Development and clinical utility of a novel diagnostic nystagmus gene panel using targeted next-generation sequencing

Abstract

Infantile nystagmus (IN) is a genetically heterogeneous disorder arising from variants of genes expressed within the developing retina and brain. IN presents a diagnostic challenge and patients often undergo numerous investigations. We aimed to develop and assess the utility of a next-generation sequencing (NGS) panel to enhance the diagnosis of IN. We identified 336 genes associated with IN from the literature and OMIM. NimbleGen Human custom array was used to enrich the target genes and sequencing was performed using HiSeq2000. Using reference genome material (NA12878), we show the sensitivity (98.5%) and specificity (99.9%) of the panel. Fifteen patients with familial IN were sequenced using the panel. Two authors were masked to the clinical diagnosis. We identified variants in 12/15 patients in the following genes: FRMD7 (n=3), CACNA1F (n=2), TYR (n=5), CRYBA1 (n=1) and TYRP1 (n=1). In 9/12 patients, the clinical diagnosis was consistent with the genetic diagnosis. In 3/12 patients, the results from the genetic diagnoses (TYR, CRYBA1 and TYRP1 variants) enabled revision of clinical diagnoses. In 3/15 patients, we were unable to determine a genetic diagnosis. In one patient, copy number variation analysis revealed a FRMD7 deletion. This is the first study establishing the clinical utility of a diagnostic NGS panel for IN. We show that the panel has high sensitivity and specificity. The genetic information from the panel will lead to personalised diagnosis and management of IN and enable accurate genetic counselling. This will allow development of a new clinical care pathway for IN.

Molecular characterization of a series of 990 index patients with albinism

“…For this reason, we recently included in our panel the X‐linked nystagmus gene FRMD7 (data not shown) and identified a pathogenic FRMD7 variant in one male patient with iris transillumination, retinal hypopigmentation, and congenital nystagmus (data not shown). Other patients may have some other disorder with nystagmus and/or various degrees of foveal hypoplasia, photophobia, fundus hypopigmentation, and visual impairment such as Aland Island eye disease ( CACNA1F gene; Jalkanen et al., ; Wutz et al., ) and atypical PAX6 ‐related phenotypes (Hood, Kerr, Smaoui, & Iannaccone, ; Thomas, Maconachie, Sheth, McLean, & Gottlob, ). Atypical presentations of the various forms of congenital stationary night blindness may also present a clinical overlap with ocular forms of albinism.…”

Genotype and Phenotype Spectrum ofFRMD7-Associated Infantile Nystagmus Syndrome

“…To date, over 70 different mutations within FRMD7 have been reported. 5,7,[9][10][11]18,19,[24][25][26][27] Many mutations cluster around the F3 lobes of the FERM and FA domains. This suggests that these domains have important roles in the function of FRMD7.…”

Identification of a novel idiopathic congenital nystagmus‑causing missense mutation, p.G296C, in the FRMD7 gene

“…The early diagnosis of congenital nystagmus is critical for facilitating habilitation, providing genetic counseling, and potential gene therapies in the future ( 30 ). The diagnosis of idiopathic congenital nystagmus remains being a challenge and potential patients are usually required to undergo numerous examinations ( 31 ). Nystagmus is currently clinically described in terms of its peak-to peak amplitude, frequency, mean velocity and waveform ( 32 ).…”

“…Recently, a next-generation sequencing panel has been used for the early diagnosis of idiopathic congenital nystagmus ( 31 ). Comprehensive understanding of the mutation spectrum is the foundation for efficient early genetic diagnosis.…”