene inherited in an autosomal recessive manner. The gene encodes an importer flippase protein that prevents the build-up of vitamin A derivatives that are toxic to the RPE. Diagnosing ABCA4R is complex due to its phenotypic variability and the presence of other inherited retinal dystrophy phenocopies. ABCA4 is a large gene, comprising 50 exons; to date >2000 variants have been described. These include missense, nonsense, splicing, structural, and deep intronic variants. Missense variants account for the majority of variants in ABCA4. However, in a significant proportion of patients with an ABCA4R phenotype, a second variant in ABCA4 is not identified. This could be due to the presence of yet unknown variants, or hypomorphic alleles being incorrectly classified as benign, or the possibility that the disease is caused by a variant in another gene. This underlines the importance of accurate genetic testing. The pathogenicity of novel variants can be predicted using in silico programs, but these rely on databases that are not ethnically diverse, thus highlighting the need for studies in differing populations. Functional studies in vitro are useful towards assessing protein function but do not directly measure the flippase activity. Obtaining an accurate molecular diagnosis is becoming increasingly more important as targeted therapeutic options become available; these include pharmacological, gene-based, and cell replacement-based therapies. The aim of this review is to provide an update on the current status of genotyping in ABCA4 and the status of the therapeutic approaches being investigated.

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The genetic architecture of Stargardt macular dystrophy (STGD1): a longitudinal 40-year study in a genetic isolate

Cited by 11 publications

References 45 publications

The genetic landscape of inherited eye disorders in 74 consecutive families from the United Arab Emirates

The genetic landscape of inherited eye disorders in 74 consecutive families from the United Arab Emirates

Very long chain fatty acid-containing lipids: a decade of novel insights from the study of ELOVL4

An Overview of the Genetics of ABCA4 Retinopathies, an Evolving Story

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