@article{f9869b3eb4f846fd9c0d3b3be8eee021,
title = "Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes",
abstract = "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.",
keywords = "inherited, macula, maculopathies, penetrance, retinal, sequencing",
author = "Hitti-Malin, {Rebekkah J.} and Panneman, {Daan M.} and Zelia Corradi and Boonen, {Erica G.M.} and Galuh Astuti and Dhaenens, {Claire Marie} and Heidi St{\"o}hr and Weber, {Bernhard H.F.} and Dror Sharon and Eyal Banin and Marianthi Karali and Sandro Banfi and Tamar Ben-Yosef and Damjan Glava{\v c} and Farrar, {G. Jane} and Carmen Ayuso and Petra Liskova and Lubica Dudakova and Marie Vajter and Monika O{\l}dak and Szaflik, {Jacek P.} and Anna Matynia and Gorin, {Michael B.} and Kati K{\"a}mpj{\"a}rvi and Miriam Bauwens and {De Baere}, Elfride and Hoyng, {Carel B.} and Li, {Catherina H.Z.} and Klaver, {Caroline C.W.} and Inglehearn, {Chris F.} and Kaoru Fujinami and Carlo Rivolta and Rando Allikmets and Jana Zernant and Winston Lee and Podhajcer, {Osvaldo L.} and Ana Fakin and Jana Sajovic and Alaa AlTalbishi and Sandra Valeina and Gita Taurina and Vincent, {Andrea L.} and Lisa Roberts and Raj Ramesar and Giovanna Sartor and Elena Luppi and Downes, {Susan M.} and {van den Born}, {L. Ingeborgh} and McLaren, {Terri L.} and {De Roach}, {John N.} and Lamey, {Tina M.} and Thompson, {Jennifer A.} and Chen, {Fred K.} and Tracewska, {Anna M.} and Smaragda Kamakari and Sallum, {Juliana Maria Ferraz} and Bolz, {Hanno J.} and H{\"u}lya Kayserili and Susanne Roosing and Cremers, {Frans P.M.}",
note = "Funding Information: This research was funded by the HRCI HRB Joint Funding Scheme 2020-007, Stichting Oogfonds Nederland (UZ 2020-17), Pro Retina Deutschland, Stichting tot Verbetering van het Lot der Blinden, Stichting voor Ooglijders and Stichting Blindenhulp (R.J.H.M, S.R, F.P.M.C). The following funding resources also, in part, supported this work: GA UK n.321522 (to P.L. and M.V.) and AZV NU20-07-00182 research grant from the Ministry of Health of the Czech Republic (to P.L. and L.D.); Retina Australia (J.N.D., J.A.T., T.L.M., T.M.L.), Australian National Health and Medical Research Council (MRF1142962, F.K.C.); WA Health (F.K.C.); Retina South Africa and the South African Medical Research Council (MRC) and Velux Stiftung (L.R., R.R.); the National Science Center (Poland) grant number N N402 591640 (5916/B/P01/2011/40) (M.O.); RP Fighting Blindness and Fight for Sight UK (RP Genome Project GR586) (C.F.I.); NIH/NEI grants R01EY028203, R01EY028954, R01EY029315, P30EY019007, Foundation Fighting Blindness award PPA-1218-0751-COLU, and the Unrestricted funds from the Research to Prevent Blindness (RPB) to the Department of Ophthalmology, Columbia University, New York, NY, USA. (R.A., W.L. and J.Z.). Publisher Copyright: {\textcopyright} 2024 by the authors.",
year = "2024",
month = mar,
day = "19",
doi = "10.3390/biom14030367",
language = "English",
volume = "14",
journal = "Biomolecules",
issn = "2218-273X",
publisher = "MDPI Multidisciplinary Digital Publishing Institute",
number = "3",
}