Detailed analysis of an enriched deep intronic ABCA4 variant in Irish Stargardt disease patients

Whelan, Laura; Dockery, Adrian; Stephenson, Kirk A. J.; Zhu, Julia; Kopčić, Ella; Post, Iris J. M.; Khan, Mubeen; Corradi, Zelia; Wynne, Niamh; O’ Byrne, James J.; Duignan, Emma; Silvestri, Giuliana; Roosing, Susanne; Cremers, Frans P. M.; Keegan, David J.; Kenna, Paul F.; Farrar, G. Jane

doi:10.1038/s41598-023-35889-9

Cited by 2 publications

(1 citation statement)

References 72 publications

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“…Differences in functional visual outcomes and DDAF area between siblings with STGD1 were already observed by Valkenburg et al [26] and Heath Jeffery et al [51]. This is interesting to note and suggests a role of potential environmental factors [52,53] and modifier variants in and outside the ABCA4 locus [3,[54][55][56].…”

Section: Variable Disease Courses Among Siblingssupporting

confidence: 55%

Natural History of Stargardt Disease: The Longest Follow-Up Cohort Study

Sajovic

Meglič

Fakin

et al. 2023

Genes

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Long-term natural history studies are important in rare disease research. This study aimed to assess electrophysiological and fundus autofluorescence (FAF) progression rate in 18 genetically confirmed Stargardt disease (STGD1) patients with a minimum follow-up of 10 years. Age at the first and last exams, age at onset, Snellen decimal visual acuity (VA), electroretinography (ERG), and FAF images were evaluated. Patients were classified into four Fishman stages and three electroretinography groups, and areas of definitely decreased autofluorescence (DDAF) were measured. Patients were further substratified based on genotype, and phenotype-genotype correlations were performed. The median follow-up was 18 (range 10–26) years. The median yearly VA loss was 0.009 (range 0.002–0.071), while the median progression rate of the DDAF area was 0.354 (range 0.002–4.359) mm2 per year. Patients harbouring p.(Gly1961Glu) or p.(Asn1868Ile) allele had significantly slower DDAF area progression when compared to patients with other genotypes (0.07 mm2 vs. 1.03 mm2, respectively), as well as significantly later age at onset (20 years vs. 13 years, respectively). Results showed that structural and functional parameters, together with genotype, should be considered when counselling patients regarding prognosis and monitoring disease progression. Patients harbouring hypomorphic variants p.(Gly1961Glu) or p.(Asn1868Ile) presented with overall milder disease than patients with other genotypes.

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Section: Variable Disease Courses Among Siblingssupporting

confidence: 55%

Natural History of Stargardt Disease: The Longest Follow-Up Cohort Study

Sajovic

Meglič

Fakin

et al. 2023

Genes

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Family-based GWAS for dental class I malocclusion and clefts

Bezamat,

Carver,

Vieira

2024

BMC Oral Health

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Background Individuals born with cleft lip and/or palate who receive corrective surgery regularly have abnormal growth in the midface region such that they exhibit premaxillary hypoplasia. However, there are also genetic contributions to craniofacial morphology in the midface region, so although these individuals appear to have Class III skeletal discrepancy, their molar relationship may be Class I. Past genome-wide association studies (GWASs) on skeletal Class II and III malocclusion suggested that multiple genetic markers contribute to these phenotypes via a multifactorial inheritance model, but research has yet to examine the genetic markers associated with dental Class I malocclusion. Thus, our goal was to conduct a family based GWAS to identify genes across the genome that are associated with Class I malocclusion, as defined by molar relations, in humans with and without clefts. Methods Our cohort consisted of 739 individuals from 47 Filipino families originally recruited in 2006 to investigate the genetic basis of orofacial clefts. All individuals supplied blood samples for DNA extraction and genotyping, and a 5,766 single nucleotide polymorphism (SNP) custom panel was used for the analyses. We performed a transmission disequilibrium test for participants with and without clefts to identify genetic contributors potentially involved with Class I malocclusion. Results In the total cohort, 13 SNPs had associations that reached the genomic control threshold (p < 0.005), while five SNPs were associated with Class I in the cohort of participants without clefts, including four associations that were identified in the total cohort. The associations for the SNPs ABCA4 rs952499, SOX1-OT rs726455, and RORA rs877228 are of particular interest, as past research found associations between these genes and various craniofacial phenotypes, including cleft lip and/or palate. Conclusions These findings support the multifactorial inheritance model for dental Class I malocclusion and suggest a common genetic basis for different aspects of craniofacial development.

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Detailed analysis of an enriched deep intronic ABCA4 variant in Irish Stargardt disease patients

Cited by 2 publications

References 72 publications

Natural History of Stargardt Disease: The Longest Follow-Up Cohort Study

Natural History of Stargardt Disease: The Longest Follow-Up Cohort Study

Family-based GWAS for dental class I malocclusion and clefts

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