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Noncanonical Splice Site and Deep Intronic FRMD7 Variants Activate Cryptic Exons in X-linked Infantile Nystagmus

Authors
 Junwon Lee  ;  Han Jeong  ;  Dongju Won  ;  Saeam Shin  ;  Seung-Tae Lee  ;  Jong Rak Choi  ;  Suk Ho Byeon  ;  Helen J Kuht  ;  Mervyn G Thomas  ;  Jinu Han 
Citation
 TRANSLATIONAL VISION SCIENCE & TECHNOLOGY, Vol.11(6) : 25, 2022-06 
Journal Title
TRANSLATIONAL VISION SCIENCE & TECHNOLOGY
Issue Date
2022-06
MeSH
Cytoskeletal Proteins* / genetics ; Exons ; Genetic Diseases, X-Linked* ; Humans ; Introns ; Membrane Proteins* / genetics ; Mutation ; Nystagmus, Congenital* / genetics ; RNA Splicing / genetics
Abstract
Purpose: We aim to report noncoding pathogenic variants in patients with FRMD7-related infantile nystagmus (FIN).

Methods: Genome sequencing (n = 2 families) and reanalysis of targeted panel next generation sequencing (n = 2 families) was performed in genetically unsolved cases of suspected FIN. Previous sequence analysis showed no pathogenic coding variants in genes associated with infantile nystagmus. SpliceAI, SpliceRover, and Alamut consensus programs were used to annotate noncoding variants. Minigene splicing assay was performed to confirm aberrant splicing. In silico analysis of exonic splicing enhancer and silencer was also performed.

Results: FRMD7 intronic variants were identified based on genome sequencing and targeted next-generation sequencing analysis. These included c.285-12A>G (pedigree 1), c.284+63T>A (pedigrees 2 and 3), and c. 383-1368A>G (pedigree 4). All variants were absent in gnomAD, and the both c.285-12A>G and c.284+63T>A variants were predicted to enhance new splicing acceptor gains with SpliceAI, SpliceRover, and Alamut consensus approaches. However, the c.383-1368 A>G variant only had a significant impact score on the SpliceRover program. The c.383-1368A>G variant was predicted to promote pseudoexon inclusion by binding of exonic splicing enhancer. Aberrant exonizations were validated through minigene constructs, and all variants were segregated in the families.

Conclusions: Deep learning-based annotation of noncoding variants facilitates the discovery of hidden genetic variations in patients with FIN. This study provides evidence of effectiveness of combined deep learning-based splicing tools to identify hidden pathogenic variants in previously unsolved patients with infantile nystagmus.

Translational relevance: These results demonstrate robust analysis using two deep learning splicing predictions and in vitro functional study can lead to finding hidden genetic variations in unsolved patients.
Files in This Item:
T202202582.pdf Download
DOI
10.1167/tvst.11.6.25
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
Yonsei Authors
Byeon, Suk Ho(변석호) ORCID logo https://orcid.org/0000-0001-8101-0830
Shin, Saeam(신새암) ORCID logo https://orcid.org/0000-0003-1501-3923
Won, Dongju(원동주) ORCID logo https://orcid.org/0000-0002-0084-0216
Lee, Seung-Tae(이승태) ORCID logo https://orcid.org/0000-0003-1047-1415
Lee, Jun Won(이준원) ORCID logo https://orcid.org/0000-0003-0543-7132
Choi, Jong Rak(최종락) ORCID logo https://orcid.org/0000-0002-0608-2989
Han, Jinu(한진우) ORCID logo https://orcid.org/0000-0002-8607-6625
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/189456
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