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Autozygome-guided exome-first study in a consanguineous cohort with early-onset retinal disease uncovers an isolated RIMS2 phenotype and a retina-enriched RIMS2 isoform

Marta del Pozo Valero (UGent) , Basamat Almoallem Mohammed, Alfredo Dueñas Rey (UGent) , Quinten Mahieu (UGent) , Mattias Van Heetvelde (UGent) , Laila Jeddawi, Miriam Bauwens (UGent) and Elfride De Baere (UGent)
(2024) CLINICAL GENETICS. 106(2). p.127-139
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Abstract
Leber congenital amaurosis (LCA) and early-onset retinal degeneration (EORD) are inherited retinal diseases (IRD) characterized by early-onset vision impairment. Herein, we studied 15 Saudi families by whole exome sequencing (WES) and run-of-homozygosity (ROH) detection via AutoMap in 12/15 consanguineous families. This revealed (likely) pathogenic variants in 11/15 families (73%). A potential founder variant was found in RPGRIP1. Homozygous pathogenic variants were identified in known IRD genes (ATF6, CRB1, CABP4, RDH12, RIMS2, RPGRIP1, SPATA7). We established genotype-driven clinical reclassifications for ATF6, CABP4, and RIMS2. Specifically, we observed isolated IRD in the individual with the novel RIMS2 variant, and we found a retina-enriched RIMS2 isoform conserved but not annotated in mouse. The latter illustrates potential different phenotypic consequences of pathogenic variants depending on the particular tissue/cell-type specific isoforms they affect. Lastly, a compound heterozygous genotype in GUCY2D in one non-consanguineous family was demonstrated, and homozygous variants in novel candidate genes ATG2B and RUFY3 were found in the two remaining consanguineous families. Reporting these genes will allow to validate them in other IRD cohorts. Finally, the missing heritability of the two unsolved IRD cases may be attributed to variants in non-coding regions or structural variants that remained undetected, warranting future WGS studies.
Keywords
RIMS2, retina-enriched isoform, non-syndromic, exome sequencing, early-onset retinal disease, consanguinity, autozygome, CONGENITAL AMAUROSIS, MUTATIONS, DYSTROPHY, VARIANTS, CABP4, GENE, PATHOGENICITY, PIGMENTOSA, C21ORF2, PROTEIN

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Citation

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MLA
del Pozo Valero, Marta, et al. “Autozygome-Guided Exome-First Study in a Consanguineous Cohort with Early-Onset Retinal Disease Uncovers an Isolated RIMS2 Phenotype and a Retina-Enriched RIMS2 Isoform.” CLINICAL GENETICS, vol. 106, no. 2, 2024, pp. 127–39, doi:10.1111/cge.14517.
APA
del Pozo Valero, M., Almoallem Mohammed, B., Dueñas Rey, A., Mahieu, Q., Van Heetvelde, M., Jeddawi, L., … De Baere, E. (2024). Autozygome-guided exome-first study in a consanguineous cohort with early-onset retinal disease uncovers an isolated RIMS2 phenotype and a retina-enriched RIMS2 isoform. CLINICAL GENETICS, 106(2), 127–139. https://doi.org/10.1111/cge.14517
Chicago author-date
Pozo Valero, Marta del, Basamat Almoallem Mohammed, Alfredo Dueñas Rey, Quinten Mahieu, Mattias Van Heetvelde, Laila Jeddawi, Miriam Bauwens, and Elfride De Baere. 2024. “Autozygome-Guided Exome-First Study in a Consanguineous Cohort with Early-Onset Retinal Disease Uncovers an Isolated RIMS2 Phenotype and a Retina-Enriched RIMS2 Isoform.” CLINICAL GENETICS 106 (2): 127–39. https://doi.org/10.1111/cge.14517.
Chicago author-date (all authors)
del Pozo Valero, Marta, Basamat Almoallem Mohammed, Alfredo Dueñas Rey, Quinten Mahieu, Mattias Van Heetvelde, Laila Jeddawi, Miriam Bauwens, and Elfride De Baere. 2024. “Autozygome-Guided Exome-First Study in a Consanguineous Cohort with Early-Onset Retinal Disease Uncovers an Isolated RIMS2 Phenotype and a Retina-Enriched RIMS2 Isoform.” CLINICAL GENETICS 106 (2): 127–139. doi:10.1111/cge.14517.
Vancouver
1.
del Pozo Valero M, Almoallem Mohammed B, Dueñas Rey A, Mahieu Q, Van Heetvelde M, Jeddawi L, et al. Autozygome-guided exome-first study in a consanguineous cohort with early-onset retinal disease uncovers an isolated RIMS2 phenotype and a retina-enriched RIMS2 isoform. CLINICAL GENETICS. 2024;106(2):127–39.
IEEE
[1]
M. del Pozo Valero et al., “Autozygome-guided exome-first study in a consanguineous cohort with early-onset retinal disease uncovers an isolated RIMS2 phenotype and a retina-enriched RIMS2 isoform,” CLINICAL GENETICS, vol. 106, no. 2, pp. 127–139, 2024.
@article{01HTY9A9DB0ZCZ0YV7TQC8PPNK,
  abstract     = {{Leber congenital amaurosis (LCA) and early-onset retinal degeneration (EORD) are inherited retinal diseases (IRD) characterized by early-onset vision impairment. Herein, we studied 15 Saudi families by whole exome sequencing (WES) and run-of-homozygosity (ROH) detection via AutoMap in 12/15 consanguineous families. This revealed (likely) pathogenic variants in 11/15 families (73%). A potential founder variant was found in RPGRIP1. Homozygous pathogenic variants were identified in known IRD genes (ATF6, CRB1, CABP4, RDH12, RIMS2, RPGRIP1, SPATA7). We established genotype-driven clinical reclassifications for ATF6, CABP4, and RIMS2. Specifically, we observed isolated IRD in the individual with the novel RIMS2 variant, and we found a retina-enriched RIMS2 isoform conserved but not annotated in mouse. The latter illustrates potential different phenotypic consequences of pathogenic variants depending on the particular tissue/cell-type specific isoforms they affect. Lastly, a compound heterozygous genotype in GUCY2D in one non-consanguineous family was demonstrated, and homozygous variants in novel candidate genes ATG2B and RUFY3 were found in the two remaining consanguineous families. Reporting these genes will allow to validate them in other IRD cohorts. Finally, the missing heritability of the two unsolved IRD cases may be attributed to variants in non-coding regions or structural variants that remained undetected, warranting future WGS studies.}},
  author       = {{del Pozo Valero, Marta and Almoallem Mohammed, Basamat and Dueñas Rey, Alfredo and Mahieu, Quinten and Van Heetvelde, Mattias and  Jeddawi, Laila and Bauwens, Miriam and De Baere, Elfride}},
  issn         = {{0009-9163}},
  journal      = {{CLINICAL GENETICS}},
  keywords     = {{RIMS2,retina-enriched isoform,non-syndromic,exome sequencing,early-onset retinal disease,consanguinity,autozygome,CONGENITAL AMAUROSIS,MUTATIONS,DYSTROPHY,VARIANTS,CABP4,GENE,PATHOGENICITY,PIGMENTOSA,C21ORF2,PROTEIN}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{127--139}},
  title        = {{Autozygome-guided exome-first study in a consanguineous cohort with early-onset retinal disease uncovers an isolated RIMS2 phenotype and a retina-enriched RIMS2 isoform}},
  url          = {{http://doi.org/10.1111/cge.14517}},
  volume       = {{106}},
  year         = {{2024}},
}
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