Multimodal Imaging of a novel MFSD8/CLN7 mutation associated with non-syndromic symmetric adult-onset macular dystrophy.

PURPOSE: To report multimodal imaging features of a novel MFSD8/CLN7 pathogenic variant associated with bilateral and symmetric non-syndromic macular dystrophy. METHODS: A 63-year-old female patient presented complaining of a gradual subjective decline in visual acuity in both eyes over the previous months. This patient underwent a comprehensive ophthalmological assessment, including multimodal retinal imaging and electrophysiological testing. Given suspicion for a hereditary retinal disorder, genetic testing was pursued. RESULTS: The eye examination revealed blunted foveal reflexes and no lesions or abnormalities in the equatorial or anterior retinal periphery. Multimodal imaging showed a bilateral and almost symmetrical subfoveal interruption of the outer retinal layers including an optical gap. Genetic testing revealed that the MFSD8/CLN7 gene exhibited a homozygous variant, specifically p.Ala484Val (c.1451C>T). This variant was identified as the likely causative factor for the condition. CONCLUSION: We herein describe the clinical findings of a previously unreported homozygous variant in the MFSD8/CLN7 gene, resulting in a non-syndromic form of bilateral central macular dystrophy.

DNA methylation analysis in patients with neurodevelopmental disorders improves variant interpretation and reveals complexity.

Analysis of genomic DNA methylation by generating epigenetic signature profiles (episignatures) is increasingly being implemented in genetic diagnosis. Here we report our experience using episignature analysis to resolve both uncomplicated and complex cases of neurodevelopmental disorders (NDDs). We analyzed 97 NDDs divided into (1) a validation cohort of 59 patients with likely pathogenic/pathogenic variants characterized by a known episignature and (2) a test cohort of 38 patients harboring variants of unknown significance or unidentified variants. The expected episignature was obtained in most cases with likely pathogenic/pathogenic variants (53/59 [90%]), a revealing exception being the overlapping profile of two SMARCB1 pathogenic variants with ARID1A/B:c.6200, confirmed by the overlapping clinical features. In the test cohort, five cases showed the expected episignature, including (1) novel pathogenic variants in ARID1B and BRWD3; (2) a deletion in ATRX causing MRXFH1 X-linked mental retardation; and (3) confirmed the clinical diagnosis of Cornelia de Lange (CdL) syndrome in mutation-negative CdL patients. Episignatures analysis of the in BAF complex components revealed novel functional protein interactions and common episignatures affecting homologous residues in highly conserved paralogous proteins (SMARCA2 M856V and SMARCA4 M866V). Finally, we also found sex-dependent episignatures in X-linked disorders. Implementation of episignature profiling is still in its early days, but with increasing utilization comes increasing awareness of the capacity of this methodology to help resolve the complex challenges of genetic diagnoses.