Clinical utility gene card for FRMD7-related infantile nystagmus

Dawar, Basu; Kuht, Helen J; Han, Jinu; Maconachie, Gail; Thomas, Mervyn G

doi:10.1038/s41431-021-00826-9

Cited by 5 publications

(2 citation statements)

References 25 publications

(34 reference statements)

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“… 5 , 6 , 10 In FIN, causative variants were detected in approximately 83% to 94% of familial cases. 11 , 12 To date, copy number variations and large structural variants were only identified in four families including exon 2 to 4 deletion, exon 2 to 12 deletion, and a large deletion including the entire FRMD7 . 5 , 13 – 15 In addition, a deep intronic variant (c.285-118C>T) was reported, but to date, no functional assay has been conducted.…”

Section: Introductionmentioning

confidence: 99%

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

Lee

Jeong

Won

et al. 2022

Trans. Vis. Sci. Tech.

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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.

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Section: Introductionmentioning

confidence: 99%

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

Lee

Jeong

Won

et al. 2022

Trans. Vis. Sci. Tech.

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“…The prevalence of infantile nystagmus syndrome was estimated from 1 in 3000 to 1 in 1000 [3,4]. Infantile nystagmus can be idiopathic or associated with other ocular diseases, such as retinal disease, albinism, low vision, or loss of vision [5][6][7][8][9][10][11][12]. It can also occur as a common presenting sign of many neurologic and systemic diseases.…”

Section: Introductionmentioning

confidence: 99%

TUBB3 M323V Syndrome Presents with Infantile Nystagmus

Jin

Park

Won

et al. 2021

Genes

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Variants in the TUBB3 gene, one of the tubulin-encoding genes, are known to cause congenital fibrosis of the extraocular muscles type 3 and/or malformations of cortical development. Herein, we report a case of a 6-month-old infant with c.967A>G:p.(M323V) variant in the TUBB3 gene, who had only infantile nystagmus without other ophthalmological abnormalities. Subsequent brain magnetic resonance imaging (MRI) revealed cortical dysplasia. Neurological examinations did not reveal gross or fine motor functions, which are inconsistent with the clinical characteristics of patients with the M323V syndrome reported so far. A protein modeling showed that the M323V mutation in the TUBB3 gene interferes with αβ heterodimer formation with the TUBA1A gene. This report emphasizes the importance of considering TUBB3 and TUBA1A tubulinopathy in infantile nystagmus. A brain MRI should also be considered for these patients, although in the absence of other neurologic signs or symptoms.

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Best-corrected visual acuity results facilitate molecular diagnosis of infantile nystagmus patients harboring FRMD7 mutations

Chen

et al. 2023

Experimental Eye Research

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Clinical utility gene card for FRMD7-related infantile nystagmus

Cited by 5 publications

References 25 publications

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

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

TUBB3 M323V Syndrome Presents with Infantile Nystagmus

Best-corrected visual acuity results facilitate molecular diagnosis of infantile nystagmus patients harboring FRMD7 mutations

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