FRMD7関連乳児眼振の遺伝的特徴と臨床的特徴：大規模社内データセットおよび文献レビューに基づく

Variants in the FERM domain containing protein 7 gene (FRMD7) constitute one of the most common etiologies underlying idiopathic infantile nystagmus (IIN). This study aimed to clarify the pathogenicity of FRMD7 variants and their associated clinical features based on in-house databases and a literature review.

Families with various genetic eye diseases were collected, and exome sequencing was performed. A comparative bioinformatics analysis, utilizing a total of 38 prediction tools, and comparative analysis with the Genome Aggregation Database (gnomAD) were conducted on all FRMD7 variants detected in our databases and published variants. Pathogenic or likely pathogenic (P/LP) variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines, following confirmation by Sanger sequencing. Detailed clinical data were summarized, including visual acuity (VA), anterior segment photography, fundus photography, and optical coherence tomography.

In our database, a total of 56 P/LP variants (24 truncation, 31 missense, and one indel) were identified in 75 families, including 33 novels. The pathogenicity of the truncation variants in FRMD7 was well established. P/LP missense variants with high predictive scores were predominantly and evenly distributed in all exons regions excluding exon 12. Five in silico tools (REVEL, BayesDel_addAF, VEST4, BayesDel_noAF, and MetaRNN) exhibited gene-specific sensitivity (>90%) and specificity (>85%) in determining pathogenicity for FRMD7 missense variants. The penetrance in males was 100% (77/77) and in females 39.3% (22/56). The VA was available for 63 patients, ranging from -0.10 to 0.82 logMAR (Snellen 1.25-0.15), of whom 58 (92.1%) had VA of better than 0.52 logMAR (Snellen 0.30). The VA of patients with heterozygous variants was significantly better than that of hemizygotes (P = 8.78e-3). Follow-up surveys were available in 31 patients, 11 of whom had an amelioration of nystagmus with age.

This study summarized the pathogenic characteristics of FRMD7 variants and identified FRMD7-specific optimal assessment tools for missense variants. Patients with FRMD7-related infantile nystagmus (FIN) show preserved vision (92.1% above the criteria for low vision). These findings provide a valuable reference for clinical diagnosis and genetic counseling of FIN.