Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes

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dc.contributor.authorHitti-Malin, Rebekkah J.
dc.contributor.authorPanneman, Daan M.
dc.contributor.authorCorradi, Zelia
dc.contributor.authorBoonen, Erica G.M.
dc.contributor.authorAstuti, Galuh
dc.contributor.authorDhaenens, Claire Marie
dc.contributor.authorStöhr, Heidi
dc.contributor.authorWeber, Bernhard H.F.
dc.contributor.authorSharon, Dror
dc.contributor.authorBanin, Eyal
dc.contributor.authorKarali, Marianthi
dc.contributor.authorBanfi, Sandro
dc.contributor.authorBen-Yosef, Tamar
dc.contributor.authorGlavač, Damjan
dc.contributor.authorFarrar, G. Jane
dc.contributor.authorAyuso, Carmen
dc.contributor.authorLiskova, Petra
dc.contributor.authorDudakova, Lubica
dc.contributor.authorVajter, Marie
dc.contributor.authorOłdak, Monika
dc.contributor.authorSzaflik, Jacek P.
dc.contributor.authorMatynia, Anna
dc.contributor.authorGorin, Michael B.
dc.contributor.authorKämpjärvi, Kati
dc.contributor.authorBauwens, Miriam
dc.contributor.authorDe Baere, Elfride
dc.contributor.authorHoyng, Carel B.
dc.contributor.authorLi, Catherina H.Z.
dc.contributor.authorKlaver, Caroline C.W.
dc.contributor.authorInglehearn, Chris F.
dc.contributor.authorFujinami, Kaoru
dc.contributor.authorRivolta, Carlo
dc.contributor.authorAllikmets, Rando
dc.contributor.authorZernant, Jana
dc.contributor.authorLee, Winston
dc.contributor.authorPodhajcer, Osvaldo L.
dc.contributor.authorFakin, Ana
dc.contributor.authorSajovic, Jana
dc.contributor.authorAlTalbishi, Alaa
dc.contributor.authorValeiņa, Sandra
dc.contributor.authorTaurina, Gita
dc.contributor.authorVincent, Andrea L.
dc.contributor.authorRoberts, Lisa
dc.contributor.authorRamesar, Raj
dc.contributor.authorSartor, Giovanna
dc.contributor.authorLuppi, Elena
dc.contributor.authorDownes, Susan M.
dc.contributor.authorvan den Born, L. Ingeborgh
dc.contributor.authorMcLaren, Terri L.
dc.contributor.authorDe Roach, John N.
dc.contributor.authorLamey, Tina M.
dc.contributor.authorThompson, Jennifer A.
dc.contributor.authorChen, Fred K.
dc.contributor.authorTracewska, Anna M.
dc.contributor.authorKamakari, Smaragda
dc.contributor.authorSallum, Juliana Maria Ferraz
dc.contributor.authorBolz, Hanno J.
dc.contributor.authorKayserili, Hülya
dc.contributor.authorRoosing, Susanne
dc.contributor.authorCremers, Frans P.M.
dc.contributor.institutionDepartment of Ophthalmology
dc.date.accessioned2025-02-25T11:50:01Z
dc.date.available2025-02-25T11:50:01Z
dc.date.issued2024-03
dc.descriptionPublisher Copyright: © 2024 by the authors.
dc.description.abstractInherited 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.en
dc.description.statusPeer reviewed
dc.format.extent1271176
dc.identifier.citationHitti-Malin, R J, Panneman, D M, Corradi, Z, Boonen, E G M, Astuti, G, Dhaenens, C M, Stöhr, H, Weber, B H F, Sharon, D, Banin, E, Karali, M, Banfi, S, Ben-Yosef, T, Glavač, D, Farrar, G J, Ayuso, C, Liskova, P, Dudakova, L, Vajter, M, Ołdak, M, Szaflik, J P, Matynia, A, Gorin, M B, Kämpjärvi, K, Bauwens, M, De Baere, E, Hoyng, C B, Li, C H Z, Klaver, C C W, Inglehearn, C F, Fujinami, K, Rivolta, C, Allikmets, R, Zernant, J, Lee, W, Podhajcer, O L, Fakin, A, Sajovic, J, AlTalbishi, A, Valeiņa, S, Taurina, G, Vincent, A L, Roberts, L, Ramesar, R, Sartor, G, Luppi, E, Downes, S M, van den Born, L I, McLaren, T L, De Roach, J N, Lamey, T M, Thompson, J A, Chen, F K, Tracewska, A M, Kamakari, S, Sallum, J M F, Bolz, H J, Kayserili, H, Roosing, S & Cremers, F P M 2024, 'Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes', Biomolecules, vol. 14, no. 3, 367. https://doi.org/10.3390/biom14030367
dc.identifier.doi10.3390/biom14030367
dc.identifier.issn2218-273X
dc.identifier.urihttps://dspace.rsu.lv/jspui/handle/123456789/17137
dc.identifier.urlhttp://www.scopus.com/inward/record.url?scp=85188807245&partnerID=8YFLogxK
dc.language.isoeng
dc.relation.ispartofBiomolecules
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectinherited
dc.subjectmacula
dc.subjectmaculopathies
dc.subjectpenetrance
dc.subjectretinal
dc.subjectsequencing
dc.subject3.4 Medical biotechnology
dc.subject1.6 Biological sciences
dc.subject3.1 Basic medicine
dc.subject1.1. Scientific article indexed in Web of Science and/or Scopus database
dc.subjectBiochemistry
dc.subjectMolecular Biology
dc.titleTowards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genesen
dc.type/dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article

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