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.
RIMS2
autozygome
consanguinity
early-onset retinal disease
exome sequencing
non-syndromic
retina-enriched isoform
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
11 Mar 2024
11 Mar 2024
Historique:
revised:
19
02
2024
received:
20
12
2023
accepted:
23
02
2024
medline:
12
3
2024
pubmed:
12
3
2024
entrez:
12
3
2024
Statut:
aheadofprint
Résumé
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.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ghent University Special Research Fund
ID : BOF20/GOA/023
Organisme : John W. Mouton Pro Retina Fund
Organisme : H2020 MSCA ITN
ID : 813490 StarT
Organisme : EJPRD19-234 Solve-RET
Organisme : College of Medicine Research Center, Deanship of Scientific Research, King Saud University
Organisme : Fundación Alfonso Martin Escudero
Organisme : StarT
ID : 813490
Organisme : Research Foundation-Flanders
ID : 1802220N
Informations de copyright
© 2024 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.
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