Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing-a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.

• Klíčová slova
• inherited, macula, maculopathies, penetrance, retinal, sequencing,
• MeSH
• ABC transportéry genetika   MeSH
• fenotyp MeSH
• kadherinové proteiny MeSH
• lidé MeSH
• makulární degenerace * genetika   MeSH
• mutace MeSH
• oční proteiny MeSH
• penetrance MeSH
• proteiny nervové tkáně genetika   MeSH
• retina MeSH
• rodokmen MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportéry MeSH
• ABCA4 protein, human MeSH Prohlížeč
• CDHR1 protein, human MeSH Prohlížeč
• kadherinové proteiny MeSH
• oční proteiny MeSH
• proteiny nervové tkáně MeSH
• RP1L1 protein, human MeSH Prohlížeč