Next-generation sequencing identifies a novel frameshift variant in FRMD7 in a Chinese family with idiopathic infantile nystagmus

Abstract

Background: Idiopathic infantile nystagmus (IIN) is a high genetically heterogeneous ophthalmic disease and is often associated with pathogenic mutations in FRMD7 and GPR143, respectively. Idiopathic infantile nystagmus manifests as involuntary periodic rhythmic oscillation of the eyes in the very early life, which decreases visual acuity and affects the quality of life.

Objective and methods: The aim of our study was to reveal a possible pathogenic variant through the investigation of a Chinese Han family with IIN with an implementation of a next-generation sequencing method. Isolated DNA analysis was followed by Sanger sequencing validation. We also performed the detailed ophthalmological examination of family members.

Results: We identified a novel frameshift variant in FRMD7 (NM_194277.2: c.1419_1422dup, p.Tyr475fs), which leads to a frameshift mutation since tyrosine (Tyr) at 475 codon of FRMD7 protein (p.Tyr475fs) and co-segregates with IIN phenotype in this family.

Conclusions: We found a novel frameshift FRMD7 variant in a Chinese Han family, which may be causative variant for IIN and can further enrich the mutation spectrum and uncover the etiology of IIN.

Keywords: FRMD7; Next-generation sequencing; idiopathic infantile nystagmus; variant.

Figure 1

Pedigree chart of the family with Idiopathic infantile nystagmus. Circles and squares represent females and males, respectively. Black symbols indicate patients. The arrow represents the proband

Figure 2

Flow chart of data analysis

Figure 3

Sanger sequencing chromatograms. The male patient (A) had the novel variant, (NM_194277.2: c.1419_1422dup, p.Tyr475fs). The two rectangles indicate the location leading to frameshift variant of FRMD7. His daughter (B) (a carrier) is shown on the below

Figure 4

Multiple sequence alignments. Multiple sequence alignments of the FRMD7 protein including Mus musculus, Alligator mississippiensis, Bos taurus, Cebus capucinus imitator, Neotoma lepida, and Capra hircus. The p.Tyr475fs variant is located within a highly conserved region which shown in the rectangle

Figure 5

Prediction map of protein damage. The frameshift mutation resulted in translation errors from p.475Tyr and terminated at p.478, resulting in a truncated protein of 477‐amino acid