Case Report: A novel intronic FRMD7 variant associated with X-linked infantile nystagmus: functional validation by a minigene splicing assay

The X-linked ocular motor disorder known as FRMD7 associated infantile nystagmus syndrome: X-linked congenital nystagmus type 1 (NYS1; OMIM 310700) is typified by involuntary conjugate ocular oscillations starting in early infancy, typically without significant structural ocular abnormalities. Several infantile nystagmus waveforms are linked to pathogenic FRMD7 variants, which impair ocular motor development. A subset of affected individuals has been reported to exhibit periodic alternating nystagmus. In our clinical practice, we identified a male infant with nystagmus and conducted comprehensive testing on him and his parents. The proband exhibited persistent nystagmus at 1 months old and gradually worsened. Whole-exome sequencing revealed a novel intronic variant, c.206-9T>G in the FRMD7 gene (NM_194277.3) inherited from his unaffected mother. Pathogenicity analysis via minigene splicing assays demonstrated that the c.206-9T>G variant caused exon 4 (79 bp) skipping at the mRNA level. Based on the patient’s clinical features and functional validation of the genetic variant, the infant was diagnosed as X-linked congenital nystagmus type 1 (OMIM: 310700). The intronic variant c.206-9T>G happened in FRMD7 gene was verified pathogenic by minigene assay, and the study further broadened the mutational spectrum of FRMD7 and providing a molecular basis for genetic counseling for NYS1.