Precision Medicine through Next-Generation Sequencing in Inherited Eye Diseases in a Korean Cohort

Abstract

In this study, we investigated medically or surgically actionable genes in inherited eye disease, based on clinical phenotype and genomic data. This retrospective consecutive case series included 149 patients with inherited eye diseases, seen by a single pediatric ophthalmologist, who underwent genetic testing between 1 March 2017 and 28 February 2018. Variants were detected using a target enrichment panel of 429 genes and known deep intronic variants associated with inherited eye disease. Among 149 patients, 38 (25.5%) had a family history, and this cohort includes heterogeneous phenotype including anterior segment dysgenesis, congenital cataract, infantile nystagmus syndrome, optic atrophy, and retinal dystrophy. Overall, 90 patients (60.4%) received a definite molecular diagnosis. Overall, NGS-guided precision care was provided to 8 patients (5.4%). The precision care included cryotherapy to prevent retinal detachment in COL2A1 Stickler syndrome, osteoporosis management in patients with LRP5-associated familial exudative vitreoretinopathy, and avoidance of unnecessary phlebotomy in hyperferritinemia-cataract syndrome. A revision of the initial clinical diagnosis was made in 22 patients (14.8%). Unexpected multi-gene deletions and dual diagnosis were noted in 4 patients (2.7%). We found that precision medical or surgical managements were provided for 8 of 149 patients (5.4%), and multiple locus variants were found in 2.7% of cases. These findings are important because individualized management of inherited eye diseases can be achieved through genetic testing.

Genetic spectrum and characteristics of autosomal optic neuropathy in Korean: Use of next-generation sequencing in suspected hereditary optic atrophy

“…The clinical information of SOPH syndrome and PTPN23 optic atrophy were described in our previous study (19,20). P8, P9, and P10 were reported in our previous study (1,21).…”

“…The molecular diagnostic yield for hereditary optic atrophy is relatively low compared to that for other hereditary eye diseases such as inherited retinal dystrophy or infantile nystagmus syndrome (diagnostic rate: 75–90%) ( 1 , 9 ). Previous studies reported various diagnostic rates for hereditary optic atrophy ranging from 20.2–40% ( 12 – 14 ).…”

“…Inherited optic atrophy is the major underlying etiology of inherited visual impairment ( 1 ). This condition is the end result of injury to either the retinal ganglion cells, retinal nerve fiber layer, optic nerve, optic chiasm, or optic tract, and it is caused by various factors such as hereditary, metabolic, radiation-induced, malnutrition-induced, toxic, ischemic, inflammatory, or infiltrative lesions.…”

Effectiveness of whole-exome sequencing for the identification of causal mutations in patients with suspected inherited ocular diseases

“…Many patients with genetic diseases may receive an incorrect diagnosis 35,36 or live many years without a specific diagnosis 37 . Not having an accurate diagnosis has a negative impact on the quality of life of patients with genetic diseases, who may undergo numerous unnecessary examinations that are displeasing and costly 38 . In our study, 10 patients had a change in diagnosis based on their genetic findings, which was of great importance since their clinical management was improved.…”

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

“… 5 – 8 A prompt genetic diagnosis enables clinicians to provide visual prognosis and genetic counselling for future family planning. 9 Moreover, the identification of pathogenic variants in infantile nystagmus syndrome could prevent further unnecessary investigations such as electrodiagnostic testing and brain imaging in affected children. 5 , 6 , 10 In FIN, causative variants were detected in approximately 83% to 94% of familial cases.…”