The aim of this study was to investigate the genetic characteristics of the mutation site of four-point-one ezrin-radixin-moesin domain-containing 7 (FRMD7) gene in a family with congenital nystagmus (CN).

Clinical data of 19 cases in four-generation of a Chinese family with a diagnosised CN in the Department of Ophthalmology and Clinical Centre of Optometry, Peking University People′s Hospital in October 2021 were collected. The leukocytes of the peripheral blood was extracted from 3 cases with CN and 9 cases with normal eyes. The best corrected visual acuity (BCVA) of patients, anterior segment and fundus were performed; the type of CN, head position, whether there is median and eye position were evaluated. Targeted gene was captrued using liquid chromatography and exon region and its flanking region containing 811 candidate genes related to ophthalmic disorders was captured. The high throughput sequencing technology was performed for the proband, then the pathogenic genes and mutation sites were selected and Sanger sequencing was performed for the other family members to verify the candidate disease-causing mutation. The gene mutation type of mutation sites was analyzed by MutationTaster software; 3D structure and function of mutated protein was evaluated.

The proband (Ⅲ6) was a 11-year old male, whose BCVA of right eye and left eye were 0.7 and 0.8, respectively. Proband′s cousin (Ⅲ9) was a 2-year old male, whose BCVA examination was failed. The proband′s grandfather (Ⅰ1) was a 73-year old male, whose BCVA of right eye and left eye were 0.3 and 0.4, respectively and his bilateral lens were opacite. Three patients had a pendular oscillation in both eyes, and normal ocular alignment, no abnormal head posture; the anterior segment and fundus of patients were normal. 3 patients in this family with CN were male, showing intergenerational genetic characteristics, which was consistent with X-linked recessive inheritance. Sequencing analysis identified a hemizygote mutation (c.822C>A) in exon9 of FRMD7 gene in this Chinese family with CN. Three females (Ⅱ6, Ⅱ8, Ⅲ8) had a heterozygous mutation in this region. This mutation resulted in a amino acid mutation (p.Y274X) due to a single nucleotide substitution of C→A at position c. 822. It caused the earlier appearance of the termination codon stopping proteins encoding, which causing numerous missing of amino acids. According to the standard and guide of genomics classification of genetic mutation of American Society for Medical Genetics, it has been estimated that this mutation was likely pathogenic. The mutagenesis nature was a nonsense mutation through MutationTaster software. The analysis of 3D structure and function of mutated protein was shown that there was a unstable protein structure, which probably causing the damaged function.

The mutation c. 822C>A (p.Y274X) of FRMD7 was a nonsense mutation, which was a novel site. This mutation had a capability of causing CN, and broaden the muation spectrum of FRMD7.